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Addiction: Making the

Connection Between Behavioral

Changes and Neuronal Plasticity
in Specific Pathways

Photo by Jay Justice

here is an emerging consensus that drug addiction is a form of

The image evokes the

T maladaptive learning. Drugs of abuse usurp the neuronal circuitry
alluring yet sinister nature of involved in motivation and reward, leading to aberrant engagement
cocaine. By usurping
neuronal pathways normally of learning processes. As a result, drug-associated cues can trigger
involved in motivated
craving and compulsive drug-seeking behavior, and voluntary control
behavior, cocaine promotes
"learning" of compulsive over drug use is lost. Abused drugs can also modulate long-term
behavioral responses that
potentiation (LTP) and long-term depression (LTD) in neuronal
underlie drug craving and
addiction. circuits associated with the addiction process, suggesting a way for

the behavioral consequences of drug-taking to become reinforced by

learning mechanisms. This review will assess progress in correlating

these effects on LTP and LTD with behavioral changes in animal

models of addiction, particularly behavioral sensitization.

Marina E. Wolf
Department of Neuroscience, The Chicago Medical School,
3333 Green Bay Road
North Chicago, IL 60064-3095

Addiction and Neuronal Plasticity

INTRODUCTION dependent changes in the strength of interneuronal connections.

In LTP, brief repetitive activation of excitatory glutamate-
Cocaine and amphetamines enter the brain and interfere with the containing pathways (produced by high frequency stimulation, or
function of cell membrane transporters that normally remove tetanus) leads to an increase in the strength of glutamate synapses
dopamine and other monoamines (serotonin and norepinephrine) that lasts many hours in brain slices and even for weeks in intact
from the synapse after these transmitters are released. This animals (12, 13). Thus, a test stimulus applied to a pathway
interference produces a rapid elevation of dopamine levels that before the tetanus will produce a postsynaptic response of a
results in psychomotor stimulation: a feeling of being “high.” certain magnitude, whereas the same test stimulus applied to a
Although these interactions are becoming better understood, it pathway after tetanus will produce a larger response. Subsequent
remains a mystery how this initial elevation in dopamine levels studies showed that weaker patterns of stimulation produce an
leads, in some people, to a compulsive pattern of drug-seeking opposite change, termed long-term depression (LTD).
and drug-taking behavior. Even if abstinence is achieved, cocaine The cellular basis of LTP and LTD continues to be the focus
addicts remain vulnerable for years to episodes of craving and of intense investigation. In general, an N-methyl-D-aspartate
relapse triggered by stimuli previously associated with drugs (1, 2). (NMDA) receptor–mediated increase in postsynaptic calcium
This persistent vulnerability to drug-conditioned stimuli is also concentrations is required for the development of both LTD and
observed in animal models of addiction (3). LTP, with small increases in calcium preferentially activating
These features of addiction suggest that it may be an protein phosphatases and producing LTD, whereas larger increases
exceptionally powerful form of neuronal plasticity, which can be in calcium preferentially activate protein kinases and produce LTP
broadly defined as the ability of the nervous system to modify its (14). The expression of LTP involves enhanced transmission
response to a stimulus based on prior experience, and is believed through the -amino-3-hydroxy-5-methylisoxazole-4-propionate
