Brain Research Reviews 25 Ž1997.

312–334

Full-length review

Burst firing in midbrain dopaminergic neurons
P.G. Overton ) , D. Clark
Neuropsychopharmacology Laboratory, Department of Psychology, UniÕersity of Wales, Singleton Park, Swansea SA2 8PP, UK Accepted 9 September 1997

Abstract Midbrain dopaminergic ŽDA. neurons fire bursts of activity in response to sensory stimuli, including those associated with primary reward. They are therefore conditional bursters – the bursts conveying, amongst other things, motivationally relevant information to the forebrain. In the forebrain, bursts give rise to a supra-additive release of dopamine, and possibly favour the release of co-localised neuropeptides. Evidence is presented that in rat DA neurons, bursts are engendered by the activity of cortically-regulated afferents. Certain factors are identified which, in combination, lead to burst production: Ž1. A burst of activity in EAAergic afferents to DA neurons arising from non-cortical sources, but controlled by the medial prefrontal cortex; Ž2. N-methyl-D-aspartate receptor activation, producing a slow depolarising wave in the recipient neuron; Ž3. activation of a high threshold, dendritically located calcium conductance which produces a ‘plateau potential’; Ž4. activation of a calcium-activated potassium conductance, which terminates the burst. These factors are argued to operate in the context of an ‘optimal’ level of intracellular calcium buffering for bursting. Other factors which appear to be involved in bursting in other systems, in particular a low threshold calcium conductance, are rejected as being necessary for bursting in DA neurons. The factors which do play a crucial role in burst production in DA neurons are integrated into a theory from which arises a series of hypotheses amenable to empirical investigation. Additional factors are discussed which may modulate bursting. These may either act indirectly through changes in membrane potential Žor intracellular calcium concentration., or they may act directly through an interaction with certain conductances, which appear to promote or inhibit burst firing in DA neurons. q 1997 Elsevier Science B.V.
Keywords: Ventral tegmental area; Substantia nigra pars compacta; Plateau potential; Slow EPSP; Calcium activated potassium conductance; Rat

Contents 1. Natural burst firing in midbrain dopaminergic neurons 2. Functional aspects of burst firing . 3. Afferent control of burst firing

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4. The mechanism of burst firing . . . . . . . . . . . 4.1. Distal influences . . . . . . . . . . . . . . . . 4.2. Proximal influences . . . . . . . . . . . . . . 4.2.1 Synaptic factors . . . . . . . . . . . . . 4.2.2 Intrinsic membrane properties . . . . . 4.2.3 Role of intracellular calcium buffering .

5. A theory of natural burst firing in dopaminergic neurons 6. Endogenous modulatory influences on bursting 6.1. Indirect modulatory influences . . . . . . 6.2. Direct modulatory influences . . . . . . .

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Corresponding author. Fax: q44 Ž1792. 295679; E-mail: p.overton@swansea.ac.uk

P.G. OÕerton, D. Clark r Brain Research ReÕiews 25 (1997) 312–334 7. Conclusions .

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Acknowledgements . References

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1. Natural neurons

1

burst firing in midbrain dopaminergic

The review will be mainly concerned with dopaminergic ŽDA. neurons belonging to the cell groups A9 and A10. Cell group A9 is located mainly in the substantia nigra pars compacta ŽSNPc., whilst cell group A10 is located mainly in the ventral tegmental area ŽVTA, which includes the paranigral nucleus and parabrachial pigmented nucleus, according to Paxinos and Watson w132x.. The third group of midbrain DA neurons, A8, located in the retrorubral field, will receive little attention, primarily because far less is known about the electrophysiological characteristics of these cells. Again, primarily due to the preponderance of studies, the review will be mainly concerned with rat DA neurons. However, information gleaned from the study of DA neurons in other species will be included wherever relevant. Although bursts in DA neurons of diverse species are almost certainly homologues of those in the rat, nonetheless some caution should be excercised when species barriers are crossed. A9 and A10 DA neurons of rats anaesthetised with chloral hydrate discharge action potentials in a pattern which consists of irregular single spikes, or bursts of spikes with short interspike intervals. Spikes within the bursts exhibit a progressively decreasing spike amplitude and a progressively increasing spike duration and interspike interval. The burst is followed by a quiescent period before spiking recommences w184,49,25,55,125x ŽFig. 1A.. This bursting pattern is exhibited by approximately 18% of A9 and 73% of A10 cells in the chloral hydrate anaesthetised rat w55x. However, the picture is different in paralysed, locally anaesthetised animals. Here, A9 cells only rarely show bursts w12,109x and A10 cells show ‘‘little or no bursting’’ w12x. This contrasts markedly with the bursting seen in cells recorded in animals under chloral hydrate anaesthesia in the same studies Že.g. Ref. w12x., and suggests that this anaesthetic increases bursting in rat DA neurons. This contention is supported by the cat literature, where an increase in bursting has been reported in DA neurons when chloral hydrate was administered in a predrugrpost-drug comparison w163x.

In contrast to the low level of bursting in locally anaesthetised, paralysed rats, in freely moving rats the level of bursting is substantially higher. Over 82% of DA neurons Žcell group unknown. were reported to burst fire in the freely moving rat by Miller et al. w113x. Likewise, over 90% of A10 neurons exhibited burst firing in the freely moving rat in Freeman and Bunney w36x. The discrepancy between the level of bursting in paralysed, locally anaesthetised rats, and freely moving rats suggests that bursting is related either to the degree of sensory stimulation Žwhich should be greater in the freely moving animal., or to an interaction between movement and stimulation. The activity pattern which is characteristic of bursting DA neurons in the rat has also been found in DA neurons of the mouse w144x, guinea-pig ŽOverton and Greenfield, unpublished observations., cat w163,176,164,177,166x and monkey w147x. Interestingly, Schultz and Romo w147x report that, in the pentobarbitone-anaesthetised monkey, ‘‘only very rarely DA neurons were recorded that discharged in burstlike patterns as described for DA cells in the rat’’. However, in the behaving monkey, as in the freely moving rat, the level of bursting is substantially higher Žsee Section 2..

2. Functional aspects of burst firing The studies above were concerned with the burst activity of DA neurons under ‘basal’ conditions, i.e. in situations where no attempt was made to correlate burst activity with the occurrence of particular stimuli or movements Žwhere relevant. in the animal. However, a number of studies in rats and other species have demonstrated that bursting is responsive. In the rat, the first hint of a correlation between bursting and stimuli or movements appeared in a paper by Miller et al. w112x. Rats were required to press a lever concomitantly with the presentation of a visual, auditory or composite stimulus. Although no quantitative data were presented, one A10 cell shown in Fig. 2 of their paper gave a burst of spikes 120 ms after the presentation of the discriminative stimulus. The relationship between the response and movement was not explored. Again, rather anecdotally, in the freely moving rat, Freeman et al. w35x reported that ‘‘wburstsx . . . appeared to be associated with an orienting response elicited by a whistle or by intrusion of the experimenter’s hand into the recording chamber’’. This

1 We will use the term ‘natural bursts’ to denote those events which DA cells exhibit as part of their normal physiological repertoire. The alternative term ‘spontaneous bursts’, which is used by some investigators, is rejected because it implies that the events are acausal, which we consider to be misleading.

The stimulus was the opening of the door of a food box into which the animal would subsequently reach for a food reward. The responses appeared to be related to the appetitive properties of the object being touched. There were no qualitative differences between the responses of neurons from the three cell groups. w31x. 1. The same is true of the cat. Analysis of the neuronal response suggested that it was not related to overt aspects of task performance. it could not be determined whether the burst was movement or stimulus related in this case. Stimulus delivery is indicated by arrow head. 9r11 neurons were activated by the opening of an ‘accessory’ box which did not contain food. this burst consists of a series of action potentials with increasing interspike intervals and decreasing action potential amplitudes. some of the cells shown in the figures exhibited a clear post-burst quiescent period. However. In addition. This conclusion is reinforced by the work of Diana et al. Bursts were also seen during manual stimulation of vibrissae. Again. were associated with the emission of a burst of spikes. However. to some extent. In 1986 Schultz w146x reported that many Ž55%. or the appearance of the experimenter in the field of vision. the bursting response engendered by vibrissal stimulation in Freeman and Bunney w36x suggests that movement is not necessary for bursting. During self-initiated movements in the monkey. ŽB. They found that the cells exhibited an increase in bursting after circular walking. Each stimulus produced a single burst temporally correlated with its presentation. in the paralysed animal Žsee Section 1. OÕerton. Although most of the cells belonged to the A9 group.G. spikes included in the burst are bracketed together. The burst was preceded by a single-spike excitation. and. DA neurons in the behaving monkey responded to a behavioural trigger stimulus in an operant task with a ‘‘short burst of impulses’’.. These findings were confirmed and extended in later studies.: a natural burst. D. where they were produced in a discrete manner – one burst per stimulus. transient increases in burst firing were seen in association with orienting responses to auditory stimuli. since most DA neurons were not activated by the touch of non-food .: a time-locked burst during an IE response elicited by single-pulse electrical stimulation of the mPFC. ŽA. For example. the relationship between the burst response and movement was not explored.. and therefore did not trigger a limb movement Žor EMG activity. Bursts in midbrain DA neurons of the rat under chloral hydrate anaesthesia. who reported that small movements of the vibrissae and snout Žas in mild sniffing. initial observation was expanded upon by Freeman and Bunney w36x. Although no formal comparison was made between the characteristics of these bursts and those in the rat. since the animals always exhibited an orienting response to the auditory stimulus. where DA neurons were recorded whilst rats walked on a circular treadmill. The conclusions derived from the rat work above regarding the stimulus-bound nature of bursting in DA neurons are supported by work in the monkey. consisting of a series of action potentials with increasing interspike intervals and decreasing action potential amplitudes. In each case. has been reported to be associated with a short Žapproximately 200 ms. cells belonging to groups A10 and A8 were also recorded. a burst of impulses was found to occur when the animal’s hand touched a morsel of food located inside a food box w143x. It must also be remembered that bursting is exhibited by DA neurons under general anaesthesia. As in the case of the natural burst. where orientation in response to a stimulus Žopening the door to the experimental room in which the cat’s chamber was housed. like reaching for the food. ‘‘burst of unit activity’’ w164x. Clark r Brain Research ReÕiews 25 (1997) 312–334 Fig.314 P.

