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5-HT and mechanisms of defence

J. F. William Deakin and Frederico G. Graeff
J Psychopharmacol 1991 5: 305
DOI: 10.1177/026988119100500414

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Journal of Psychopharmacology 5(4) (1991)305-
305-315
CRITIQUE
5-HT and mechanisms of defence
J. F. William 1
Deakin and Frederico G. Graeff
2 .
Department of Psychiatry, Rawnsley Building, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK and 2
l Laboratory
of Psychobiology, FFCLRP, Campus of the University of Sao Paulo, 14049 Ribeirao Preto, SP, Brazil
Introduction
The central idea of this paper is that brain 5-HT systems
are concerned with adaptive responses to aversive events.
Aversive stimuli can be defined as stimuli which motivate
avoidance behaviour. This definition encompasses negative
incentives and reinforcers and much of what passes under
vaguer terms such as ’punishers’ and ’stresses’. Aversive
stimuli can be considered in three groups and we suggest
they bring different anatomical structures and 5-HT
systems into play. Dysfunction in these central mechanisms
of aversion results in different groups of psychological
symptoms. The three forms of aversion are summarized
below and they form the basis of this article.
1.Acute unconditioned aversive stimuli such as pain,
asphyxia and innate fear inducing stimuli (e.g. snakes
to monkeys) evoke unconditioned reflexive freezing,
fight or flight behaviour. It is suggested that panic in
humans corresponds to spontaneous activation of the
flight reflex.
2. Acute conditioned aversive stimuli are neutral stimuli
which have acquired aversive properties because they
have been predictive of some noxious or aversive event.
They elicit fear and anticipatory anxiety. This has the
adaptive function of guiding the organism away from
danger. Dysfunctional activation of anticipatory
defense mechanisms is the suggested basis of morbid
anxiety states in humans.
3. Unconditioned or conditioned aversive stimuli may
become chronic by circumstance and if the acute
mechanisms fail to terminate exposure to them. The
behavioural effects of aversive stimuli become attenuated
with repetition. Learned helplessness and depression
may correspond to failure in central mechanisms of
adaptation, tolerance or resilience to repeated aversive
events.
Acute unconditioned aversive stimuli
The defence syndrome
Acute unconditioned aversive stimuli, such as pain and
innate fear stimuli, elicit the following reflexive triad:
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@1991 British Association for Psychopharmacology
,
autonomic activation, analgesia and behavioural reflexes
which include, with increasing proximity of the threat;
freezing, flight and defensive aggression. This syndrome
can be dramatically evoked by electrical or chemical
&dquo;
activation of a neuronal system in the brain comprising
the periaqueductal grey matter (PAG), medial hypo-
thalamus and amygdala (Hess and Brueger, 1943;
Fernandez and Hunsberger, 1962).
The behavioural and autonomic changes of the defence
reaction are likely to be the expression of an aversive
emotional-motivational state since activation of the PAG
motivates switch-off behaviour, inhibits antecedent
behaviour, facilitates escape from electric foot-shock and
acts as an aversive unconditioned stimulus in Pavlovian
conditioning and place aversion (Delgado, Roberts and
Miller, 1954; Nakao, 1958; Olds and Olds, 1962; Graeff,
1990; DiScala et al., 1987).
Functional anatomy of the defence system
The PAG may be regarded as part of a nociceptive reflex
mechanism at a low supraspinal level of integration
which, like the spinal withdrawal reflex, minimizes
nociceptive stimuli. Nociceptive information has direct
access to the PAG through the primitive spino-thalamic
tract described by Mehler, Feferman and Nauta (1960)
and probably via 5-HT projections from the raphe
magnus. The efferent arm of PAG-mediated pain reflexes
involves midbrain locomotor generators, integrated
autonomic responses and analgesic mechanisms. These
effector mechanisms terminate contact with nociceptive
stimuli and reduce their impact.
The PAG not only receives ascending nociceptive
afferents but also afferents from the tectum and from
higher levels of the defence system. Tectal and olfactory
afferents may mediate phylogenetically primitive ’hard
wired’ defensive responses to the sight, sound and smell
of predators or unfamiliar conspecifics (e.g. Hendrie,
1989). These distance stimuli are predictive of nociception
and tissue damage and their integration into the
PAG supraspinal nociceptive-defence mechanism allows
preventative anticipatory responses. However, with
phylogeny this supraspinal reflex mechanism has, in turn,
306
Table 1 Acute aversive stimuli.
come under the control of descending influences from
higher levels of defensive integration-the hypothalamus
and amygdala. Under these influences the defence
reaction becomes more directed (Schmitt et al., 1986),
flexible and, through the mechanism of learning, still
more anticipatory.