to underlie learning and memory. Plasticity might also underlie (AMPA) receptor in the postsynaptic cell. Important mechanisms
addiction, because signaling through glutamate, the key contributing to the formation of LTP include phosphorylation of
neurotransmitter for producing and maintaining synaptic plasticity, the AMPA receptor and increased insertion of AMPA receptors at
is important for the formation of behavioral sensitization—a synaptic membranes, whereas AMPA receptor dephosphorylation
prominent animal model of addiction (4, 5). This role for and internalization may contribute to LTD (15, 16, 17).
glutamate receives further support from imaging studies of the LTP was first demonstrated in the hippocampus, a brain region
brains of human cocaine addicts: stimuli previously associated important for learning, which was part of the reason that LTP was
with drug use (e.g., drug paraphernalia) trigger intense drug speculated to underlie memory formation. However, many
craving, and at the same time, activate glutamate-rich neuronal investigators now question whether LTP plays a simple role in
circuits implicated in learning and memory (6). Animal studies learning and memory—particularly the kinds of complex associative
implicate the same glutamate-rich circuits, and suggest that the learning that contribute to drug-seeking behavior and relapse (18).
progression to addiction is a form of habit-based learning (7). Alternatively, LTP (and LTD) occur in many brain regions other than
Parallels between addiction and learning are reflected in the the hippocampus, suggesting that these phenomena represent
striking similarities between the signal transduction cascades and general mechanisms for altering synaptic strength in response to
molecular adaptations associated with both processes (8). For changes in synaptic use (regardless of whether this directly underlies
example, chronic administration of amphetamine or cocaine memory formation). We have hypothesized that drugs of abuse alter
produces dramatic changes in the morphology of dendritic spines LTP or LTD in neuronal pathways, by altering activity in networks
in addiction-related brain regions, which closely resemble those related to motivation and reward, or influence the ability of
associated with learning (9, 10). “normal” patterns of activity to produce appropriate forms of LTP
and LTD (19). Abnormal engagement of LTP or LTD may be the first
ADDICTION AND LONG-TERM step in the cascade leading to structural changes that underlie
POTENTIATION persistent modifications in brain function (20). Recent studies have
provided general support for this hypothesis, showing that drugs of
Learning and memory are thought to be encoded by changes in abuse can, in fact, modify or induce LTP and LTD in neuronal
the usage of interneuronal connections (11). In other words, pathways related to addiction.
synapses that experience frequent use will be strengthened, This review focuses on the challenging task of making
whereas those that receive less use are weakened. In this way, an connections between behavioral changes related to cocaine and
experience (which results in activation of pathways and increased amphetamine addiction and LTP or LTD in specific neuronal
synaptic “use”) may produce a long-lasting enhancement of circuits. After reviewing the neuronal circuits involved in drug
communication between neurons in those pathways (resulting in a action, we then consider how addiction may be related to changes
memory). For thirty years, long-term potentiation (LTP) has been in neuronal pathways converging in the nucleus accumbens. We
the most compelling model for studying the synaptic basis of use- know that these pathways are important for addiction, but we are