Although the studies by Schultz and colleagues show that DA neurons in the monkey produce a burst response in the presence of appetitive stimuli. They found that more DA neurons responded to delivery of liquid reward during learning than after task performance was established. However. Given that the DA systems innervate. but failed to respond to the touch of food in the box. This issue was more fully investigated by Schultz et al.64x. Burst firing in DA neurons is almost certainly of functional significance. Subsequent studies have confirmed that Žsome. in the slice Žwhere the cells lack medium and long-length afferents. can produce greater peptide release w98. via an unknown afferent. not only does the burst elevate transmitter release in the forebrain. inter alia.. we will now turn our attention to the source of the afferent input which produces bursts in DA neurons. it is possible that preferential release of these peptides occurs during bursts.-2-carboxypiperazin-4-yl. in that CCK mRNA appears to be lacking in the human substantia nigra w130x. However. DA neurons discharged a burst of impulses in response to the opening of the food box door.71x. but it also decreases the uncertainty inherent in neurotransmission w89x. Many conditional bursting cells have been identified in vertebrates Že. This suggests that DA neurons may respond to novel stimuli with properties uncertain to the animal.propyl-1phosphonic acid. DA neurons exhibit a phasic response to novel stimuli Že. The frontal cortex has been . DA neurons are ‘conditional’ rather than ‘intrinsic’ or ‘constitutive’ bursters. Importantly. but largely disappeared with more regular testing. Clark r Brain Research ReÕiews 25 (1997) 312–334 315 objects in the box when the monkey entered the box in absence of food w143x.P.. Major EAAergic inputs to DA neurons arise from the frontal cortex. Ref. and that the bursts have some effect in the forebrain which is related to motivation. and the pedunculopontine nucleus ŽPPN. although bursting in the monkey appears to be stimulus-related. In one of the two monkeys.. In particular. reduce the level of bursting w125. in a variation on the task. Given that dopamine is co-localised with cholecystokinin ŽCCK. Indeed. OÕerton. which is beyond the scope of this review.g. it appears to signal the occurrence of ethologically significant or salient stimuli. bursts seem to signal the occurrence of salient stimuli Žwith a positive valence. However. stimuli w115x. Hence. rather than simply appetitive stimuli. and AP-5 ŽŽ". Afferent control of burst firing It is likely that the afferent in question utilises an excitatory amino-acid ŽEAA. but can transfer under appropriate circumstances to conditioned stimuli. In summary. Numerous subsequent studies demonstrated that DA neurons respond to conditioned stimuli once task performance is established Žfor example in a go-no go task w148x or a delayed alternation task w91x. bursts seem to communicate motivationally relevant information to forebrain structures involved in response execution. responses were present when the task was used infrequently. one rewarded Žanimals reached for food when it opened.g. 38% of DA neurons were activated by the light. w149x. and one unrewarded Žanimals refrained from reaching.g. to the DA neurons. since iontophoretic application of the competitive N-methyl-D-aspartate ŽNMDA. established performance in three operant tasks.20x. which is unrelated to limb movement Žor EMG activity. the preferential release of peptides during bursts has not been demonstrated in the ascending dopamine systems of the rat.2. Having said this. Once established. subthalamic nucleus ŽSTN. This suggests that the response of the DA neuron is not immutably associated with primary reinforcers. This is probably the result of a build up of calcium in the terminal during closely spaced spikes w189x.-2-amino-5-phosphonopentanoic acid. In Schultz and Romo w148x animals performed a go-no go task. who examined learning vs. Instead. a light was illuminated 2–3 s before door opening. since this would involve a full examination of the function of dopamine in the forebrain. especially in bursts. and invertebrates Že.. DA neurons exhibit a highly regular pacemaker-like firing pattern w136. The pattern of cell firing has been found to be important in other systems for the release of co-localised peptide neurotransmitters. The fact that bursting in DA neurons is stimulus-bound in vivo suggests that burst activity in these cells is under the control of afferent inputs. w92x..50x. or neurotensin in some A9 and A10 DA neurons in the rat w63. antagonists CPP Ž3-ŽŽ". neurons responded to the conditioned stimuli used in the tasks. high frequency firing. suggesting that bursts signal salient stimuli with a positive valence. The various issues surrounding the selectivity of this effect are fully discussed below in Section 4.157. the functional aspects of the postsynaptic actions of transmitter release during bursts will not be addressed here. forebrain areas concerned with motor control Že. the extent to which DA neurons contain co-localised peptides may be species-specific. Hence. D.. Furthermore. the neostriatum. neurons of the guinea-pig subthalamic nucleus w126x.G. During stimulus-triggered movements. but see w111x. or eye movements. Dopaminergic neurons were activated by opening of both go and no go doors. since electrical stimulation of the axons of these cells in a pattern which resembles natural burst firing produces significantly greater dopamine release in the forebrain than is observed with stimuli delivered at the same overall frequency but with a constant inter-stimulus interval w41x. which produces an increase in the probability of release w165x.. consisting of two doors.1. This implies that highly processed information is being passed. Hence.g. the anterior burster neuron of the stomatogastric ganglion of the spiny lobster w60x.. 3. DA neurons are not activated by aversive Žbut nonnoxious. certain findings suggest that the burst response is not limited to appetitive stimuli.

instead. D. of the mPFC on the extracellular activity of A10 and A9 DA neurons w173x. primate.g. are probably homologous. Given these factors. Given that natural bursts are produced by the activity of EAAergic afferents. Likewise. As stated above.316 P. amongst other things. In addition to the frontal cortex. OÕerton. Indeed. The mPFC receives extensive inputs from the limbic system Žrat. Bursting Žexpressed as the percentage of spikes occurring in bursts.3-dione. the excitatory phases of IE and E responses. some neurons of which have been shown to be immunoreactive for glutamate andror aspartate w103x.25 mA and 57% at 1 mA.. 42% of responses at 0. anterior and dorsal to the genu of the corpus callosum Žsee Refs. Further investigation revealed that the excitatory phase of IE responses was not causally related to the preceding inhibition w128x. cell groups combined. monosynaptic EAAmediated excitations have been recorded in A10 neurons following stimulation of the habenula nucleus w99x. has been reported to reduce burst activity of A10 DA neurons. these results increase the degree of analogy between the two burst phenomena.25 mA and 27% at 1 mA. by iontophoresis to DA neurons exhibiting time-locked bursts during mPFC stimulation w174x. In the rat. several subdivisions of the amygdaloid complex project to the VTA. Hemisections at the level of the anterior STN or just anterior to the STN significantly increases the regularity of neuronal firing in both A9 and A10 cells w192x. the degree of analogy between natural bursts and time-locked bursts in DA neurons is high. activation of the splanchnic nerve w181x and effects on gastric motility w70x. w156x. w69x. reviewed by Neafsey et al. The majority of cells were responsive to the stimulation. dendrites w150x. A more comprehensive analysis by the present authors investigated the effects of single pulse electrical stimulation Ž0. Until recently. Ref. and two main patterns of activity were elicited. These effects of CPP and CNQX on time-locked bursting mirror the effects previously reported for these drugs on natural bursting. Ž1. although the details are unclear. w86x and w6x. The mPFC is the medial projection cortex of the mediodorsal nucleus of the thalamus. responses characterised by an initial excitation ŽE responses.. and to forebrain structures directly connected to autonomic centres Že. EAA antagonists should attenuate them. we applied the competitive NMDA antagonist CPP and the AMPA Ž"-a-amino-3-hydroxy-5methylisoxazole-4-propionic acid. Since natural bursting and bursting induced by mPFC stimulation are both blocked selectively by CPP. 43% of responses at 0. only one short manuscript ŽRef. CG2 and CG3 as demarcated by Zilles w194x. The PPN projects to both the SNPc and the VTA w72x and the STN directly to the SNPc w81x. If the mPFC is involved in the production of burst activity. and an aspartatergic projection to the VTA w24x. In contrast. Both the PPN w26x and the STN w3x contain neurons which appear to be glutamatergic. in the induction of burst firing in midbrain DA neurons. the laterodorsal tegmental nucleus contains glutamate immunoreactive neurons w26x and projects to the SNPc w43x.. Hence. then stimulation of the mPFC should be associated with a stimulus-bound excitatory event which bears some resemblance to natural bursts. Stimulation of either nucleus produces excitation in a high proportion of responsive DA neurons w145. Stimulation of the mPFC produces. CNQX Žat currents which antagonised AMPA responses. and the excitatory action of the PPN on the activity of DA neurons is blocked by an EAA antagonist w145x. In particular. w120x. STN and PPN there are other more minor sources of EAAergic afferents to the ventral midbrain.25 and 1 mA. pressor and depressor responses w13x. the relationship between these bursts and natural bursts in DA neurons was not explored. The major EAAergic source anterior to STN is the frontal cortex. bursts of activity in DA neurons seem to signal the occurrence of salient stimuli.G. Time-locked bursts consist of two or more spikes with increasing . The authors reported that activation of the mPFC produced bursts in a small number of A10 and A9 cells in the rat. w40x. CPP produced a significant reduction in time-locked bursting. Cooling the mPFC w167x or injection of a local anaesthetic into this area w118x Žbut see Ref. if mPFC-induced time-locked bursts are homologues of natural bursts. the mPFC is in a good position to supply such motivationally relevant information.rkainate antagonist CNQX Ž6-cyano-7-nitroquinoxaline-2. the mPFC sends projections to brainstem and spinal structures involved in autonomic control.83x. Clearly. reviewed by Uylings and van Eden w179x. including the basolateral subdivision w133x. Analysis of the excitatory phases of E and IE responses revealed that approximately one third contained events which resembled natural bursts in DA neurons. and Ž2. had focused on the effects of electrical stimulation of the mPFC on the burst firing activity of DA neurons. which synapses directly with tyrosine hydroxylase-positive Žpresumably DA. An increasingly large amount of evidence implicates the medial prefrontal area of the frontal cortex ŽmPFC. which is glutamatergic w17. 1B. whilst chemical stimulation of the mPFC has been found to increase bursting w118x. it is not surprising that this area of the cortex has been referred to as ‘‘ visceral motor cortex’’ w120x. which implies that some regulatory control over bursting comes from structures which are anterior to STN.. cell groups combined. and the time-locked bursts which they contain. and indirectly to the VTA via a projection to the PPN w72x. responses characterised by excitation following an initial inhibition ŽIE responses. Finally. and it is clear that it plays a role in the somatic processes which underlie motivation. For example. Clark r Brain Research ReÕiews 25 (1997) 312–334 shown to send a projection to the SNPc w119x. and which were closely time-locked to the stimulus ŽFig. did not. consisting of areas CG1.. is reduced in both A9 and A10 cells by this manipulation.141x.