The defence system and human anxiety
Experiences of intense fear and distress accompanied by
autonomic activation have been reported by human
patients when electrically stimulated at the PAG, medial
hypothalamus and amygdala during the course of
stereotaxic brain surgery (reviewed in Graeff, 1990). For
example, Nashold, Wilson and Slaughter (1974) reported:
&dquo;Activation of the area in or near the lateral edge of the
central grey resulted in strong reactions in most patients.
Feelings of fear and death were often expressed.
Autonomic activation such as contralateral piloerection
and sweating, increase in the pulse and respiratory rate,
blushing over the entire face and neck.... were noted&dquo;.
The similarity with Freud’s description of ’anxiety
attacks’ will be apparent: &dquo;(anxiety can) erupt
...
suddenly into consciousness without being called forth
by any train of thought ... a feeling of anxiety alone
... associated with the nearest interpretation, such as
sudden death, a stroke, or approaching insanity ... an
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accompanying disturbance ... of the bodily functions,
such as respiration, hearts actions, vasomotor innerva-
tion, or glandular activity&dquo;. Graeff (1990) has suggested
that spontaneous panic attacks are due to spontaneous
activation of the flight component of the PAG defence
reaction in the absence of an unconditioned stimulus. In
some patients panic attacks are more likely to occur in
certain situations (DSM-III-R ’situationally predisposed
panic’) while in others panics are always and only elicited
by a phobic stimulus (’situation bound panic’; Klein and
Klein, 1989). More situationally determined panics may
arise from activation of higher levels of the defence
system. PET scans of patients during a panic attack
evoked by lactate infusion showed metabolic activation
of the entire defence system-including anterior temporal
lobe, amygdala and, subjacent to the superior colliculi,
possibly the PAG (Reiman et al., 1989).
Acute conditioned aversive stimuli
Components of conditioned aversive responses
Warnings of unconditioned aversive stimuli occur either
because they are detected at a distance by vision, hearing
and olfaction or because the threats are predicted by
conditioned stimuli. Warning stimuli evoke autonomic
preparations for fight/flight and analgesic preparations

for tissue damage (’fear inhibits pain’, Bolles and
Faneslow, 1980) but do not evoke the fight or flight
components of the proximal defence reaction. Instead,
anticipatory anxiety motivates avoidance behaviour so
that the organism is guided away from potentially noxious
stimuli and environments, towards safety cues. This
involves approach and avoidance mechanisms organized
in the basal ganglia and ventral striatum. We suggest that
during anticipation of threat, 5-HT projections from the
dorsal raphe nucleus mediate or facilitate avoidance
behaviour and restrain or disconnect the fight/flight
components of the proximal defence system. The clinical
implication is that 5-HT facilitates anticipatory anxiety
but restrains spontaneous panic (Table 1).
Conditioned fear
Analysers of anticipation
The amygdala is a likely route by which innate distal
threats and aversively conditioned cues activate the
amygdalo-hypothalamico-PAG defence system. Cortical
afferents to amygdala arise mainly from anterior
temporal cortex (Turner, Mishkin and Knapp, 1980). This
region codes high order stimuli, probably in all modalities
but particularly in the distance modalities-olfaction,
vision and hearing. In the visual system of the primate,
for example, some infero-temporal units respond only to
images of the faces and gestures of conspecifics (e.g.
Yamane, Kaji and Kawano, 1988). The temporal pole and
connections with the frontal lobes (basolateral circuit)
may organize the processing and expression of social
communication (Brothers, 1990; Deakin et al., 1991a).
Such highly processed sensory information may be innately
aversive (e.g. threats from conspecifics; calls of predators)
or may acquire emotional significance through the mech-
anism of classical conditioning. Many studies suggest that
the amygdala is of crucial importance in aversive classical
conditioning as typically studied with discrete conditioned
stimuli such as tones and lights (LeDoux et al., 1988,
1990; Blanchard and Blanchard, 1972).
While the amygdala has been implicated in aversively
conditioned responses to cues, recent evidence suggests
that conditioned aversions to contexts are disrupted by
hippocampal but not amygdala lesions (Selden et al. ,
1991). This suggests that information about context and
perhaps place, coded in the hippocampus, can directly
activate sub-amygdalar levels of the defence system
through hippocampal projections to hypothalamus or
PAG (Nauta, 1958). We suggest this pathway may also
be important in determining the form of the defence
reaction. Freezing is the response evoked by aversive cues
detected at a distance but flight supervenes when the cues
become proximal. In the absence of hippocampal
information about spatial and perhaps temporal
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307
proximity, the primitive or default reaction to aversive
stimuli may be undirected escape. This could contribute
to the failure of suppression of behaviour by aversive
stimuli in animals with hippocampal lesions (Gray, 1982).