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just beginning to understand how drugs of abuse modify their release of dopamine in the brain, and because dopamine neurons
activity. Additionally, we will consider plasticity in the ventral participate in the elicitation of normal behaviors related to
tegmental area (VTA). Here, we are closer to making connections motivation and reward. Indeed, dopamine is readily integrated
between plasticity and specific changes in neuronal activity that into glutamate-based models for addiction because glutamate- and
contribute to an animal model for addiction, behavioral dopamine-containing pathways converge in many brain regions,
sensitization. including the nucleus accumbens (Figure 1). Thus, the same
nucleus accumbens neurons that receive limbic and cortical
NEURONAL PATHWAYS IMPORTANT IN glutamate inputs also receive dopamine inputs from the VTA (25).
ADDICTION Dopamine regulates interactions between glutamate inputs to
nucleus accumbens neurons (26, 27), both by directly influencing
The nucleus accumbens (also termed ventral striatum) plays a synaptic transmission and by modulating voltage-dependent
central role in the neuronal circuits that are responsible for conductance (28), in a manner complicated by the ability of the
motivated, goal-directed behaviors—in other words, the type of same glutamate inputs to influence dopamine transmission (29).
behaviors that underlie compulsive drug-seeking in cocaine VTA dopamine neurons also project to limbic and cortical regions
addicts (Figure 1). Goal-directed behaviors are produced by important for addiction, such as the prefrontal cortex and the
glutamate-containing projections that originate in limbic and amygdala. Dopamine transmission in these regions modulates the
cortical regions [most importantly, the basolateral amygdala (BLA), activity of addiction-related circuits (30) and is necessary for some
the hippocampus and the prefrontal cortex] and converge on a types of drug-seeking behavior (31, 32, 33).
common postsynaptic target: the medium spiny neuron of the
nucleus accumbens. The output of these nucleus accumbens NUCLEUS ACCUMBENS GLUTAMATE AND
neurons, conveyed through their projections to the ventral DRUG-SEEKING BEHAVIOR
pallidum and ventral mesencephalon, is responsible for motor
execution of these goal-directed behaviors. Thus, the nucleus Animal models have been used extensively to study the circuits
accumbens serves as an interface between limbic and motor and neurotransmitters involved in drug-seeking behavior. Rats
systems (21, 22), and ultimately, drug-seeking behavior depends learn to associate drug availability with a stimulus (such as a
on glutamate transmission in the nucleus accumbens (23, 24). flashing light or a particular environment), and will perform
Dopamine has long been the focus of addiction research conditioned behaviors that are related to drug seeking when
because cocaine and other stimulants act initially by increasing the presented subsequently with that stimulus. Rats can also learn to
self-administer drugs
Prefrontal Glutamate (e.g., by pressing a bar
Cortex GABA that delivers an
Dopamine intravenous drug
infusion) in response
Hippocampus Thalamus to a priming injection
of drug or a
conditioned stimulus
Nucleus that was previously
Accumbens associated with drug
Ventral glutamate inputs to
Pallidum nucleus accumbens
neurons have different
functions in drug-
VTA seeking behavior.
Behavioral Projections from the
Output BLA to the nucleus
Figure 1. The neural circuitry involved in drug addiction. The nucleus accumbens, an interface between limbic and motor accumbens are
systems, plays a central role in this circuitry. Goal-directed behaviors are elicited by glutamate projections from limbic and
important for learned
cortical regions to the nucleus accumbens, while projections from the nucleus accumbens to motor regions are responsible for
motor execution of these behaviors. Dopamine neurons located in the VTA innervate many limbic and cortical regions associations between
important for addiction, including nucleus accumbens and prefrontal cortex. Dopamine and glutamate inputs typically stimuli and drug
converge on common postsynaptic targets. BLA, basolateral amygdala; VTA, ventral tegmental area. [Based on (7).] reward, and for the