. local injection of a GABA A agonist into the STN decreases bursting in nigral DA neurons w160x. This conclusion receives further support from the fact that stimulation of STN produces a burst-like event in 35% of A9 DA neurons. originating for example from the STN or PPN. independent of the cortex.. and therefore conduction velocity is low. CorticonigralrVTA fibres are very thin w119x. However.7 mrs for fibres projecting from the mPFC to the substantia nigra. Furthermore. and the degree of temporal variation in the latency of each burst. This conclusion is supported by the fact that lesions of STN reduce bursting in DA neurons of the lateral SNPc without affecting firing rate w160x. and this increase in bursting is blocked by the NMDA antagonist AP-5. both natural bursts and time-locked bursts are increased by picrotoxin Žalthough in the latter case only in the lower dose range.23x and the ventral midbrain of the rat w16x. excitatory post-synaptic potentials ŽEPSPs. local injection of a GABA A antagonist into the STN increases bursting. One possibility is that these cultures contain EAAergic cells. In the SNPc of the guinea-pig. it is difficult to ascertain how cultured neurons or those in the slice would perform in the presence of full circuitry in vivo. again without affecting firing rate w160x. the bursts themselves had a median latency of around 150 ms. bursts could arise as a consequence of activity patterns in pathways afferent to DA neurons. In cultured mouse DA neurons. w171x.07 mrs – ten times slower than the slowest fibres reported by Thierry et al. STN neurons appear to be intermixed with DA neurons w127x. we hypothesised that the bursts were polysynaptically generated w173x. which is excitatory w82x. they respond in a similar manner to certain pharmacological agents. suggests that there may be an EAAergic cell population in the SNPc of other rodent species besides the guinea-pig. These results indicate that the STN can influence bursting in certain DA neurons. referred to here as ‘distal influences’. which was within the realms expected for a monosynaptic event. of natural bursts and time-locked bursts exhibited by the same neuron w173x. The same may be true for the mouse and rat. bursts could arise as a consequence of factors at the level of the cell itself. 4. which is well in excess of that normally expected for monosynaptic events. and that it plays a role in natural bursting in these cells. a median burst latency of 150 ms would give a conduction velocity of 0. Likewise. Some E responses Žand occasional IE responses.G. w171x found velocities as low as 0. there are two levels at which factors could exist which ultimately lead to the production of bursts in DA neurons. D. are observed w23x. this still leaves open the question of how the afferents responsible for bursting induce the phenomenon.. at least in the cat w116x. Broadly speaking. Bursting DA neurons have been reported in primary cultures derived from the mesencephalon of the mouse w22. although Thierry et al. and NMDA-mediated bursts have been reported in DA neurons in slices from immature rats w111x. which exhibited a reasonable degree of temporal invariance. There is also evidence of a cortical projection to the PPN. Hence. since the mPFC has been shown to send a substantial projection to the STN in the rat w15x. and a latency Žmedian 25 ms.e. Involvement of non-cortical sources in the burst activity of DA neurons may also be inferred from cell culture studies. Significantly. Although the existence of a population of local.119x. The mechanism of burst firing The observation that bursting is linked to specific stimuli in vivo suggests that the phenomenon is afferent driven. or as a conse- . but not by the AMPArkainate antagonist CNQX w21x. Conversely. In addition to these similarities in the characteristics of the two burst phenomena. Firstly. burst interspike interval and duration of the post-burst quiescent period. we believe that the above similarities make time-locked bursts induced by cortical stimulation a valid model of natural bursting in DA neurons. burst generating neurons appears to raise the possibility that non-cortical EAAergic sources can exert autonomous control over bursting in DA neurons. However. Secondly. which has been demonstrated anatomically w150. OÕerton. and decreased by dopamine agonists w128x. the mPFC could be operating indirectly through the STN. as with mPFC stimulation in our own work. 1B. Coupled with the fact that the cortex is involved in producing both time-locked and natural bursting. long-duration excitations Žalthough other similarities between the two burst phenomena remain to be established. The simplest explanation for the time-locked bursts is that they are produced by the excitatory action of the monosynaptic input to DA neurons from the mPFC. these events were long-latency. there is a positive correlation between the characteristics Žspikes per burst. showed a short-latency single-spike excitation before the main response ŽFig. consisting of ‘‘2–5 spikes exhibiting decreasing amplitude and increasing duration’’ w160x. in the induction of natural burst activity in DA neurons. Given this. Clark r Brain Research ReÕiews 25 (1997) 312–334 317 interspike intervals and decreasing spike amplitudes w173x ŽFig. Hence. either arising from the properties of certain synapses impinging upon the cells. However. i. However. the fact that EAA-mediated excitatory post-synaptic currents ŽEPSCs.P. have been recorded in DA neurons in rat nigral slices w110x. The most straightforward scenario is that stimultion of the mPFC affects pathways which ultimately result in the activation of EAAergic afferents to the DA neurons. 1. although the nature of the transmitter which underlies them is unknown. The principal problem for this hypothesis is the latency of the burst events. as do natural bursts w49x.. In this regard it is interesting that ibotenic acid lesions of the STN reduce the number of cells in the substantia nigra pars reticulata which show excitatory responses to cortical stimulation w37x. This could be achieved with comparatively few synapses. with an approximate interelectrode distance in our study of 10 mm.

. since it was blocked by the NMDA antagonists ketamine and AP-5 Žthe AMPArkainate antagonist CNQX was ineffective against the depolarisation. Hence. based on results derived from our model of bursting. The findings of Mercuri et al. which was partly NMDA receptor mediated. We must stress that we are ultimately interested in the mechanism which generates natural bursts in DA neurons. and administration of a GABA A antagonist Žin the lower dose range. w108x in vitro parallel very closely those obtained by our group in vivo during mPFC-induced time-locked burst production in DA neurons. w108x and Shen and Johnson w153x suggests that time-locked bursts do not necessarily have to be generated via a polysynaptic route.19x.. Clark r Brain Research ReÕiews 25 (1997) 312–334 quence of intrinsic membrane properties of the cells.1. 5–20 stimuli. This train elicited a short latency. the long-latency NMDA-mediated excitation is preceded by another short-latency excitation w173x ŽFig. elicited a slow EPSC. Intrinsic bursting neurons are pyrami- . Although there is evidence from our work that cortical control of bursting may occur via an indirect route. since bursting can be elicited by this means in some systems. These factors are referred to here as ‘proximal influences’.101. Importantly. Hence. Evidence suggests that single-pulse stimulation of EAAergic afferent fibres in the slice does not elicit bursts in DA neurons w73. but this bursting may have little relevance to the natural burst activity of these cells. 4. this raises the possibility that natural bursts are also dependent upon a burst of activity in relevant EAAergic afferent sources. A similar finding was recently obtained by Shen and Johnson w153x. who reported that a train of pulses applied to the VTA Žusing stimulation parameters very similar to Mercuri et al. receptors. neurons in a number of areas w28. and GABA antagonists were found to enhance the late excitation. Mercuri et al.. However. these different mechanisms may work in concert to generate bursts. It is possible that some are produced directly. as far as we are aware. bursts can arise as an emergent property of a neuronal network. largely via the activation of a low threshold calcium conductance. enhances the late excitation w128x. long-duration depolarisation. and the response began with the hyperpolarisation. for example the cortex. producing a low threshold calcium spike w126x ŽLTS. As we mentioned above.318 P. DA cells simply follow a distal lead. OÕerton. certain factors may produce bursting in DA neurons. In effect. the longlatency excitation follows a period of inhibition. the STN and the PPN. a large part of which is mediated by the activation of NMDA receptors. which is part of the mPFC. 1B. Hence. STN neurons are capable of generating bursts in response to synaptic activation. where single pulse activation of afferent fibres produces bursting in ‘intrinsic bursting’ ŽIB. PPN neurons exhibit an LTS which can be activated by depolarising or hyperpolarising current pulses w75x. These parallels between our results and those of Mercuri et al.. Furthermore. including the anterior cingulate cortex w101x. Perhaps the most straightforward example of a ‘network’ influence would be a scenerio in which the EAAergic cells which innervate DA neurons and which are responsible for burst induction themselves burst fire. In some cells. the fast depolarisation was not seen. w87x. Furthermore. the long-latency of the monosynaptic NMDA-mediated depolarising envelope in Mercuri et al. applied to EAAergic afferents in VTA. burst-like events were elicited which closely resembled natural bursts in DA neurons. w108x are quite striking. stimulation of the mPFC elicts a long-latency excitation. Since these bursts appear to be a valid model of natural bursts. w108x used a train of pulses Ž40–200 ms. If we hypothesise that a bursting pattern of activity is required in the relevant EAAergic afferent pathways to produce bursts in DA neurons. This deficiency cannot be attributed to a general inability of single-pulse stimulation to elicit bursts via afferent stimulation in the slice. Some Žnoncholinergic. the response of DA neurons is very different when EAAergic afferents in the slice are stimulated in a ‘burst-like’ manner. activation of afferent fibres to cortical neurons using single-pulse stimulation can produce bursts in IB neurons in various areas of the cortex. Bursts may be produced in DA neurons because the requisite cell population which innervates them is bursting.. it is important to realise that burst firing in DA neurons can be produced by more than one mechanism Žsee Ref. followed by a long latency. in the majority of responsive cells. that time-locked bursting in DA neurons produced by stimulation of the mPFC arises from activity in non-cortical EAAergic afferents. Distal influences In other systems. Activation of AMPArkainate receptors does not appear to play a role w174x. short duration depolarisation Žpresumably AMPArkainate mediated.110. However. a large compo- nent of the slow EPSC was mediated by the activation of metabotropic glutamate ŽmGlu. for example the bursting of lumbar motoneurons of the rat in vitro induced by the application of bicuculline and strychnine w14x. the ability of afferent activity to generate bursts in PPN neurons has not been demonstrated directly. This makes it theoretically possible that cortical stimulation could lead to an afferent-induced burst response in STN cells. via the monosynaptic pathway from the mPFC to A10 and A9 neurons which has been demonstrated anatomically w150. In their study. In some cases. Of course.57x Žalthough in the first two studies holding current may have been applied to the cell during afferent stimulation.119x.G. D. w108x. single-pulse stimulation of the mPFC must ultimately lead to a burst of activity being generated in the most likely EAAergic afferent sources. We argued above. The fast and slow depolarisations were separated by a GABA-mediated hyperpolarisation. in our study. The latter was found to be mediated by NMDA receptor activation.