Effectors of avoidance-the dorsal raphe
negative incentive system
Deakin (1983) suggested that the dorsal raphe nucleus
(DRN) 5-HT system is activated by conditioned aversive
stimuli and components of the behavioural response are
differentially mediated by 5-HT release in the various
terminal areas. Activation of the DRN during spatial or
temporal anticipation of aversion may occur from the
hippocampal and tempero-amygdalar analysers via the
prominent innervation of the DRN by the lateral
habenula (Nauta, 1958). There are also direct projections
from frontal cortex and the central nucleus of the
amygdala to the DRN.
Dopamine and DRN 5-HT projections innervate the
same structures in the forebrain (Azmitea and Segal,
1978). Much experimental evidence is compatible with an
incentive function for dopamine although the precise
mode of operation is still to be elucidated (see Fibiger
and Philips, 1988). Crow (1973) and Crow and Deakin
(1985) suggested that the organism ’locks onto’ incentives
by activation of dopaminergic approach mechanisms. By
tracking incentives the organism is ’homed-in’ onto
reinforcers. Deakin (1983) suggested that DRN projections
to the same structures oppose the actions of dopamine
and mediate avoidance behaviour elicited by negative
incentive stimuli.
The ventral striatum receives a prominent innervation
from amygdala and hippocampus. These projections are
thought to transmit information about the incentive value
of cues and their spatial and temporal proximity and this
influences approach/withdrawal motor programs. The
balance between approach and withdrawal is determined
by the balance between ventral striatal dopamine and
5-HT release (Carter and Pycock, 1976, 1977; Costall,
Hui and Naylor, 1979; Lyness and Moore, 1981) evoked
by the various incentives currently being processed.
Equivalent interactions in the pallidum and other parts
of the basal ganglia determine the direction of approach
to safety cues and retreat from aversive cues. Thus the
organism is guided away from aversive cues and towards
safety signals (Deakin, 1983).
5-HT and studies
fear-animal
An extensive early literature suggests that active and
passive avoidance behaviour is disrupted by interference
with 5-HT function and this is compatible with a role of
5-HT in conditioned fear (see Deakin, 1983). However,
most animal models of anxiety involve mixes of con-
ditioned, innate, proximal and distal aversive mechanisms.
Studies of local manipulation of 5-HT on ’isolated’
 308
psychological mechanisms of aversion are lacking.
Nevertheless, in behavioural models of anxiety, such as
the conflict test and the social interaction test, there have
been several demonstrations that inactivation of DRN
projections exerts anxiolytic-like effects. Microinjections
into the DRN of the selective neurotoxin 57-dihydroxy-
tryptamine, of benzodiazepines, the inhibitory neuro-
transmitter GABA, and 5-HT1A soma-dendritic auto-
receptor agonists such as 5-HT itself, gepirone and
buspirone have all been reported to reduce behavioural
measures of anxiety (Green and Hodges, 1986; Hindley
et al., 1985; Thiebot, Jobert and Soubie, 1980; DeVry
et al., 1991).
Microinjections of 5-HT and the 5-HTIA agonist
8-OH-DPAT into the amygdala enhanced response
suppression by punishment in one study (Hodges, Green
and Glenn, 1987) and others have found that 5-HT
.
antagonists, including ketanserin, released punished
responding (Petersen and Scheel-Kruger, 1984; Shibata
et al., 1982). This suggests that 5-HTIA and the 5-HT2
receptor family (which includes the closely related
5-HT,c receptor) facilitate aversion in the amygdala-
perhaps by facilitating the influence of neuronal
representations of aversive cues on the amygdala or
ventral striatum. An entirely opposite effect of 5-HT
appears to operate in the PAG where 5-HT inhibits escape
behaviour evoked by stimulation of the PAG (see above).
As discussed below, this may have the function of
preventing undirected flight responses, organized in the
PAG, from interfering with directed avoidance during
anticipation of an aversive UCS.
Detailed anatomical studies indicate a specific associa-
tion of the 5-HT2 receptor family with terminals of the
DRN system, particularly in frontal cortex (Blue et al.
1988). In humans, 5-HTID receptors are concentrated in
basal ganglia and substantia nigra and these structures
are innervated by the DRN. However, a proportion of
5-HTIp receptors are autoreceptors. Whether 5-HT33
receptor antagonists exert their anxiolytic-like effects
(Costall, Naylor and Tyers, 1990) by antagonizing
components of the DRN system is not yet clear.
5-HT and fear-human studies
Several large clinical trials indicate that antidepressants
are more effective than benzodiazepines in the treatment
of anxiety (Johnstone et al., 1986; Kahn et al., 1986).
Deakin (1988) suggested that the shared ability of
antidepressant drugs to either block or to down-regulate
5-HT2~lc receptors and thus to block the DRN fear
system, might contribute to their anxiolytic efficacy.