Addiction and Neuronal Plasticity

expression of motor behavior that is driven by motivationally unregulated manner than natural stimuli, because these drugs
relevant stimuli. These projections play a key role in drug-seeking interact with the dopamine transporter and interfere with the
behavior elicited by discrete cues that were previously paired with removal of dopamine from the synaptic cleft. Over the span of
drug exposure (34, 35). On the other hand, drug-seeking behavior several repeated drug exposures, compensatory changes occur in
triggered by injection of a low priming dose of cocaine does not dopamine-receptive neurons that presumably start a chain reaction
require the amygdala—perhaps because this involves a response to of events that ultimately influences basic mechanisms of synaptic
drug itself, rather than to a conditioned stimulus—but does plasticity. Possible mechanisms involved in this process have been
require a circuit that includes the VTA, prefrontal cortex, nucleus reviewed recently (19). The important point is that drugs of abuse
accumbens, and ventral pallidum (31, 34). The hippocampus may usurp normal learning mechanisms and thereby “cement”
be involved in conditioning to general contexts, such as a behavioral responses related to drug-seeking behavior. In some
particular cage or room environment previously associated with people, this progresses to a form of habit-based learning so strong
drug availability. The direct and indirect connections of the that it persists even in the face of tremendous adverse personal
hippocampus to the nucleus accumbens may enable such consequences (7).
contextual cues to influence drug-seeking behavior (36), although The behavioral changes that underlie the transition from drug
the role of the hippocampus in cue-elicited craving has been experimentation to compulsive drug-seeking behavior may be due
studied far less extensively than that of the amygdala. The to synaptic plasticity in the neuronal circuits depicted in Figure 1.
prefrontal cortex is implicated in executive control of behavioral Based on what is known about the role of particular pathways in
output based on stimulus value and expected outcome, and plays drug-seeking behavior, we can speculate about how plasticity in
an important role in animal models of addiction (37). Excitatory particular pathways might contribute to various aspects of
inputs from the prefrontal cortex, BLA, and hippocampus are addiction (Figure 2). For example, strengthening the synaptic
integrated by dopamine to determine the net level of excitatory connections between the amygdala and the nucleus accumbens
output to neurons in the nucleus accumbens (26, 38). may underlie the abnormally strong stimulus-reward learning that
occurs in addiction, enabling drug-associated cues to elicit craving
WHAT UNDERLIES THE TRANSITION TO and relapse even after long periods of abstinence. This increase in
ADDICTION? conditioned control of behavior may be enhanced by sensitization
of brain systems to the incentive-motivational effects of drugs, an
The dopamine neurons that participate in motivation and reward effect that may underlie the transition from “wanting” to “craving”,
have their cell bodies in the VTA and project to a number of and at least initially, may involve LTP in VTA dopamine neurons.
limbic and cortical brain regions, including the nucleus Another important change may involve an increase in impulsive
accumbens. These dopamine neurons
are activated by natural, rewarding Prefrontal
stimuli such as food or sex, resulting in
increased dopamine release in target
brain regions. Activation of dopamine- Drug-related cues Loss of
releasing neurons is important in drive behavior inhibitory control
predicting the likelihood of reward when
an animal is presented with reward-
related stimuli (39). Thus, one normal Nucleus Compulsive
function of dopamine may be to help Accumbens drug-seeking and
consolidate stimulus-response learning, drug-taking behavior
so individuals acquire the habit of
pursuing those stimuli that are both
VTA Sensitization
rewarding and necessary for survival. (wantingcraving)
If the same neuronal circuits are
Figure 2. Possible relationships between neuronal plasticity in particular pathways and behavioral
involved in responding for “good changes that lead to addiction. Several types of behavioral changes may contribute to compulsive drug-
rewards” such as food or sex, and “bad seeking and drug-taking behavior in addicts. Alterations in transmission between the BLA and the
rewards” such as cocaine, why is it that nucleus accumbens may strengthen stimulus-reward learning, increasing the ability of drug-related cues
cocaine, but usually not food or sex, to control behavior. Sensitization of the incentive-motivational effects of drugs, due to alterations in
transmission between the VTA and the nucleus accumbens, may transform drug “wanting” to “craving”.
leads to addiction? The answer is
Alterations in transmission between the prefrontal cortex and limbic targets, including nucleus
probably related to the fact that cocaine accumbens, may lead to impairment of inhibitory control mechanisms that normally govern reward-
and amphetamines increase dopamine seeking behavior. Ultimately, drug-seeking behavior depends on glutamate transmission in the nucleus
release in a more prolonged and accumbens. BLA, basolateral amygdala; VTA, ventral tegmental area. [Based on (37).]