it will be instructive to look more closely at the study which originally demonstated the involvement of the NMDA receptor in the burst activity of DA neurons. kainate. AMPArkainate receptor-mediated EPSCs have been detected in DA neurons in the slice w110x. which is contained in afferents impinging on neurons of the A9 cell group w11x. Here. produced bursting even though the latter two compounds increased firing rate. neurons w114x. Although NMDA may have been producing bursting indirectly via a depolarisation of the membrane potential Žsee above. not only did the AMPArkainate antagonist CNQX fail to decrease bursting in DA neurons. CPP was administered directly onto the cell under investigation using iontophoresis. the burst reduction produced by CPP was not accompanied by a firing rate change. because only one subtype of EAA receptor appears to be involved. some of which may project directly to the ventral midbrain. w174x. some of which project subcortically w186x. does not appear to play a role in bursting. since firing rate is proportional to membrane potential in DA neurons w157x. where iontophoretic application of NMDA to a subpopulation of slow. did not. However. bursting was blocked by local application Žiontophoresis and pressure ejection. w20x. However. given the fact that the locus of action was known. Indeed. the selective involvement of the NMDA receptor in the burst activity of DA neurons does not appear to result from a lack of endogenous activity at AMPArkainate receptors on these cells. and the fact that CPP selectively attenuated the bursting firing pattern. This means that simple changes in firing rate could lead to apparent Žspurious. For example. The second interpretational difficulty which is encountered in the literature on bursting is engendered by the use of intravenous drug administration. Clark r Brain Research ReÕiews 25 (1997) 312–334 319 dal neurons w101x. This raises the possibility that there may be a lack of endogenous activity at AMPArkainate receptors on DA neurons under normal circumstances. namely the NMDA receptor. but not quisqualate or kainate. is very different from that of . OÕerton. Most Žextracellular. rat nucleus basalis neurons in vitro w78x and cat caudate neurons in vivo w61x. Rather. since intravenous administration of CP 96. the study provides a categorical demonstration that bursting in DA neurons is produced by the activation of NMDA receptors located on DA neurons. Synaptic factors As we stated above.. In the study by Chergui et al. substance P. w20x. D. w47x. This suggests that during single-pulse stimulation of the cortex.. This finding was confirmed and extended by Chergui et al. How specific is the involvement of NMDA receptors in the burst activity of DA neurons? DA neurons receive afferents from some non-EAAergic sources which are excitatory. the site of action of the drug relative to the cell being studied is unknown. there may be a subpopulation of cells where bursting is produced by this more direct route. it does not simply appear to be the distinction between non-EAAergic afferents and EAAergic afferents which is important for bursting in DA neurons. consider burst onset to be indicated by an interspike interval of 80 ms or less. studies of bursting in DA neurons use simple temporal criteria to discriminate burst from non-burst events. Other burst characteristics are usually ignored. changes in bursting. namely Overton and Clark w125x. w20x. it may arise as a consequence of the properties of the NMDA receptor itself.g. NMDA did increase firing rate. The high degree of latency variability of the time-locked bursts in individual cells suggests that in most cases the phenomenon is generated polysynaptically. 4. These criteria. In Overton and Clark w125x. this possibility is made less likely by the fact that NMDA. in that they did not encounter certain interpretational difficulties which must be borne in mind when assessing the literature on burst production in DA cells. of the NMDA antagonist AP-5 but not by the AMPArkainiate antagonist CNQX Žalso see Ref.1. but it also failed to affect firing rate. this seems unlikely. one important proximal influence appears to be the properties of this receptor. stimulation of afferent fibres to IB neurons in the vicinity will produce bursts in these neurons.2.G. leaves basal bursting unaffected in A9 Žand A10. Furthermore. produced bursting whereas similar application of other EAA agonists Žquisqualate. A role for NMDA in the burst activity of DA neurons is supported by fact that NMDA produces burst firing in DA neurons w125x and in other systems. and burst termination to be indicated by an interspike interval of 160 ms or more.345. Where changes in bursting are produced when a drug is given intravenously. Other studies have also found that the action of NMDA Žor NMDA agonists.P. and any effect on bursting produced by a drug which affects firing rate may occur indirectly via a change in membrane potential. non-bursting DA cells. The reason for this is uncertain at present. the answer appears to be negative. rat supraoptic nucleus neurons in vitro w67x. an antagonist at the neurokinin-1 receptor at which subtance P acts. Before we examine this issue more fully. some of which it excites w137x. based on the work of Grace and colleagues Že. Proximal influences 4. The results of this study were clear-cut. This opinion is reinforced by the findings of Chergui et al. Hence. Bursting in DA neurons appears to be influenced by membrane potential Žsee below.. evidence suggests that activation of the NMDA receptor plays a crucial role in the burst activity of DA neurons. Is there any evidence for the involvement of these transmitters in bursting? From the comparatively little data that exists. In Overton and Clark w125x. for example rat abducens motoneurons in vivo w32x. Hence.. Ref. However. changes in firing rate may reflect changes in membrane potential.2. Hence. given that DA neurons have functional subsynaptic AMPArkainate receptors w73x.

iontophoretically applied NMDA Žand the NMDA receptor agonist quinolinate. The dissimilarity between natural bursts in DA neurons and those reported in Johnson et al. which suggests that the injection of holding current may not be an absolute requirement for the occurrence of NMDA induced bursting in vitro. the post-burst quiescent period is extremely long compared to that of natural bursts w74x. bath application of NMDA produces bursting whereas AMPA does not w67x. How ‘natural’ bursts are which evolve over such a time-frame is uncertain. Why does continuously applied NMDA substitute for NMDA receptor activation by synaptic inputs? The latter occurs during the discrete. At first sight.. However. after recovery from the process which forcibly terminates the burst. enhance burst firing in vivo w159x. On a related point. Instead. whereas natural bursts in DA neurons are critically dependent on intracellular calcium w49x. w185x were characterised by a progressive decrease in the interspike interval rather than a progressive increase as is seen in natural bursts Žsee Ref. Natural bursts in DA neurons appear to be delimited by intrinsic membrane properties of the cell Ževidence indicates that a calciumactivated potassium conductance is involved. Hence. w185x found that bath application of NMDA produced a burst-like pattern in DA neurons without the injection of hyperpolarising current if prolonged exposure Ž1–3 min. w191x. for example cholecystokinin-8 w190x. whereas only the latter are stimulated during normal synaptic transmission. judging by Fig.. Likewise. or has been present throughout in the bath in vitro. Finally.. w74x and Wang et al. w74x are homologues of natural bursts in DA neurons. w74x reported that bursting could be produced in DA neurons during bath application of NMDA. Ref.g. w49x. there are serious problems with the bursts in Johnson et al. concurrent activation of an inhibitory influence was necessary for natural bursting in DA neurons. Likewise. their bursts Žor at least the membrane potential oscillation which underlies them. the effects of continuous application and discrete release during synaptic transmission may be closer than they superficially appear.G. D. This latter study is important. problem for the NMDA hypothesis of bursting in DA neurons was that initial evidence suggested that NMDA did not produce bursting in the slice w151x. w74x required the injection of hyperpolarising current. w74x are sodium dependent. One Žapparent. but not kainate or quisqualate. This is aberrant given the high calcium:sodium permeability ratio of NMDA receptor-associated ionophores in other systems Že.. w152x. apamin was reported to be unnecessary for bursting in this preparation Že. see Ref. the cell becomes susceptible again to agonist. Johnson et al. w74x and Wang et al.320 P. Ref. in A10 DA neurons recorded in vitro. afferent pathways will ‘substitute’ for bath applied drug. aspartate and quisqualate do not w61x. bursts in DA neurons can occur as ‘isolated’ events Žsee Section 2.. Clark r Brain Research ReÕiews 25 (1997) 312–334 other EAA receptor agonists. continuous application of a drug which produces bursting may not be as ‘unnatural’ as it may at first appear. Wang et al. especially when their endogenous counterparts are produced over a millisecond time-frame via receptor agonism during neurotransmission. the bursts in Wang et al.. Given that this is the case. bursting in DA neurons is dependent on intracellular calcium w49x. calcium makes little contribution to the current Žsee Ref. w185x aside. and as mentioned above. whether this is delivered synaptically in vivo. in the lamprey spinal cord w183x. Yet drugs which depolarise the membrane potential of DA neurons. Hence. simply assuring ourselves that bath applied and synaptically applied NMDA receptor agonists can in some senses be considered equivalent Žignoring the fact that non-synaptic and subsynaptic receptors will be stimulated by bath application. time-limited release of transmitter which takes place during synaptic activation.. in locomotion. the assumption being that the two routes can achieve qualitatively similar effects. However. the NMDA receptor is a calcium ionophore w100x.g. whereas glutamate. OÕerton. However. in the rat supraoptic nucleus in vitro. However. which produce bursts of action potentials in the absence of tetrodotoxin ŽTTX.. This would imply that. Wallen and Grillner w183x point out that. if hyperpolarising current was injected into the cells to maintain spike threshold at predrug levels and the bee venom toxin apamin was added to the medium. After all. Secondly. Furthermore. if this in vitro bursting was homologous to natural bursting. w74x found that burst firing was produced by bath application of NMDA. Therefore. the NMDA-induced bursting in DA neurons in Johnson et al. are not calcium dependent. What properties of NMDA receptors might be involved in burst firing in DA neurons? Firstly. AMPA receptors on DA neurons have a low calcium permeability w42x. Johnson et al. continuously applied NMDA produces membrane potential oscillations in the majority of neurons. to the agonist was allowed.. the NMDA receptor is clearly implicated in the generation of natural burst activity in DA neurons. w74x. bursts can be produced by the simple injection of depolarising pulses in vivo w49x and in DA neurons in . in the cat caudate nucleus in vivo. In subsequent papers. there may seem to be a problem with continuous application of NMDA in these studies. spike height does not appear to reduce within the burst as it does in natural bursts Žsee Ref. and the fact that others w105x have found that the current produced by bath applied NMDA in DA neurons is reduced by lowering the extracellular calcium concentration. w49x. Firstly. produces bursting. Johnson et al. These sodium dependent bursts may arise as a consequence of the fact that sodium is the principal charge carrier through the NMDA receptor-associated ionophore in their studies. Indeed. does not mean that the bursts elicited by Johnson et al. 2 of Johnson et al. However. the bursts in Johnson et al. w185x can perhaps be inferred from the fact that the characteristics of the elicited bursts differ from those of natural bursts. w49x. w74x. However. w100x.