Furthermore, 5-HTIA agonists such as buspirone and
ipsapirone also share the ability of antidepressants to
gradually down-regulate 5-HT2 receptor numbers (Eison
and Yocca, 1985). This may explain why the full
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anxiolytic effects of 5-HT lA agonists take time to
emerge.
To test the hypothesis that antidepressants exert their
anxiolytic effects by decreasing neurotransmission through
receptors of the 5-HT2 family, a placebo-controlled trial
of the selective 5-HT2/lc antagonist ritanserin was carried
out in 56 neurotic outpatients (Deakin and Wang, 1991).
Speilberg self-ratings of trait anxiety improved more in
patients treated with ritanserin than placebo. There were
no other main effects of drug treatment but on all ratings
ritanserin was more effective in males and in those with
more severe neurotic illnesses. This trial suggests that, as
predicted, decreasing 5-HT2/lc receptor neurotransmission
may be a mechanism common to several anxiolytic
therapies. However, treatment effects were small and
other mechanisms must be involved in mediating anxiety
symptoms.
There is evidence that ritanserin may, as predicted,
exert its anxiolytic effects by attenuating aversively
conditioned responses (Hensman et al., 1991). Habituation
of skin conductance responses (SCRs) to a series of 10
neutral tones were recorded in groups of 10 healthy
volunteers. Tone 11was followed by a loud aversive white
noise. This reinstated SCRs to a further series of tones
and the responses did not extinguish. This has been shown
to involve an associative mechanism. In 10 subjects,
ritanserin had no effect during habituation but completely
blocked conditioned SCRs. The same effect was observed
using the same paradigm with the patients in the clinical
trial (Guimaraes, Wang and Deakin, 1990). The action
of ritanserin was confined to the post-conditioning phase
and this is compatible with a selective involvement of
5-HT2/lc receptors in conditioned fear responses in
normal and anxious humans.
Conditioned inhibition of proximal
defence reactions
We have discussed the idea that DRN 5-HT projections
to amygdala, accumbens and other forebrain structures
may function as a negative incentive or fear system which
guides the organism from danger cues. The DRN also
innervates lower levels of the defence system through the
dorsal raphe-periventricular tract and this may function
to restrain flight and aggression-components of the
defence reaction to proximal threat-during distal threat.
5-HT inhibits unconditioned aversion
Kiser et al. (1980) showed that electrical stimulation of
the dorsal raphe nucleus reduced the aversiveness of PAG
stimulation as revealed by decreased lever-pressing to
reduce the intensity of PAG stimulation. Microinjections
into the PAG of 5-HT itself, 5-methoxy dimethyl-
tryptamine, 5-HT re-uptake blockers and the terminal

autoreceptor antagonists propranolol and isomaltane
reported to inhibit escape from PAG stimulation (Audi,
de Aguiar and Graeff, 1988; Schutz, de Aguiar and
Graeff, 1985; Kiser and Lebovitz, 1975; Jenck, Broekkamp
and Van Delf, 1989). Furthermore, the anti-aversive
effects of enhancing 5-HT function have been reversed
by 5-HT antagonists, including ritanserin, in most of the
studies. These results suggest that 5-HT restrains PAG
aversion, probably through 5-HT2,lc receptors. In
keeping with this view, inhibition of 5-HT synthesis
with PCPA facilitated stimulation-induced escape and
administration of the 5-HT receptor antagonists methy-
sergide and cyproheptadine accelerated lever pressing to
switch off PAG stimulation (Kiser and Lebovitz, 1975;
Schenberg and Graeff, 1978; Clarke and File, 1982).
There is some disagreement about the influence of 5-HT
receptor subtypes on PAG aversion (Graeff, 1990; Jenck,
Broekkamp and Van Delft, 1989). This may be due in
part to differences in route of drug administration and
in the behavioural procedures. Recently, a clear anti-
aversive effect of 5-HT1A agonists was reported following
microinjection into the PAG (Beckett et al., 1991).
However, systemic 8-OH-DPAT was markedly pro-
aversive in another study (Jenck, Broekkamp and
Van Delft, 1989). The explanation may be that systemic
8-OH-DPAT reduced 5-HT release in the PAG by its
actions on dorsal raphe cell body autoreceptors and these
.
would not have been affected by PAG administration.
An important behavioural difference may be that the
Jenck et al. paradigm permits anticipatory escape
responses from PAG stimulation, and anticipatory
anxiety, we are suggesting, has a very different
pharmacology to unconditioned escape evoked by PAG
stimulation (Graeff, 1990).