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behavior owing to the loss of inhibitory control mechanisms. The nucleus accumbens or striatal neurons to drug challenge might be
prefrontal cortex is responsible for cognitive functions related to different after repeated drug exposure because inhibitory
working memory and planning. Normally, descending projections mechanisms are dampened. The second kind of change may
from the prefrontal cortex (to the nucleus accumbens, amygdala involve an alteration in the strength of particular synaptic
and other brain regions) exert inhibitory control over reward- connections that long outlasts the period of drug administration.
seeking behaviors. Recent evidence, from both rat and human For example, nucleus accumbens slices prepared from mice two
studies, indicates that chronic cocaine exposure impairs these weeks after discontinuing repeated cocaine treatment exhibited
inhibitory control mechanisms. Decreased inhibitory control, LTD at excitatory synapses between cortical afferents and nucleus
combined with enhanced responsiveness to drug-related cues and accumbens neurons (51). This observation is consistent with
sensitization of “drug wanting”, may explain the compulsive previous work indicating that the nucleus accumbens is less
nature of drug-seeking behavior in addicts (7, 35, 37). excitable after chronic stimulant exposure (19), and suggests that
Does intensification of stimulus-reward associations reflect decreases in the cortical regulation of nucleus accumbens neuronal
LTP in pathways between BLA and nucleus accumbens? Does loss activity could be related to the loss of inhibitory control that is
of inhibitory control reflect LTD in pathways between prefrontal implicated in addiction and thought to involve prefrontal cortex
cortex and its limbic targets? While it is not yet possible to answer dysfunction (37). Loss of inhibitory control at the level of the
these questions, recent studies have made significant progress prefrontal cortex may also contribute to the expression of
towards characterizing LTP and LTD in reward-related brain behavioral sensitization (7).
regions, including the prefrontal cortex (40, 41) and amygdala These are exciting findings; nonetheless, we are a long way
(42). The remainder of this article will consider the role in from understanding the relationship between LTP or LTD in a
addiction of synaptic plasticity in the nucleus accumbens and the particular pathway and a specific behavioral change in animal
VTA. models or human studies of addictive behavior. Part of the
difficulty is that we do not yet understand how dopamine and
SYNAPTIC PLASTICITY IN THE NUCLEUS glutamate work together to determine the output of nucleus
ACCUMBENS accumbens neurons under normal conditions (28, 52), let alone
after chronic drug administration. In contrast, we are closer to
Both LTP and LTD are produced in the nucleus accumbens in understanding how plasticity in the VTA may contribute to
response to repetitive stimulation of projections from the behavioral sensitization, an animal model of addiction.
prefrontal cortex (43). LTP is also produced by repetitive
stimulation of hippocampal projections to the nucleus accumbens GLUTAMATE AND BEHAVIORAL
(44). NMDA receptor activation is required for both LTP and LTD SENSITIZATION
in nucleus accumbens neurons (43, 45, 46). While LTP may be
modulated by dopamine, LTD is not affected by application of Behavioral sensitization refers to the progressive enhancement of
dopamine (46). It is notable that the properties of LTP and LTD in species-specific behavioral responses that occurs during repeated
the nucleus acumbens (ventral striatum) differ from those in drug administration and persists even after long periods of
dorsal striatum (8, 19), where these processes have been better withdrawal. Sensitization occurs in humans (53), but most studies
characterized (47). have focused on sensitization of locomotor activity in rodents.
Neurons in the nucleus accumbens are normally quiescent, There is compelling evidence that locomotor sensitization provides
and their activation requires synchronous stimulation of multiple a useful model for sensitization of drug craving. Both depend on
excitatory inputs (38). Therefore, any drug-induced change that VTA dopamine neurons projecting to limbic and cortical regions
either enhances or depresses their response to a particular input (Figure 1). Prior exposure to cocaine or amphetamine, resulting in
will have a very significant influence on their activity. Recent locomotor sensitization, promotes drug self-administration and
studies suggest that two kinds of changes may occur. First, enhances stimulus-reward learning and responding for
modulatory effects of stimulants (or dopamine itself) on LTP may conditioned reward (7). Finally, both sensitization in rats and drug
be altered after repeated drug administration. Li and Kauer craving in humans are strongly modulated by environmental
reported that the application of amphetamine blocked the stimuli, conditioning and stress (54, 55). Once established,
induction of LTP in nucleus accumbens slices prepared from sensitization is very long-lasting—amphetamine sensitization can
control rats, whereas amphetamine did not block LTP in slices last up to a year in rats, a species that lives only one or two years
prepared from rats pretreated with amphetamine for six days (48). (56)—and is accompanied by dramatic changes in addiction-
A relative shift towards LTP that may be attributable to loss of D2 related neuronal circuits at molecular, cellular, and systems levels
receptor-mediated inhibitory effects has also been reported in (7, 57–59).
striatal slices prepared from rats chronically treated with Robinson and Berridge have developed an incentive-
methamphetamine or ethanol (49, 50). Thus, the response of sensitization theory of addiction (60, 61) that remains one of the