94x and elsewhere have been found to possess a low threshold calcium conductance which produces a regenerative depolarising potential Žthe low threshold calcium spike or LTS. but they may also arise as a consequence of intrinsic membrane properties of the cells. and hence we consider that it is the ability of the NMDA receptor to generate long-duration depolarisations which is critical for bursting in DA neurons. Low threshold calcium conductance. one aspect of depolarising current pulses Žwhich elict bursts in DA neurons. However. w30x. the underlying conductance is largely inactivated at the resting . Ref. where NMDA and other agents produce membrane potential oscillations and bursting. w80x. The LTS itself gives rise to a burst of sodium spikes Žsee Ref.2. Cells in the thalamus w30x. w79x propose that intrinsic membrane properties may shape the response in some cells. Grace and Bunney w49x found that long pulses were effective whereas short pulses were ineffective. In vitro. 4. if the rate of rise of the NMDA receptor mediated EPSP in DA neurons is actually slower than that of non-NMDA mediated EPSPs. The NMDA receptors on nigral DA neurons show the slowest rate of deactivation found amongst a range of basal ganglia neurons w42x. at the termination of hyperpolarising pulses. Here. Effects mediated via the NMDA receptor also seem to have slower kinetics than those mediated by AMPArkainate receptors in DA neurons. Furthermore. Likewise for NMDA induced bursts in cat neocortical neurons. seems to play a fundamental role in burst firing in certain neuronal systems. Below. Hence. The pulses used to elicit bursts in DA neurons in culture. However. is that they have a rapid rate of rise.2.2.G.4. These cells already show a degree of negative slope conductance.g. Kiehn et al. Given that bursts can be elicited by depolarising pulses and by NMDA receptor activation. this cannot be the critical determinant underlying the role of the NMDA receptor in burst firing. the critical property shared by NMDA receptor activation and current pulses is unlikely to be calcium entry per se. all of these examples concern the generation of rhythmic bursting. w100x. were all long-duration events. D.. With an NSR. NMDA receptor mediated EPSPs in the hippocampus take considerably longer to reach a peak than non-NMDA receptor mediated EPSPs w27x. Since the depolarisation produced by current injection is unlikely to raise intracellular calcium levels more effectively than burst-ineffective EPSPs Žproduced by AMPArkainate receptor activation for example.e. due to the blockade of the ion channel by magnesium at relatively negative membrane potentials Že. As we discussed above. as in many neuronal systems. we consider certain intrinsic membrane properites which have either been found to be important for bursting in other systems. A negative slope region ŽNSR. Clearly.191x. rhythmical burst firing in spinal interneurons of the rat induced by certain pharmacological agents Žincluding NMDA. not only could bursts arise as a consequence of synaptic factors. Evidence reviewed below ŽSection 4. The NSR effectively turns the depolarisation into a regenerative spike. appears to be associated with the enhancement of a NSR w79x.2.. iontophoretic NMDA induces membrane potential oscillations Ž‘depolarising shifts’. In what way might the NSR be important for burst firing in DA neurons? It may increase the rate of rise of the depolarisation associated with NMDA receptor activation. the rate of rise of the depolarisation will be steeper.. In particular.2. What other properties are shared by NMDA receptor activation and the depolarising pulses used to elicit bursts? One remaining parameter is duration. although most slice workers have been unable to elicit bursts using depolarising pulses.9 mV w48x. activation of NMDA receptors on DA neurons produces a region of negative slope conductance in the current–voltage relationship measured under voltage clamp w105. So. non-inactivating sodium current. and that this property is specific to NMDA receptors. Intrinsic membrane properties As mentioned above. Indeed. the activation of NMDA receptors on DA neurons can produce a prolonged depolarisation. or for which there may be evidence of involvement in the burst activity of DA neurons themselves. when NMDA receptors are activated synaptically in vivo. OÕerton.. surmounted by bursts of action potentials w34x.2. 5 of Kita et al. this implies that there must be some common property shared by NMDA receptor activation and depolarising pulses which is relevant to bursting.. see Grace and Onn w50x. which AMPArkainate receptor activation does not appear to produce w108x. inferior olive w93. i. for example. It thereby calls into question the the necessity of the NMDA-receptor mediated NSR for bursting in these neurons. the current associated with synaptic activation of NMDA receptors has a NSR which spans the resting membrane potential of the cell Žactive DA cells in vivo have a resting membrane potential of y55 " 2. Burst-like events can also be produced by depolarising pulses in DA neurons in the slice under certain circumstances w139x Žalso see Fig. The second property of the NMDA receptor which may be crucial for bursting in DA neurons is that. suggests that long-duration depolarisations are necessary for evoking burst-relevant cellular phenomena. In spinal interneurons.1. NMDA can enhance the NSR w34x. it is likely that the membrane potential at the time will be in the NSR of the current–voltage relationship. EPSCs in DA neurons which are generated by NMDA receptor activation have a NSR between y70 and y30 mV w110x. in the slice and in vivo. produced by the activation of a persistent. Clark r Brain Research ReÕiews 25 (1997) 312–334 321 primary cell cultures w23x. the rate of rise of NMDA receptor-mediated EPSCs are much slower w110x. 4.P. A NSR appears to be a prerequisite for burst firing in molluscan neurons w161x.

this low threshold calcium conductance seems to be deinactivated to some extent even at the resting membrane potential.94x.322 P.. rather than the long-duration depolarisation found in some neuronal systems Že. when the degree of dendritic transection inflicted on DA neurons during the preparation of coronal slices Žused. the weight of evidence does not support the contention. further observations make it unlikely that an LTS plays any role. Firstly. and hence resemble those of cells recorded in vivo. w104x. and hence it is. STN w126x.. If this was the case. Furthermore. However. Hyperpolarisation should deinactivate T-channels. w50x. the LTS is a calcium spike. However. there is evidence of the activation of a calciumactivated potassium conductance ŽGK Ca . also responds to changes in membrane potential in the appropriate way w102x. These responses to depolarisation parallel those expected of a system in which T-channels underlie the burst activity. intracellular injection of constant depolarising current leads to an increase in burst frequency. involvement of T-channels in the natural burst activity of cells remains unproven. is gradually increased. w39x.g. has been formally examined w138x. many aspects of the morphology of natural bursts in DA neurons can be accounted for by an LTS. reducing the size of the LTS.16x. in a recent extracellular study w111x. unpublished observations. although it does not preclude involvement. The dendrites of these cells are intact and extensive w22. This small amount of dendritic damage is unlikely to be of significance for bursting in DA neurons. in a sense.77x. and Žin the former case. or why sustained injection of depolarising current increases bursting w49x. the LTS elicited from these cells is of a comparable size to the LTS elicited in the slice Žsee Fig. a conductance looking for a function. and natural bursts have been shown to be critically dependent on intracellular calcium levels w49x. Indeed.117. but see Ref. suggests that an LTS is not involved in a simple way in the burst activity of DA neurons. There is a certain amount of evidence in favour of LTS involvement in the natural burst firing of DA neurons.g. some DA neurons in coronal slices from immature rats were found to exhibit burst activity. be a problem with dendritic transection...23x and neonatal rats w16x burst fire both naturally. as the current Žand hence level of depolarisation.1. Finally. and finally to a change in firing mode to a single-spike pattern. Depolarising agents Že. In vivo. Natural bursts consist of a series of action potentials of decreasing amplitude and increasing interspike interval. in the absence of current injection w33x. presumably removing a proportion of the channels which underlie the conductance. D. flunarazine. Instead. At the termination of the burst. by Grace and Onn w50x. also cause a shift in firing mode from bursting to single spike activity w186x. not from DA neurons in the slice... An LTS can give rise to an almost identical set of phemonena Žsee Ref. however. In these cells. the low threshold calcium conductance does not appear to be involved in the generation of single-spike activity in DA neurons w38. . Secondly. in spite of prima facie evidence for the involvement of an LTS in the natural burst activity of DA neurons. w49x. Finally. neocortex w19x. Firstly. in response to current pulses w23x.23. it leads to an increase in bursting firing. even though there is evidence of significant dendritic truncation in this preparation. In support of this contention. dorsal root ganglia w96x. However. which blocks the T-type calcium channel Žsee Ref. IB cells in the guinea-pig neocortex in vitro. and is revealed by the injection of hyperpolarising current w93. it is unclear why agents which depolarise the membrane potential of DA neurons should increase bursting Žsee Section 4... Clark r Brain Research ReÕiews 25 (1997) 312–334 membrane potential of the cells. The fact depolarising pulses can elicit bursts from DA neurons in primary cultures but Žusually. thalamic cells recorded intracellularly in the whole animal produce a burst of spikes riding on a slow depolarisation at the termination of brief hyperpolarising pulses. cells behave as if an LTS underlies the burst activity. the LTS would be expected to be larger in vivo. reduce burst firing w35x. OÕerton. which gives prima facie evidence for the involvement of an LTS in the natural burst activity of these cells. STN w126x. it has been concluded that little dendrite is actually removed.76. In a number of bursting systems.121x. Interestingly. yet the LTS appears to be of a similar magnitude in the two preparations.2. there are a number of problems for an LTS theory of bursting in DA neurons. This may. Hence. Thus. which hyperpolarise the membrane potential of DA neurons w47x. Firstly. probably by virtue of its action as a dopamine antagonist Žsee Ref. 6A in Chiodo and Kapatos w23x. since 10% of DA neurons in cultures of dissociated adult cells burst fire w56x.168x. There are a number of systems in which bursts elicited by the intracellular injection of current pulses appears to be due to the activation of T-channels Že. if an LTS was involved in natural bursting. The presence of a similar conductance in rat DA neurons has been clearly demonstrated by Kang and Kitai w76.g. low amplitude depolarisation. In some cell types. For example. Ref. for example. the LTS seems to be generated by a conductance which is located in the dendrites w95. which ride on a slow depolarisation. it is unclear why agents such as apomorphine.77x. Depolarisation should lead to increased inactivation of T-channels. Secondly. About 50% of IB neurons exhibit bursting at the resting membrane potential. w126x. noradrenaline and acetylcholine. bursts cannot be elicited in the slice in situations where an LTS can be demonstrated Že. DA neurons in cultures derived from embryonic mice w22.G. Dopaminergic neurons have been shown to possess very long dendrites w121. the LTS exhibited by DA neurons in the slice seems to be only a short. some of which may be transected in the slice.g. Natural burst activity in the reticular nucleus of the thalamus Žthe cells of which exhibit an LTS. However. does not reduce burst firing in DA neurons when given intravenously ŽOverton and Clark. w104x.

OÕerton. This possiblility is supported by the fact that one of the differences between ‘burst’ and ‘non-burst’ events elicited by depolarising pulses in vivo is that in the former there is less spike accommodation Žsee Fig. Calcium-actiÕated potassium conductance. Apamin blocks SK Ca channels in many cell types w7x. 8 in Grace and Bunney w49x. for example during the AHP.P. This point is reinforced by the observation that the voltage excursions produced by apamin. one of the most important is the transient outward rectifier. natural bursts in DA neurons are critically dependent on intracellular calcium w49x.. As we mentioned earlier. What is the relationship between these seemingly diverse compounds? The one factor which they have in common is that they alter Žor are likely to alter. The fact that the characteristics of apamin-induced bursts in DA neurons resemble those of natural bursts.. DA neurons in the slice exhibit substantially less accomodation than DA neurons in vivo w45x. and hence a floor effect may prevent apamin from exerting clear effects on accomodation. Although it has been argued that apamin does not affect spike accomodation in DA neurons in the slice w155x. Voltage-gated potassium channels. This potassium current. although many of the reported characteristics of apamin-induced bursts resemble those of natural bursts in DA neurons. Although caesium does not block SK Ca channels. Interstingly. These changes occur in the absence of a change in membrane potential w180x. the post-spike afterhyperpolarisation ŽAHP.90x. and the fact that a burst-producing blockade of a GK Ca can occur via the action of a transmitter substance in other systems. The specific relationship between the blockade of a GK Ca and natural bursting in DA neurons is further called into question by the fact that a phenomenon which resembles apamin-induced bursting can be produced by the potassium channel blocker caesium w107x. apamin blocks SK Ca channels w155x. GK A is blocked in mouse and rat DA neurons in primary culture w23. The decay of the AHP is accelerated. D. 4B of Ping and Shepard w135x. nifedipine. an L-type calcium channel antagonist w122x. Phenylepherine increases the discharge rate of dorsal raphe neurons by reducing the duration of the AHP. even though SK Ca channels are permeable to caesium ions w131x. Of the currents which contribute to the AHP. which underlies spike production in DA neurons w76x will oppose the depolarisation. the a 1-adrenoceptor agonist phenylepherine blocks GK A w2x. Apamin acts as an antagonist at one type of calciumactivated potassium channel. 5-HT appears to work by blocking a GK Ca w66x. in turtle motoneurons. SK Ca channel w18x.. The smaller amplitude action potentials towards the end of the bursts exhibited prolonged initial segment-somatodendritic ŽIS-SD. suggests that apamin-induced bursts in DA neurons may not be as ‘unnatural’ as they may at first seem.2. superimposed on a depolarising envelope. 3A of Ref. The involvement of a GK Ca has been implicated in the burst activity of other systems. w62x. 5-HT produces bursting by ‘revealing’ a plateau potential mediated by calcium. Externally applied barium blocks a GK A -like conductance in these cells w58x. However. the interspike interval increases within the burst and the spike height reduces.. The earlier finding was expanded upon in an intracellular study by the same authors in 1991 w155x. with a progressive increase in interspike interval and reduction in spike amplitude. w155x. SK Ca channels appear to play a role in spike accommodation in many neuronal systems Žsee Ref.2. Shepard and Bunney w154x reported that apamin produced bursts in DA neurons recorded extracellularly in the slice. upon which the bursts of spikes ride.2.. although the identity of the GK Ca is not known. The bursts consisted of between 2 and 12 spikes. The same appears to be true of the apamin burst illustrated in Fig. This raises the possibility that SK Ca channels might play a role in the natural burst activity of DA neurons. In dorsal raphe neurons. including DA neurons w155x.3. Although the mean interspike interval within the bursts is shorter than that of natural bursts in vivo. This suggests that apamin-induced bursts and natural bursts are not entirely homologous. bursting has also been reported in guinea-pig DA neurons recorded in vitro during the bath application of barium w59x Žin the absence of calcium. I A . suggesting that they are calcium dependent. the termination of which was triggered by a ‘spontaneous’ repolarisation Žor application of a brief hyperpolarising pulse. prolonging the AHP Žsee Ref. Potassium channel blockade with intracellular caesium produces bursts in DA neurons recorded in vitro. breaks and were generally broader than spikes occurring earlier in the burst. 4. it interacts with another current which contributes to the AHP in DA neurons. We propose that interference with the AHP of DA neurons by caesium and apamin allows the . The subsequent activation of this conductance during the depolarising phase of the slow oscillatory potential ŽSOP. In 1988. These reported characteristics of apamin-induced bursts closely resemble those of natural bursts in DA neurons. Clark r Brain Research ReÕiews 25 (1997) 312–334 323 4. which is deinactivated by hyperpolarisation. when CsCl-filled recording electrodes are used. the example of an intracellularly recorded apamin burst which appears in Shepard and Bunney w155x shows a burst whose interspike interval decreases as the burst progresses Žsee Fig. rather than increases as in natural bursts.2. the small conductance. One consequence of this is that it reduces the AHP in DA neurons w155x.2. are abolished by the dihydropyridine ŽDHP. w58x. which DA neurons exhibit w158x. whilst the initial amplitude of the AHP is unaffected.. Although externally applied caesium has no effect on the GK A -like conductance w58x or the AHP w59x in DA neurons..G. Hence. So. apamin and intracellularly applied caesium both produce events in DA neurons which are similar to natural bursts. which consist of a depolarising plateau giving rise to 2–10 action potentials w107x. is produced by a conductance ŽGK A . As we discussed above. Bursts produced by apamin consisted of 3–12 spikes.