Fear and 5-HT inhibit
panic
Two unexpected clinical predictions follow from the
idea that conditioned fear activates DRN projections to
inhibit the fight/flight component of the defence
reaction. First, if it is correct that panic corresponds
to spontaneous activation of brain flight/defence
systems, fear should inhibit panic. Second, very selective
anxiolytic drugs might alleviate generalized or anticipatory
anxiety but at the cost of disinhibiting panic or not
affecting it.
There is no direct evidence that fear inhibits panic but
the prediction does make sense of the otherwise
completely counter-intuitive phenomenon of relaxation-
induced panic in which patients have panic attacks when
carrying out relaxation exercises-still misguidedly pre-
scribed (Adler, 1987). Nocturnal panics could also involve
loss of the restraining influence of fear. Panic patients
prefer to hold themselves in a state of anxious tension
and fill their time with activity to avoid being still and
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309
are risk an attack. Klein documented how, as panic disorder
evolves, the attacks become less frequent and are replaced
by increasing anticipatory anxiety (Klein and Klein, 1989).
This has been attributed to phobic avoidance of places
associated with panics but the mechanism could be
physiological-restraint of panic by conditioned fear,
mediated by the 5-HT innervation of the PAG.
A specific prediction from the pharmacology of PAG
aversion would be that selective 5-HT2 (or possibly ic)
antagonists would ameliorate anticipatory or generalized
anxiety (see above) but aggravate panic. Agents of this
selectivity are not yet available but there is suggestive
evidence from experience with the mixed 5-HT2/IC
antagonists ritanserin and trazodone. Clinical trials (see
Deakin and Wang, 1991) suggest both these agents have
efficacy in the treatment of depression and generalized
anxiety but it is clear that neither drug is effective in
patients with panic disorder (Charney et al., 1986;
DenBoer and Westenberg, 1990). Furthermore, in a
recent re-analysis of the placebo-controlled trial of
ritanserin in general neurotic outpatients described above,
patients with a retrospective diagnosis of panic improved
less on ritanserin than panikers on placebo.
Evidence was presented above that ritanserin blocked
an aversively conditioned autonomic response as
predicted by the DRN-anticipatory anxiety theory.
However, in remarkable contrast, we have recently found
that ritanserin potentiated the anxiety induced by public
speaking in normal volunteers-an unconditioned form
of anxiety (Guimaraes, Zuardi and Graeff, 1987). The
opposed effects of ritanserin in panic versus generalized
anxiety, and in human models of conditioned versus
unconditioned anxiety, mirror the opposed effects of
5-HT2,lc antagonists in amygdala and PAG in the
conflict and stimulation aversion models of anxiety.
These opposing effects are resolved by the suggestion that
5-HT systems are brought into play in conditioned anxiety
and restrain unconditioned flight responses.
We suggest that some of the drugs which precipitate
panic do so by removing the restraining influence of 5-HT
by their ability to activate autoreceptors; buspirone on
cell body autoreceptors, MCPP on terminal autoreceptors
and 5-HT re-uptake blockers on both somatic and terminal
autoreceptors. Suggestion that the drugs precipitate panic
by post-synaptic actions on 5-HT receptors are in-
compatible with the delayed therapeutic effect of selective
5-HT re-uptake blockers which progressively enhance
5-HT neurotransmission.
Chronic aversive stimuli
5-HT1A receptors and resilience
There is evidence that rats become tolerant or adapted
to aversive events onrepeated presentation such that the
310
immediate response becomes progressively attenuated.
Kennett, Dickinson and Curzon (1985) showed that
whereas a single 2 h episode of immobilization caused
marked decrements in rat locomotor activity measured
in an open field 24 h later, no abnormalities in open field
behaviour were seen after seven daily immobilizations.
This was associated with behavioural evidence of
enhancement of 5-HTIA-mediated neurotransmission.
Furthermore, the effects of a single immobilization stress
on subsequent open field behaviour were prevented by
a large dose of 8-OH-DPAT administered immediately
after immobilization (Kennett, Dourish and Curzon, 1987).
The authors attribute the latter effect to desensitization
of autoreceptors causing an enhancement of 5-HT
function during the open field test. However, it will be
argued that a direct action of 8-OH-DPAT on post-
synaptic hippocampal 5-HTIA receptors is also a plausible
mechanism.
Post-synaptic 5-HT lA receptors are localized in high
concentration in the hippocampus. This structure receives
a prominent innervation from the median raphe nucleus
(MRN) and caudally adjacent 5-HT neurones of the
midbrain raphe (B5, 6) which also innervate neocortex
and hypothalamus. These projections parallel nor-
adrenergic projections from the locus coeruleus and are
distinct from the innervation of dopaminergic structures
by the DRN and anteriorly placed 5-HT neurones of the
midbrain raphe (Azmitia and Segal, 1978; Imai, Steindler
and Kitai, 1986).