Addiction and Neuronal Plasticity

most influential in the field. A key element of this theory is that a transient increase in the firing rate of dopamine neurons (57).
“liking” and “wanting” are produced by distinct neuronal This, in turn, would increase dopamine release in the nucleus
mechanisms, and it is “wanting” that intensifies with repeated drug accumbens and other addiction-related brain regions that are the
use. In other words, repeated drug exposure does not increase the targets of dopamine projections (including prefrontal cortex,
pleasure produced by a drug, but does increase craving. According amygdala and hippocampus). Drug-induced changes in dopamine
to this theory, addictive drugs produce long-lasting adaptations in release may be one of the triggers for the persistent
brain systems mediating incentive-motivational effects, leading to electrophysiological and neurochemical changes observed in these
sensitization of these systems to drugs and, importantly, to cues regions after discontinuing drug use (57, 58).
that trigger pursuit of rewarding stimuli (62). Sensitization of Once it has developed, LTP is expressed as an enhancement
incentive-motivational effects would promote compulsive behavior, of postsynaptic AMPA receptor transmission. Thus, if the initiation
perhaps by contributing to the enhanced stimulus-reward learning of behavioral sensitization is associated with LTP at glutamate
discussed above in relation to projections from the amygdala to synapses on VTA dopamine neurons, and if LTP is responsible for
the nucleus accumbens (Figure 2). In fact, although we will focus transient activation of dopamine cell firing during early
on VTA below, the amygdala might also participate in the withdrawal, then dopamine neurons in sensitized rats should
induction of sensitization (57). exhibit increased responsiveness to AMPA at early withdrawal
times, but not at later times. This prediction has been confirmed
SYNAPTIC PLASTICITY IN THE VTA in two ways. First, VTA dopamine neurons recorded from chronic
cocaine- or amphetamine-pretreated rats are more responsive to
The circuitry involved in sensitization is complex, because the excitatory effects of AMPA (63). Second, intra-VTA
sensitization represents a cascade of events involving different administration of AMPA produces a greater increase in nucleus
brain regions and different transmitter systems at different accumbens dopamine levels in rats previously treated with
withdrawal times. However, microinjection studies have amphetamine (64). The latter study suggests that the enhancement
established that the initiation of sensitization to cocaine or of AMPA receptor transmission occurs in those VTA dopamine
amphetamine occurs in the VTA. Thus, direct injection of neurons that project to the nucleus accumbens. In both studies,
amphetamine into the VTA has no acute effect on locomotor no change in responsiveness to NMDA was observed and the
activity, but repeated intra-VTA administration results in a increased responsiveness to AMPA was evident in rats tested three
sensitized locomotor response to systemic injections of days after discontinuing drug administration but not at later times
amphetamine, cocaine, or morphine. In contrast, sensitization is when dopamine cell firing rates have normalized.
expressed in the nucleus accumbens, because direct injection of But can a drug regimen that produces sensitization in a whole
amphetamine into nucleus accumbens is sufficient to elicit a animal influence synaptic plasticity in the VTA? In prepared
sensitized response in rats that received repeated systemic or intra- midbrain slices from control mice and from mice injected the day
VTA injections (57, 58). before with a single injection of saline or cocaine, the cocaine
The anatomical separation of sites for initiation and for treatment—which produces “one-shot” behavioral sensitization—
expression implies a “transfer” of sensitization from the VTA to the produced an enhancement of AMPA receptor transmission in VTA
nucleus accumbens, presumably as a result of changes in the firing dopamine neurons that was attributable to LTP (65). Cocaine-
rate or pattern of dopamine neurons projecting from VTA to induced LTP was observed in slices prepared five days, but not ten
nucleus accumbens. Indeed, the firing rate of VTA dopamine days, after cocaine injection. Thus, cocaine-induced LTP is a
neurons is increased for several days after discontinuing repeated transient phenomenon, similar to the enhancement of AMPA
administration of cocaine or amphetamine. Firing rates then receptor transmission detected in vivo (63, 64). Furthermore, LTP
normalize within a week or so. This transient activation of was blocked by an NMDA receptor antagonist, as was
dopamine-releasing neurons is believed to be a key step in the sensitization. These findings argue strongly for linkage between
development of long-lasting behavioral sensitization. The cocaine-induced LTP and sensitization.
mechanism underlying the activation may involve increased How do dopamine-releasing psychomotor stimulants promote
glutamate transmission in the VTA during drug administration and LTP in the VTA? Amphetamine or dopamine, acting through D2
the early withdrawal period. This idea is consistent with studies dopamine receptors, can block the induction of LTD in midbrain
showing that the development of sensitization is prevented by dopamine neurons, through a mechanism that may involve
blocking glutamate transmission in the VTA, or by lesioning the inhibition of high threshold calcium channels (46, 66). Inhibiting
prefrontal cortex, which sends glutamate projections to the VTA LTD through cocaine-dependent stimulation of dopamine
(57, 58). receptors may increase neuronal excitability and thus promote LTP.
One way to account for these findings is to propose that LTP may also be promoted by stimulant-induced increases in
repeated drug administration results in LTP at synapses between glutamate levels in the VTA, although exactly how cocaine and
glutamate nerve terminals and VTA dopamine neurons, leading to amphetamine modulate VTA glutamate levels is a matter of some