. as is apparent in extracellular recordings. the prolonged SOP has to achieve a certain duration before the true plateau potential is triggered. 10C of Grace and Bunney w49x. In the slice in many laboratories this is necessary because evidence suggests Žsee Section 4. w122x.2. w180x. an action ‘‘most simply explained by blockade of the hyperpolarising phases necessary for recycling the SOP’’. since they can produce plateau potentials even when spike production is blocked w122. the voltage excursions induced by apamin which underlie apamin-induced bursting in DA neurons are blocked by the DHP calcium channel antagonist nifedipine w122x.3. they change channel gating. The plateau potentials seen in DA neurons with caesium filled electrodes can be elicited by a short-duration depolarising pulse w107x Žin the presence of TTX and TEA. w158x. in invertebrate nerve cells. Clark r Brain Research ReÕiews 25 (1997) 312–334 spike frequency elicited by a given depolarisation to be increased sufficiently to saturate the intracellular calcium buffer and produce the classical ‘burst characteristics’. based on the progressive action potential broadening which occurs during the burst. ions leads to bursting in non-bursting cells in vivo w49x. Although Grace and Bunney w49x state that the burst-enhancing effects of intracellularly injected TEA precede blockade of the AHP. External TEA does not block SK Ca channels or the channels which underlie GK A in DA neurons w158x. intracellular calcium administration accelerates the decay of the AHP Žsee Fig. A similar change is seen in dorsal raphe neurons when GK A is blocked Žsee Ref. The calcium channel antagonists nifedipine and nimodipine reduce the amplitude and duration of the plateaus. w49x. Changes to GK A may explain why intracellular calcium injection leads to bursting in non-bursting DA neurons in vivo w49x. we propose that. This suggests that during rhythmic bursting in the presence of caesium Žwhich prolongs the SOP. by altering the AHP of DA neurons. This will lead to an apparent broadening of the action potentials in the absence of inactivation. Evidence for this proposition comes from the fact that the plateau potentials produced by apamin seem to be triggered by the SOP w135x. reduction in spike height during the burst probably reflects calcium-induced inactivation of the calcium conductanceŽs. However. since the SD component of the action potential seems to largely consist of a high threshold calcium spike w44x.2.. apamin and caesium must have other burst-relevant effects additional to interference with the AHP. and reduce the number of spikes in the bursts which they generate.. 8D. GK A is the only voltage-gated potassium conductance exhibited by DA neurons which shows any degree of inactivation. who argued that a voltage-gated potassium conductance inactivates during the burst..107x. DHP-insensitive component and a later component which is sensitive to DHPs. In the case of DA neurons. OÕerton.3.G. The bursting and plateau potentials in DA neurons which are produced by intracellular caesium w107x exhibit similar properties. In Nedergaard et al.2.2.324 P. 4. rather than blocking the conductance. High threshold calcium conductance. which underlie the SD component of the spike Žsee Ref... There are relatively few findings concerning the conductances involved in repolarising the SOP in DA neurons. An action on GK A may also explain why intracellular injection of tetraethylammonium ŽTEA. D. the substantive evidence for the gradual inactivation of a voltage-gated potassium conductance during the burst is actually quite limited. accelerated decay of the AHP presumably arises because GK A is not activated until more depolarised levels of membrane potential are achieved by the depolarising phase of the SOP..2. intracellular EGTA prolongs the decay time-course of the SOP. Fig. apamin transformed the SOP into a voltage plateau. However. apamin and caesium allow the spike frequency elicited by a given depolarisation to be increased sufficiently to saturate the intracellular calcium buffer and produce the classical burst characteristics. GK A is much more sensitive to blockade by internal TEA than external TEA w84. that intracellular calcium buffering is supra-optimal for bursting. A role for GK A in the burst activity of DA neurons was anticipated by Grace and Bunney w49x. Application of apamin to DA neurons Žin presence of TTX and TEA. Although spike broadening does occur during the burst. since the disassociation will disrupt the additive effects of depolarisation arising from the two compartments.4. This is a possible target for apamin. The plateaus are blocked completely by a zero calcium medium. We propose that the agents block a conductance which is involved in repolarising the SOP.. there is a disassociation of the IS and SD components of the spike Žsee Grace and Bunney w49x. The former has to be at least 150 ms long before the latter is observed. However.3. see Section 4. leads to replacement of the SOP with a ‘‘ramp-like depolarisation followed by a prolonged plateau phase during which time the membrane potential remainwsx in a relatively depolarised state’’ w135x. This also appears to be true for GK A in DA neurons Žsee Ref. in reality. w158x. However. In addition to caesium Žand barium. As we discussed above. According to Silva et al. To reiterate.. The plateau potential consists of two components: An early. However. and allow the emergence of the classical burst characteristics in response to an appropriate depolarising event Žsee Section 4. no quantitative data are presented which might confirm or refute the possibility that the AHP had undergone a shape change consistent with the blockade of GK A .2. However. suggesting the possible involvement of a GK Ca in the repolarisation w76x.123x. other divalent cations also affect GK A . In these cells. This may decrease spike accomodation Žwhich is very marked in these cells. It may also make a contribution to the reduction in spike height which ocurs during the burst. This rather stringent requirement suggests that the underlying conductance is located at a site which is electrotonically remote from the . such that the activation and inactivation curves are shifted to more depolarised levels.

w49x. The SOP appears to be generated at the cell soma or close by w50. and that it was dendritically located. For example. Given this. these agents may also allow the triggering of a GK Ca to terminate the burst.178x. The authors hypothesise that the current was carried by calcium. Firstly.2. suggesting that natural bursting and plateau potentials may be related. For example. Many neurons can generate calcium dependent plateau potentials.e. when fast spikes have inactivated. only one of which is apamin sensitive w158x. In the slice. such that calcium-induced inactivation of the calcium spike occurs. The attenuation of the AHP in the slice implies that there is no calcium build up. such that buffering is more effective in the slice that it is in vivo. The SD component of the action potential in DA neurons is largely a high threshold calcium spike w44.G. in the absence of apamin or caesium. In this regard it is interesting that short-duration depolarising pulses do not elicit bursts in bursting DA neurons in vivo w49x.. If buffering were too strong. Over-efficient calcium buffering in DA neurons in the slice may explain why bursts are very rarely elicited by depolarising pulses in this preparation. since it was difficult to clamp effectively. which is carried in part by a non-inactivating nifedipine sensitive calcium current w68x. Role of intracellular calcium buffering Vertebrate neurons possess a series of different mechanisms for controlling the level of Ž‘buffering’. A similar phenomenon has not been reported in other slice papers. Hence. the DHP-sensitive conductance is probably located in the dendrites. a plateau-like depolarisation is clearly visible Žsee Grace and Bunney w47x.3. in one of the few published instances of a burst-like phenomenon being elicited in a DA neuron in the slice by a depolarising pulse in normal medium ŽKita et al. there are indications that intracellular calcium buffering is often disturbed in the slice. Indeed. the amplitude of the AHP is proportional to number of spikes elicited w48x. depolarising pulses also elicited plateau potentials in these cells. to elicit a high enough spike frequency to saturate the over-efficient intracellular calcium buffer. Evidence reviewed above suggests that long-duration depolarisations in vitro Žunder certain conditions. Hence. DeFazio and Walsh w29x report that voltage steps from y70 mV to greater than y30 mV evoke a large amplitude inward current. the AHP seems to be simply a continuation of the AHP following last spike in train w50x. 5-HT reveals a plateau potential in the isolated turtle spinal cord. A change in calcium buffering may explain the differential effectiveness of depolarising pulses at eliciting bursts in DA neurons in vivo and in the slice. because the calcium would be buffered instead of being allowed to accumulate. Clark r Brain Research ReÕiews 25 (1997) 312–334 325 DHP-insensitive conductance. Hence. Reduction in spike height within the burst may reflect calcium-induced inactivation of a calcium conductance Žsee Ref. and hence the classical burst charateristics are manifested.P.107x.121x. 4. In the case of DA neurons. D. there is often little accomodation in the slice w45x. can trigger the generation of plateau potentials mediated by high threshold calcium channels. sequestration in intracellular organelles and extrusion via the sodiumrcalcium exchanger w8x. Evidence suggests that plateau potentials can be triggered in DA neurons in the absence of apamin or caesium. w62x. suggesting that it reflects a calcium dependent mechanism. the AHP following spikes elicited using a depolarising pulse is much smaller in the slice than in vivo. in so far as the level of calcium buffering is negatively correlated with burst activity. These plateau-like currents ‘‘often had durations of several hundred wmsx after the termination of the voltage clamp pulse’’. w95x. including calcium binding proteins..e. Involvement of high threshold calcium channels in the burst activity of DA neurons in vivo cannot be assessed extracellularly because DHPs inhibit action potential generation in DA neurons w107. The issue has not been formally examined intracellularly. Dopaminergic neurons possess at least two GK Ca s. most likely the activation of a GK Ca by calcium influx through voltage-gated calcium channels during the spikes. However. This contention is supported by the fact that. calcium buffering also plays a role in the natural burst activity of some systems. high threshold calcium conductance Žsee Ref.. w80x. 5B. by depolarisation. It is possible that the GK Ca which contributes to the termination of the burst is distinct from the apamin-sensitive GK Ca which generates the post-spike AHP.. it may be possible to re-characterise the action of apamin and caesium on DA neurons in the slice as substituting for the effects of disrupted calcium buffering. spike accomodation Ži.. OÕerton. which increases the electrotonic length of the neuron Žsee Ref. in response to the injection of depolarising pulses is much more prominent in vivo. cytosolic free calcium. Accomodation usually involves the activation of a GK Ca Žsee Ref. evidence suggests that under ‘normal’ circumstances Ži.. These manipulations may allow depolarisation Žthe prolonged SOP and plateau potential combination. w77x. At the same time. Fig. Secondly. its absence in the slice can be interpreted as reflecting the fact that the calcium which enters the neuron through voltage-gated channels during each spike is being buffered so efficiently that it produces less activation of the GK Ca . in . DA neurons are capable of generating calcium dependent plateau potentials via a dendritically located conductance in response to depolarisation. The AHP following a series of spikes is attenuated by the intracellular injection of the calcium chelator EGTA w48x.. such inactivation may not take place. Hence. although in natural bursts recorded intracellularly. a progressive increase in the interspike interval. in DA neurons in the slice recorded under voltage clamp. Dopaminergic neurons have been shown to exhibit a very slowly inactivating. In vivo. This hypothesis is supported by the fact that the DHP-sensitive component of the plateau potential can only be elicited in the presence of TEA w107x.