Deakin (1989) has suggested that MRN projections to
hippocampal 5-HTIA receptors mediate behavioural
adaptation to chronic aversive events. This, it is suggested,
corresponds to resilience in humans. According to this
view, impaired functioning in the MRN-hippo-
campal-5-HTIA system causes learned helplessness in
animals and depression in humans. Antidepressants work
by restoring 5-HT1A neurotransmission.
Does impaired 5-HT lA function
cause depression?
There is almost no direct evidence that hippocampal
5-HT1A neurotransmission is impaired in learned help-
lessness or depression. A careful study of 8-OH-DPAT-
displaceable 5-HT binding to samples of hippocampus
from the post-mortem brains of suicides reported re-
ductions which were related to the presence of depressive
illness (Cheetham et al., 1990). Reductions in 5-HT
binding in other sites have not been described although
some studies report increased 5-HT2 binding in frontal
cortex.
Several studies have shown that depression is associated
with a clear attenuation of pituitary release of prolactin
(PRL) and growth hormone (GH) following intravenous
infusions of tryptophan, the dietary precursor of 5-HT
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(see Deakin et al., 1990). There is evidence that these
responses involve a 5-HT, receptor link (Smith, Ware
and Cowan, 1991). Blunting of PRL responses to the
5-HT-releasing agent fenfluramine is also a fairly
consistent finding in depression (Asnis et al., 1988; Siever
et al., 1984; Coccaro et al., 1989). While the findings do
not identify the site of impairment-peripheral 5-HT
metabolism, pre-synaptic 5-HT neurones, the receptors
themselves or mechanisms beyond the receptor-this is
not crucial to the theory, which simply postulates
defective functional neurotransmission through systems
which involve 5-HT lA receptors.
In a group of 10 patients fully recovered from
depression and free of medication for months, blunted
PRL and GH responses to tryptophan had returned to
normal (Llpadhyaya et al., 1991). Thus, the abnormalities
of 5-HT neuroendocrine function in depression are likely
to be state-dependent and do not indicate persistent
vulnerability. This allows the possibility that impaired
5-HT1A neurotransmission causes depression but does
not exclude the reverse-that depression (e.g. via
anorexia) causes the neuroendocrine changes. Against the
latter possibility, however, is the evidence discussed below
that drugs which reverse the deficit of 5-HT, neuro-
transmission reverse depression.
Do antidepressants work by
enhancing 5-HT1A function?
Electrophysiological studies strongly suggest that all
effective antidepressants enhance functional 5-HT1A
neurotransmission in the hippocampus (Blier, De
Montigny and Chaput, 1987). In rats chronically treated
with tricyclic antidepressants, post-synaptic units become
more sensitive to iontophoretically applied 5-HT. This
could involve a direct enhancement of 5-HT1A receptor
function. Alternatively, antidepressants, through their
shared ability to block or down-regulate 5-HT2,lc receptor
function, could indirectly disinhibit 5-HT lA function
(Lakoski and Aghajanian, 1985; Deakin, 1989). In
contrast to tricyclics, selective 5-HT re-uptake blockers
lack direct effects on post-synaptic responsivity to 5-HT.
However, hippocampal units became more responsive to
stimulation of afferent projections from the raphe. This
suggests a gradual effect on 5-HT release mechanisms and
this may involve desensitization of autoreceptors. In
apparent contradiction to these findings, chronic
antidepressant treatment has been reported to reduce
behavioural responses evoked by administration of 8-OH-
DPAT (Goodwin, Desouza and Green, 1987). However,
it is unlikely that hippocampal 5-HTIA receptors mediate
the behavioural syndrome. Furthermore, the functional
change could be anywhere between receptor and response
and may reflect adaptation to use rather than mechanism
of action.

While antidepressants share the ability to enhance
5-HT1A receptor function and thus to reverse the putative
deficit in depression, the effects could still be incidental
to their antidepressant efficacy. However, a recent study
reported that acute depletion of circulating tryptophan
concentrations caused a temporary recrudescence of
symptoms in treated depressives (Delgado et al., 1990).
This suggests that actions on 5-HT function are central
to antidepressant efficacy. This is corroborated by the
antidepressant efficacy of direct 5-HTIA receptor agonists
such as buspirone and gepirone. That this may involve
actions on post-synaptic 5-HT1A receptors is suggested
by the finding in animals that 5-HT1A agonists remain
effective in reversing learned helplessness after denerva-
tion of 5-HT with neurotoxin lesions (Martin et al., 1990).
There would now appear to be reasonable grounds to
suspect that impaired 5-HT1A function causes depression
and that antidepressants work by reversing the deficit.