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debate (19). Dopamine receptor stimulation may also increase the Glutamate
excitability of midbrain dopamine neurons by reducing inhibitory Prefrontal GABA
effects of metabotropic glutamate receptors (67).
Cortex Dopamine
Based on results summarized above, a model for the initiation
of sensitization in the VTA should include: 1) a role for LTP
induction in VTA dopamine neurons, 2) a key role for VTA
dopamine neurons projecting to the nucleus accumbens, and 3) a
necessary role for prefrontal cortex (recall that lesions of prefrontal
cortex prevent the development of sensitization). The simplest
solution would be to propose that the LTP leading to sensitization
occurs at synapses between prefrontal cortex terminals and VTA
dopamine neurons projecting to nucleus accumbens. Nucleus
Unfortunately, this hypothesis is not consistent with recent Accumbens
anatomical findings. Sesack and colleagues have shown that
prefrontal cortex neurons do not make excitatory synapses on VTA
dopamine-releasing VTA neurons that project to the nucleus
accumbens; however, they do synapse on -aminobutyric acid
(GABA)-releasing VTA neurons that project to the nucleus
accumbens. Conversely, prefrontal cortex neurons synapse on VTA
dopamine neurons, but not on VTA GABA neurons, that project
back to the prefrontal cortex (68) (Figure 3). Neurochemical 1
findings are consistent with this anatomical arrangement (69). 2
An alternative hypothesis is that the LTP important for
sensitization occurs at synapses between prefrontal cortex neurons
and VTA dopamine neurons projecting to the prefrontal cortex
(site 1 in Figure 3), consistent with evidence for a direct excitatory
link between these populations. In this model, changes in
prefrontal cortex occur first, and then trigger longer-lived changes
in the nucleus accumbens through the many interconnections that
exist between the two regions (Figure 1). Indeed, the prefrontal Figure 3. Possible sites for LTP in the ventral tegmental area during
cortex is necessary for cocaine-induced adaptations occurring in the induction of behavioral sensitization. The VTA contains dopamine
the nucleus accumbens (70), and there is evidence for changes in neurons that project to nucleus accumbens (mesoaccumbens dopamine
both glutamate and dopamine transmission in the prefrontal neurons) and dopamine neurons that project to prefrontal cortex
(mesoprefrontal dopamine neurons). Likewise, the VTA contains
cortex shortly after discontinuing repeated cocaine or
mesoaccumbens GABA neurons and mesoprefrontal GABA neurons. VTA
amphetamine administration (7). However, this proposed site for dopamine and GABA neurons also innervate other brain regions not
LTP (site 1 in Figure 3) is not consistent with evidence that AMPA shown in the diagram. Glutamate projections from the prefrontal cortex
receptor transmission is enhanced in those VTA dopamine neurons synapse on mesoaccumbens GABA neurons but not mesoaccumbens DA
that project to nucleus accumbens (64). neurons, and on mesoprefrontal DA neurons but not mesoprefrontal GABA
neurons (68). Some evidence suggests that prefrontal cortex also
Another possibility is that VTA dopamine neurons projecting to
communicates with mesoaccumbens dopamine neurons indirectly, via
nucleus accumbens are excited by glutamate (and cholinergic) projections to the LDT. The LDT sends both glutamate and cholinergic
projections from the laterodorsal tegmentum (LDT) and neighboring projections to mesoaccumbens dopamine neurons (71). The cholinergic
mesopontine nuclei (71). Thus, the LTP important for initiating fibers are not shown in the diagram. Based on this anatomy and other
sensitization might occur at synapses between the LDT and VTA evidence, two possible sites are proposed for cocaine-induced LTP leading
to the initiation of behavioral sensitization. Site 1: Excitatory synapses
dopamine neurons projecting to nucleus accumbens (site 2 in Figure
between prefrontal cortical projections and mesoprefrontal dopamine
3). Although promising, this hypothesis raises questions about how neurons. Site 2: Excitatory synapses between LDT projections and
the prefrontal cortex is brought into the circuit. The prefrontal cortex mesoaccumbens dopamine neurons. VTA, ventral tegmental area; LDT,
projects to the LDT, and it has been proposed that this indirect route laterodorsal tegmentum. [Based on (68).]
to the VTA enables the prefrontal cortex to exert excitatory effects on
midbrain dopamine neurons (72). This hypothesis is consistent with even this indirect route is not consistent with all findings, as a recent
experiments showing that the prefrontal cortex activates VTA study showed that stimulation of the prefrontal cortex at
dopamine neurons through polysynaptic pathways rather than physiologically relevant frequencies actually inhibits dopamine
through a direct monosynaptic projection (73) (Figure 4). However, release in the nucleus accumbens (74). Of course, the prefrontal