At this stage. Calcium buffering in bursting cells may be somewhere in between.326 P. However. which are considered to be endogenous calcium buffer proteins Žsee Ref. which provide EAAergic afferents to DA neurons. in continuously firing neurons. bursting SON neurons lose their phasic firing pattern with intracellular calbindin-D28k injection w88x. With supra-optimal buffering. depolarising pulses elicit spikes which rapidly accomodate Žpresumably due to the activation of a GK Ca . However. but not in slices from adult rats prepared and recorded under identical conditions w111x. With sub-optimal buffering. D. spike accomodation may be so marked that the depolarising event which underlies the burst Žin part a calcium-mediated plateau potential. events exhibiting classical burst charactersitics are not produced. Therefore. It is interesting that not only does anti-calbindin induce burst firing in nonbursting SON neurons. Additional evidence suggests that the level of calbindin-D28k in neurons of the SON and paraventricular nucleus ŽPVN. long-lasting EPSP. OÕerton. Clark r Brain Research ReÕiews 25 (1997) 312–334 the rat supraoptic nucleus ŽSON. spikes in response to depolarising pulses in the former exhibit much more accomodation than spikes in the latter Žsee Fig. buffering is set at a level which permits the occurrence of plateau potentials. In summary. The NMDA receptor activation produced by the afferent burst elicits a slow. Cells will resemble continuously firing cells in the SON.. This is hypothesised to be the situation in non-bursting cells in vivo. it is possibly significant that calcium binding protein mRNA can show activity-dependent changes over a relatively short time-scale w97x. correlates with their tendency to burst fire. The long-duration NMDA-receptor mediated EPSP triggers a plateau potential engendered by the activation of a dendritically located high threshold calcium conductance. In those cells with particularly low levels. EPSPs can also elicit plateau potentials in . Conversely. Hence. antibodies targetted at one calcium binding protein. but it also reveals calcium dependent plateau potentials in these neurons w88x. In this regard. can be explained in terms of offsetting a change in calcium buffering in DA neurons in the slice. the mechanism described below must be considered to occur against a backdrop of ‘optimal’ calcium buffering for bursting in DA neurons. 8 of Grace and Bunney w49x. there may be a change in another of the complement of calcium regulating mechanisms present in the cells.. Alternatively.4 and 5.. Spike height does not change because spike frequency does not rise sufficiently to produce enough intracellular calcium to inactivate the conductance underlying the SD component of the spike. calbindin-D28k. the depolarising event does not elicit a burst. This is hypothesised to be the usual situation for DA neurons recorded in the slice. This produces release of EAAs which act upon NMDA receptors on the recipient DA neuron.G. bursting SON neurons lose their ability to generate plateau potentials when injected with calbindin-D28k w88x. because most DA neurons appear to burst in the freely moving rat Žsee Section 1.2.. w107x. w5x. the cell simply fires a train of non-accomodating spikes in response to a depolarising pulse. we present such a synthesis. induces phasic firing.. Ref. since we contend that some of the findings in the literature.2. in neurons of the STN and PPN. It may be a change in calcium binding proteins or their intraneuronal distribution. fails to elicit spikes of sufficient frequency to inactivate the conductance underlying the SD component of the spike. In this section. in the form of a theory of natural bursting in DA neurons. Depolarising pulses can elicit plateau potentials in DA neurons Že. if the parameters are correct. see Sections 4.. suggests that the difference between intracellular calcium buffering in DA neurons in vivo and in the slice cannot simply be explained by differences in the medium bathing the cells in the two contexts Žcerebrospinal fluid and its artificial counterpart. but due to marked spike accomodation. bursting neurons of the ventral SON and lateral PVN express lower levels of calbindin-D28k mRNA than non-bursting neurons of the dorsal SON and medial PVN w182x. Likewise. Consistent with the hypothesis that non-bursting DA neurons in vivo may buffer calcium less efficiently than bursting DA neurons. Hence. Plateau potentials may still be present. for example the effects of apamin and caesium. and to activate the GK Ca which terminates the burst. it appears that there may be an ‘optimal’ level of calcium buffering for bursting in DA neurons. These findings raise the possibility that the distinction between bursting and non-bursting DA neurons in vivo may also resolve to differences in calcium buffering. The fact that bursting has been reported in DA neurons in slices from immature rats. with spike height unchanging during the train. it is unclear what underlies the difference between intracellular calcium buffering in DA neurons in vivo and in the slice. Hence. However. The theory is as follows: Cells in the mPFC elicit a volley of action potentials Ža burst. The theory itself is quite straightforward. A theory of natural burst firing in dopaminergic neurons It will be clear from the preceding sections that a substantial amount of material relevant to natural bursting in DA neurons exists in the literature. Such proteins help to maintain calcium homeostasis during neuronal activity w8x. 5.g. It is possible to elevate spike frequency sufficiently to inactivate the calcium conductance involved in the SD component of the spike. no attempt has been previously made to synthesise these diverse strands of information into an integrated whole. the distinction between non-bursting and bursting cells is not fixed and immutable. Dopaminergic neurons contain varying levels of the calcium binding proteins calbindin-D28k and calretinin w142x. where plateau potentials are suppressed. presumably..

which is a Group-1 mGlu receptor. Dopaminergic neurons predominantly express the mGluR1 subtype of mGlu receptor w170x.1. since the pattern of activation of EAAergic afferents which we hypothesise to generate bursts in DA neurons seems to activate mGlu receptors as well as NMDA receptors w153x. whilst a number of substances which hyperpolarise DA neurons decrease bursting Žsee Section 4.G. we propose that GABAergic disinhibition acts like any other depolarising influence.. as far as we are aware. Watson et al. An increase in intracellular calcium may enable bursting in non-bursting cells in vivo Žvia an alteration to the kinetics of GK A . w108x. their inclusion allows the SOP Ža previously ineffective stimulus in this regard. to be triggered by previously subthreshold events. The previous sections suggest that. A large number of GABA immunoreactive boutons are present on DA neurons w11x.. D. see Section 4. w1. The A9 neuron can be seen to burst in the periods between bursts of activity in the reticulata neuron.2. In the rather extreme cases of apamin and caesium. Changes in firing rate induced by glutamate are strongly correlated with changes in bursting w49x. it has not been demonstrated that the removal of endogenous activity at GABA receptors with GABA antagonists can produce selective effects on bursting in the absence of effects on firing rate Žthe importance of such a demonstration for determining whether a transmitter plays a direct role in bursting is discussed in Section 4.. phasic depolarisations. The most extensive inhibitory influence on DA neurons arises from GABAergic afferents. Hence. Indirect modulation of bursting in DA neurons may also occur via agents which change the concentration of intracellular calcium. However. but is neither necessary nor sufficient for bursting. but membrane potential may also be influenced by the removal of tonic activity. although conductances which interact with the post-spike AHP and repolarisation of the SOP are not necessary for natural bursting in DA neurons in vivo.2..g. they may provide a means by which natural bursting can be modulated.2.3. we have recently discovered that corticallyinduced bursting in A10 cells is not related to disinhibition via the inhibition of local inhibitory neurons in the VTA w175x. linearly related to changes in membrane potential.P.1. which implies that changes in bursting are Žpotentially. Indirect modulatory influences A number of substances which depolarise DA neurons increase bursting Žsee Section 4. Ref. Clark r Brain Research ReÕiews 25 (1997) 312–334 327 these cells. produces oscillations in membrane potential. A receptor of interest in this regard is the mGlu receptor. for example through disinhibition. modulating intracellular calcium levels will change the degree of saturation of the calcium buffer. Furtheremore. the burst progresses until it is terminated by the activation of a GK Ca . as they do in turtle motoneurons w66x. to trigger a plateau potential in DA neurons.2. However. With depolarisation. as an indirect pro-bursting modulatory factor which may be present in some cells under some circumstances. Endogenous modulatory influences on bursting 6. 6. Changes in firing rate and changes in membrane potential are linearly related in DA neurons Že. although certain GABA antagonists increase bursting in DA neurons Že. For example. as well as from proximal sources. by modulating outward currents which oppose the underlying calcium currentŽs. which suggests a possible relationship between bursting in the DA neuron and inactivity in the reticulata neuron. Metabotropic glutamate receptor activation can produce membrane potential oscillations and bursting in certain systems. which may affect the ease with which plateau potentials are elicited Žsee Section 4. Depolarisation reduces the amplitude of the postspike AHP in DA neurons w121x. However. w157x... and neurons of the substantia nigra pars reticulata in the case of A9 neurons w169x. t-ACPD Ža non-selective mGlu receptor agonist.134x. In particular...g. w169x. OÕerton. which would disinhibit the DA neuron. Likewise. evidence of a direct role for GABA-mediated transmission in bursting is sparse. in spite of the fact that the cortex sends a more substantial projection to these neurons than it does the A10 DA neurons themselves w150x. this may allow plateaus Žand hence bursts. Disinhibition via the removal of GABAergic inhibition appears to have an indirect augmentary effect on the slow NMDA mediated EPSP which we propose plays a crucial role in the bursts of DA neurons Žsee Ref. for example.2. delayed oscillatory current in Xenopus oocytes in- . w187x found that t-ACPD elicited a calcium dependent.4. It is possible that the more subtle modifications of certain conductances which are produced by alterations in membrane potential affect the threshold for the elicitation of plateau potentials. In DA neurons. some of the relevant conductances may be inactivated by depolarisation. for example. Group-1 receptors stimulate phospholipase C turnover and calcium release from internal stores Žsee Refs. In these cells. These proximal sources include the GABAergic component of the population of non-DA neurons in the VTA in the case of A10 neurons w73x.2. with bursts on top of slow.2.2.1 in relation to the NMDA receptor. there is one piece of evidence which suggests that GABAergic disinhibition may have a direct role in the burst activity of DA neurons. possibly reflecting an effect on the apamin-sensitive GK Ca . dorsal septal neurons w193x. transmitters may not only influence membrane potential by their presence. arising from distal sources such as the globus pallidus w162x..1. Figure 3 in Grace and Bunney w46x shows an oscilloscope trace of A9 neuron and a simultaneously recorded ‘local’ GABAergic neuron in the substantia nigra pars reticulata. This raises the possibility that transmitters which influence membrane potential are in a position to produce a finegrained modulation of bursting. Ref. Of course..