Resilience and the behavioural functions
of hippocampal 5-HT1A receptors
Deakin (1983) suggested that one function of MRN
projections to the hippocampus might be to disconnect
previously learned associations if these now lead to an
aversive outcome. Several studies have found that animals
depleted of 5-HT by PCPA or by selective neurotoxin
lesions, overrespond during extinction, habituation, latent
inhibition and discrimination reversal (reviewed in
Deakin, 1983). In all these behavioural paradigms,
animals normally cease responding when there is no
reinforced outcome. Some of the studies have indicated
that the MRN system may be specifically involved in this
disconnection mechanism (Deakin et al., 1979; Solomon,
Nichols and Caplan, 1980).
There is evidence that potentiating 5-HT neuro-
transmission may disrupt acquisition of new behaviours.
Administration of p-chloroamphetamine causes an acute
release of 5-HT and this has also been shown to have
disruptive effects on consolidation of new learning of
avoidance tasks (Ogren and Johannson, 1985). Recently,
administration of the selective 5-HT1A agonists 8-OH-
DPAT, buspirone and gepirone has been shown to exert
an anterograde interference with spatial learning and with
a simple step-down passive avoidance task (Rowan,
Cullen and Moulton, 1990; Winter and Petti, 1987;
Sanger and Joly, 1990; McEntee and Crook, 1991). These
studies suggest that stimulation of hippocampal 5-HTIA
receptors may interfere with new learning or consolida-
tion, especially when aversive events are involved.
In view of these precedents, the ability of 8-OH-DPAT
to prevent the effects of 2 h immobilization stress on open
field behaviour tested 24 h later (Kennet, Dourish and
Curzon, 1987) could involve a direct effect on post-
synaptic hippocampal 5-HT1A receptors which prevents
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311
or disrupts the neuronal associations which normally
mediate the stress effect. This would be analogous to post-
training disruption of consolidation in learning paradigms.
In the psychophysiological paradigm mentioned earlier
(Hensman et al., 1991) it was predicted that increasing
hippocampal 5-HT1A function using the direct receptor
agonist buspirone and the pre-synaptic agonist fluvox-
amine would accelerate habituation (disconnection) of
SCRs to neutral tones. Both drugs had the predicted
effect in groups of 10 volunteers although fluvoxamine
was only effective in males (Hellewell et al., 1989).
None of the foregoing experiments directly demon-
strated that 5-HTIA receptors in hippocampus disconnect
or disengage neuronal associations that underlie learning
and further work is needed to elucidate the effects.
Whatever the precise mechanism, the disengagement idea
seems allied to recent ideas on the role of the hippo-
campus in second order learning (Gaffan and Boulton,
1983; Frith and Frith, 1991) which suggest that an intact
hippocampus is necessary for animals to use cues as signs,
disengaged from any incentive or meaning of the cue itself
(e.g. a monkey learning that a carrot means choose the
black penny to get a food reward).
The relevance of this to coping with chronic aversion
may be that adaptation to chronic aversive stimuli occurs
by a kind of disengagement. If aversive cues become
progressively disconnected from some of their emotional
consequences with repeated presentation, there is
progressively less hindrance of other behaviours. In
human terms, such a mechanism might allow a woman
with an alcoholic husband who is sometimes violent to
continue her daily life, to laugh and joke with her friends,
to go to work and to look after the children despite the
continuous aversive conditioned stimulus of her husband.
This mechanism is analogous with the ego-defence
mechanism of denial which is said to be a mature or
normal defence. Depression in humans and learned
helplessness in animals would result when the 5-HTIA
protective mechanism is ineffective. The possible
mechanisms by which the putative hippocampal 5-HT1A
resilience system fails in depression will be discussed.
Three mechanisms of impaired 5-HT1A
function in depression
5-HT2 receptors inhibit 5-HT, neurotransmission
In earlier formulations of the 5-HT receptor imbalance
theory of affective disorder, a number of instances were
cited in which the 5-HT2 receptor family opposes 5-HTIA
receptor functioning (Backus, Sharp and Grahame-Smith,
1990; see Deakin, 1989). Thus, overactivity in DRN-
5-HT2,lc anxiety systems (due to environmental threats
or to endogenous dysregulation) may itself tend to
undermine 5-HTIA neurotransmission in the putative
312
resilience system. According to this mechanism, anxiety
is primary to, and at a lower level of dysfunction
than, depression; anxiety undermines resilience. Indeed,
depressive illnesses are often heralded by symptoms of
anxiety which often outlast the depression.
Hypercortisolaemia inhibits 5-HT, neurotransmission
Evidence from neuroendocrine studies in Manchester
suggests a second way in which impaired 5-HT1A receptor
functioning occurs in depression (Deakin et al., 1990).