and can act on dopamine autoreceptors on the DA neurons themselves w85x. Corticosterone acts at two receptors in the rat brain: mineralocorticoid receptors ŽMRs. the pathway appears to be regulated by Žandror arise from. 6. we hypothesise that MR-preferring levels of corticosterone also block an SK Ca channel in DA neurons. 7.. Similar effects on the burst activity of A9 DA neurons w51x and some A10 DA neurons w52x have also been reported with the a 2 selective agonist clonidine. Although it has recently been proposed that activation of NA afferents to DA neurons might be necessary for bursting w188x. Although 3–30 m M t-ACPD does not appear to produce bursting in DA neurons w106x. Under benign circumstances. this implies that the induction of bursting can undergo longlasting change. which we believe for the first time presents a complete picture of the phenomonon. A great deal of literature has linked the NMDA receptor with synaptic plasticity. the predominant adrenocortical hormone in the rat. the same basic mechanism can be involved in the generation of a discrete burst in response to normal synaptic transmission. corticosterone appears to block a GK Ca in CA1 neurons of the hippocampus. neurons w54x. which are unlikely to contain NA neurons.. Dopamine is released from the dendrites of DA neurons in response to afferent activity w124x. Ref. Conclusions Certain findings concerning bursting in DA neurons are firmly established. beyond this. the factors involved in the generation of bursts in DA neurons remain obscure. since bursting has recently been reported in A10 Žand A9 DA. By acting at MRs. which blocks SK Ca channels in DA neurons w155x. w35x. Although these effects may be partly explained by an action on membrane potential Ždopamine agonists hyperpolarise DA neurons. Hence. it arises more from a failure to integrate the existing findings into a coherent whole. in adrenalectomised animals. sensory stimuli.g. Ref. such that a plateau potential may no longer elicit events with classical burst characteristics.2. certain ingredients can be identified which appear to play an important role in natural bursting in DA neurons. We propose that in DA neurons. We have integrated the latter factors and others into a theory of natural bursting in DA neurons. w129x. One agent appears to be dopamine. This is not because the relevant information is lacking. Antagonism of a 1 adrenoceptors with systemic prazosin reduces bursting in A10 DA neurons without affecting firing rate w53x. Apamin. the combination of factors involved in the burst activity of DA neurons appears to resemble that found during NMDA-induced bursting in the cat neocortex w34x.G. enhance GK A in cultured rat DA neurons w90x. an effect which is probably produced by the inhibition of noradrenergic ŽNA. Where this has been investigated. effective stimuli include ones of ethological significance or salience. Another endogenous agent which may interact directly with the spike AHP in DA neurons is corticosterone. However. the mPFC. in particular.g. this raises the possibility that endogenous factors may exist which naturally modulate these conductances. one possible explanation for the reduction in bursting which accompanies decreased endogenous activity at a 1 receptors is that GK A in DA neurons has been enhanced by the removal of a tonic blockade. the role of noradrenaline appears to be limited to one of modulation. they are also consistent with the recent finding that dopamine Žand dopamine D 2 agonists. w47x. a higher concentration than this is required to produce bursting in those systems where bursting has been seen Žsee Ref. OÕerton. mediated by SK Ca channels Žsee Ref. From the literature. Enhancing GK A will limit the spike frequency obtained by a given depolarisation. which may underlie learning and memory w9x... Here. However. corticosterone replacement at MR preferring levels increases firing rate and facilitates EAA-induced bursting relative to adrenalectomised controls w129x. Furthermore. An interaction with GK A may also explain the effects of noradrenaline on the burst activity of DA neurons. We have evidence for a similar action at the level of DA neurons. this may al- . w4x. suggesting that noradrenaline itself produces an a 1-like action on bursting. A corollary of this is that bursts appear to be produced by activity in pathways afferent to DA neurons. and a 1 agonism blocks GK A in dorsal raphe neurons w2x. also increases firing rate w154x and EAA-induced bursting in DA neurons w152x. NMDA receptor activation and calcium-mediated plateau potentials. and as such the hormone is in a position to modulate bursting in these cells. Clark r Brain Research ReÕiews 25 (1997) 312–334 jected with cortical RNA. and glucocorticoid receptors ŽGRs. D. iontophoretic NMDA triggers a long-duration calcium ‘spike’ Žwhich generates a burst of action potentials in the absence of TTX. w12x. Hence. whilst dopamine antagonists Že. concerned is EAAergic. Hence. Several studies have now demonstrated that the pathwayŽs. neurons in coronal slices w111x. bursts are elicited by Žamongst other things. produced via a dendritically located conductance. in the cortex this combination of factors has only been shown to be involved in the generation of rhythmical bursting during continuous NMDA application.328 P. see Ref. and dopamine depletion w65x increase bursting. Since evidence suggests that A10 DA neurons may receive a small NA input w10x. Although bursting cells in different systems generate bursts via diverse routes. Since bursting in DA neurons seems to be critically dependent upon NMDA receptor activation. Direct modulatory influences Given that certain agents interact with conductances involved in the spike AHP and in repolarising the SOP in DA neurons. Dopamine agonists decrease bursting Že.

A.K. Cardozo. J. Burst generating and regular spiking layer 5 pyramidal neurons of rat neocortex have different morphological features.L. 15 Ž1992. Secondly. w20x K. J. w12x B. which will move us closer towards a full understanding of natural bursting in DA neurons. An autoradiographic examination of corticocortical and subcortical projections of the rat mediodorsal-projection Žprefrontal. w5x K. Blaustein. Burns. Bayer. P. 640–647. 43–59. Brunet. 463–467. Luhmann. Neurosci. J.H. Bunney.B. Rogers. DHP-sensitive dendritic calcium channels. the slow EPSP will not elicit a burst.L. Nistri.S.P. Wyss.A. 217–231. Modulation of a transient outward current in serotonergic neurones by a 1 -adrenoceptors.D.A. personal communication. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. w9x T. T. 296 Ž1990. Akaola. Ther.J. We would like to thank Dr. Since bursting in DA neurons may represent a vital locus change in dopamine hyperactivity disorders. Firstly.S. 491 Ž1989.L.J. In the latter case. 560–571. 11 Ž1988. . Neurol.S. 529 Ž1990. 43–62. Eur..F. w2x G.A. Gilman. D.L. 2691–2700. Bracci. Prince.H.G. Feline subthalamic nucleus neurons contain glutamate-like but not GABA-like or glycine-like immunoreactivity. w16x D. Dopaminergic neurons: Effects of antipsychotic drugs and amphetamine on single cell activity. w8x M.B. Clark r Brain Research ReÕiews 25 (1997) 312–334 329 low salient stimuli a ‘fast track’ to forebrain effector systems. and the Medical Research Council ŽP.W. J. EAA-mediated EPSPs..J. 137–144. G. w3x R. intracellular injection of EGTA or calbindinD28k may convert these into bursting cells if the dose is correct. given that non-bursting cells in vivo may have sub-optimal calcium buffering. 598–613. OÕerton. w11x J. Baimbridge. Pharmacol. Hence. J. Likewise. DHPs should block or attenuate both bursts and the depolarising envelope recorded intracellularly in vivo. M. 185 Ž1973. Silva.M. H. Aldridge.M. antagonists of mGluR1 receptors may decrease bursting by reducing the amplituderduration of the critical EPSP.A. 185–188. Bliss.E. Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo. Given that bursts produce a supra-additive release of dopamine in the forebrain w41x. L. A. Smith. D. The theory of bursting which we propose allows certain predictions to be made.P. GABA and substance P input to dopaminergic neurons in the substantia nigra of the rat. Valiante. an alteration in bursting may underlie disorders which are characterised by dopamine hyperactivity. according to the theory. B. Brain Res. Calcium binding proteins in the nervous system. Trends Neurosci. and D.K. 10 Ž1990. Neurosci.M. Albin. Magelby. Y. Bolam. w7x A. 184 Ž1979. w4x R. Nature 361 Ž1993. 57–78. 76 Ž1996. M. w19x Y. Neuropharmacology 21 Ž1982. J. 75 Ž1996. However.G. J. Rev. w13x S. V. Neurosci. Thirdly. M. In the absence of this sort of intervention. J. Neurol. part of each burst exhibited by DA neurons consists of a plateau potential mediated by high threshold. Ricardo. Trends Neurosci. Ballerini. P. Aghajanian. 12 Ž1989. w10x V. D. like schizophrenia and drug dependence.G. Pennefather. we have already shown that chronic administration of amphetamine enhances cortically-induced bursting in A9 and A10 neurons w172x. Calcium-activated potassium channels. appear to be elicited endogenously only by long-duration. J. Walters.H. H.. w18x N. P. Roth. C. Metabotropic glutamate receptors coupled to IP3 production mediate inhibition of I AH P in rat dentate granule neurons. Shammah-Lagnado. Aghajanian.R. 340 Ž1985. Chergui. this suggests that the relevant EAAergic afferents abut regions of the neuron which are electrotonically remote from the DHP-sensitive conductance.J.C.P. 59–65. J. 303–308. 31–39. G.L. 71–77. Brain Res. Svensson. Canteras. 3 Ž1992.O. R. Toxins in the characterisation of potassium channels. as Mercuri and colleagues have discovered ŽN. project grant G9629658N. since DA neurons in the slice may have supra-optimal calcium buffering. Since this afferent activity results not only in the activation of NMDA receptors but also in the activation of mGluR1 receptors w153x. Richards for helpful comments on an earlier version of the manuscript. Exp. Carlen. Chouvet. References w1x M. Saunier. K. a change to the process of burst-induction may also arise pathologically. S.C. Blatz. Ultrastructural localization of tyrosine hydroxylase in the rat ventral tegmental area: relationship between immunolabeling density and neuronal associations. Neurophysiol. 10 Ž1987. Chagnac-Amitai..H. S. A. A synaptic model of memory: long-term potentiation in the hippocampus.R. Carter.L. Comp. since the plateau potentials Ževidenced as bursts. Jenkinson. 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