Patients meeting DSM-III criteria for major depressive
disorder whose illnesses occurred in the setting of chronic
psychosocial stress were found to have 30% greater
resting plasma cortisol concentrations than other
depressives. Hypercortisolaemia was highly predictive of
blunted PRL responses to the 5-HT precursor tryptophan.
This result is strongly corroborated by studies which
incidentally report the association of hypercortisolaemia
and smaller PRL responses to fenfluramine challenge in
depressives (Mitchell and Smythe, 1990; Dinan and
O’Keane, 1990; Lerer et al., 1990; Lopez-Ibor, Sais-Ruis
and Inglesias, 1989). It was suggested that hyper-
cortisolaemia, perhaps acting on the high concentration of
steroid receptors in the hippocampus, might interfere with
the functioning of 5-HT1A receptors also concentrated in
the hippocampus (Deakin et al., 1990).
Several studies in animals indicate that chronic
treatment with corticosterone can interfere with the
expression of behaviours evoked by 5-HT1 receptor
agonists (Nausieda, Carver and Weiner, 1982; Buckett
and Luscombe, 1984; Dickinson, Kennett and Curzon,
1985). Furthermore, two studies suggest that the effects
of corticosteroids on 5-HT11 neurotransmission may
occur at the level of the receptor itself; adrenalectomy
increased hippocampal 5-HTIA receptor binding and
corticosterone replacement reduced it (Beigon, Rainbow
and McEwen, 1985; DeKloet, Sybesma and Reul, 1986).
These findings suggest that hypersecretion of cortisol in
depression may cause impaired hippocampal 5-HTIA
receptor functioning and we have already argued that the
latter causes depression. This mechanism may underlie
the vulnerability to depression associated with chronic
psychosocial stress.
Social isolation reduces 5-HT, neurotransmission
We conclude with the most speculative of the mechanisms
which may undermine hippocampal 5-HTIA neuro-
transmission and thus resilience. Sociological studies
of depression suggest that lack of social supports
predisposes to depression. A lack of confiding relation-
ships is thought to be an important ingredient (Brown
and Harris, 1978). Studies in animals suggest that contact
with conspecifics may have important effects on hippo-
campal 5-HTIA function. Popova and Petkov (1990)
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have recently reported that housing rats in isolation for
several weeks reduced hippocampal 5-HT1A receptor
binding. It is well known that socially isolated rats have
behavioural abnormalities such as muricidal behaviour
which are reversible with antidepressant drugs and social
isolation is a putative animal model of depression.
Dourish showed that the effects of a single immobiliza-
tion stress on open-field motility could be prevented not
only with an antidepressant and 8-OH-DPAT but also
by placing the rats into group housing after the
immobilization (Dourish et al., 1989). Thus group
housing mimicked the effects of an antidepressant and
of a 5-HT1A receptor agonist in reversing the effect of
immobilization stress. Handling and group housing may
be responsible for the increase in hippocampal 5-HTIA
(and not other) receptor binding reported in tamed wild
rats by Hammer et al. (1990). Whether the effects of
social contact on 5-HT function are mediated through
steroid or 5-HT2 receptor influences on 5-HT1 receptor
neurotransmission as discussed above or whether there
are more direct social influence on 5-HTIA systems is not
clear (see also Willner, 1989).
It will be important to know the modality by which
the effects of social contacts are transduced into changes
in 5-HT1A neurotransmission. Tactile (grooming) and
olfactory mechanisms are likely possibilities in the rat and
non-human primates. Grooming appears to be important
in the maintenance of dominance hierarchies in primates.
Subordinate baboons have chronically raised cortico-
steroid secretion (Sapolsky, 1989) and are less sensitive
to the behavioural effects of non-specific 5-HT agonist
treatments (Raleigh et al., 1985). The analogy
with, respectively, hypercortisolaemia and blunted 5-HT
neuroendocrine responsivity in depressives is evident.
Subordinance in non-human primates has obvious
affinity with low self-esteem in humans, a trait which is
thought to predispose to depressive illness. It has been
suggested that self-esteem is calibrated by degree of social
support and confiding relationships. Clearly there is
more to social support in humans than touch, but lack
of touch is likely to be highly correlated with lack of social
support. The evolution of higher cerebral mechanisms of
social cognition in humans has no doubt overridden or
elaborated upon the neurochemical mechanisms of social
behaviour which operate in other primates and in rodents.
Nevertheless, it remains an intriguing possibility that the
interface between social stimuli and 5-HT systems is an
important mechanism in the pathogenesis of depression
and in the mechanism of action of antidepressants.
Address for correspondence
J. F. W. Deakin
Department of Psychiatry

Rawnsley Building
Manchester Royal Infirmary
Oxford Road
Manchester M13 9WL
UK
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