Addiction and Neuronal Plasticity

Cortex Figure 4. Addiction-related
pathways in the rat brain. The VTA
contains both dopamine and GABA
neurons that innervate the nucleus
accumbens, prefrontal cortex, and
other forebrain targets not shown in
the diagram. The prefrontal cortex
sends glutamate projections to VTA,
LDT, nucleus accumbens, and other
limbic regions not shown in the
diagram (see Figure 1). In the VTA,
glutamate inputs from prefrontal
cortex synapse on mesoaccumbens
GABA neurons and mesoprefrontal
Nucleus DA neurons. Mesoaccumbens
Accumbens dopamine neurons also receive
glutamate and cholinergic inputs from
Glutamate Ventral Laterodorsal the LDT (cholinergic inputs not
GABA Tegmental Area Tegmentum shown). See legend to Figure 3 for
Dopamine (VTA) (LDT) more details.

cortex could be brought into the circuit later, after changes have A cornerstone of the above hypotheses is that the induction
occurred in the pathway from LDT to VTA to nucleus accumbens, of sensitization is prevented by blocking NMDA receptors in the
through interconnections between these regions (Figure 1). VTA, which also prevents the induction of LTP by systemic
cocaine (65), but it is possible that the two are not linked. An
alternative possibility is that the important effect of NMDA
receptor blockade in the VTA is to alter the activity of VTA GABA
neurons that project locally as well as to the nucleus accumbens
and other forebrain regions (57, 75). Unlike dopamine neurons,
GABA neurons of the VTA do not exhibit LTP under normal
conditions (76) or after cocaine treatment (65). While VTA GABA
neurons can exhibit LTD (66), effects of cocaine on this process
have yet to be examined. Nevertheless, there is evidence that the
activity of these GABA neurons is altered by repeated drug
administration. For example, GABAB receptor transmission in the
VTA is enhanced after withdrawal from amphetamine and other
drugs (77). Another exciting finding is that brief (two or three
Figure 5. Dopamine regulates cell surface AMPA receptor expression.
Insertion and removal of AMPA receptors from synaptic sites is important minutes) co-activation of group I metabotropic and NMDA
for LTP and LTD (16,17). In cultured nucleus accumbens neurons, D1 glutamate receptors in the ventral midbrain produced a long-
dopamine receptor stimulation increased the density of AMPA receptor lasting (greater than one hour) enhancement in the rhythmicity of
puncta on the cell surface, suggesting a mechanism by which dopamine GABAergic inhibitory synaptic activity (78). This effect involved
might influence LTP and LTD (83). Primary cultures were prepared from
direct electrical coupling of neurons through gap junctions (78), a
nucleus accumbens of postnatal day one rats. AMPA receptors on the cell
surface were visualized by incubating live cells (twenty-one days in vitro) phenomenon that is altered by chronic amphetamine treatment in
with antibody that recognizes the extracellular portion of the AMPA other brain regions (79). A role for this mechanism in sensitization
receptor subunit GluR1, fixing cultures, and then incubating with would account for the fact that the development of sensitization is
fluorescent secondary antibody. To quantify GluR1 surface expression, a inhibited by administration of either NMDA or metabotropic
standard length of neurite was defined using a circle 25 M in diameter
glutamate receptor antagonists into the VTA (80). Alterations in
and the number of cell surface GluR1 puncta on a single neurite within
the circle was counted using MetaMorph Imaging software. Left panel: inhibitory tone, which controls basal firing characteristics of VTA
Control conditions. Right panel: Incubation with the D1 agonist SKF dopamine neurons, would be expected to have major effects on
81297 (1 M, for fifteen minutes) increased the density of surface GluR1 the response of these neurons to excitatory inputs (29).
puncta. Nucleus accumbens interneurons are shown in these pictures, but
the same results were obtained for medium spiny neurons, the projection
neurons of the nucleus accumbens (83). In the same culture system, D1 FUTURE DIRECTIONS
receptor stimulation increased phosphorylation of GluR1 at the protein
kinase A site, suggesting another way that dopamine may influence basic The demonstration that drugs of abuse alter LTP and LTD in
mechanisms of synaptic plasticity (81). reward-related neuronal pathways is a very exciting development.

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Volume 2, Issue 3 153

The next challenge is to study LTP and LTD in the context of cocaine or amphetamine administration—to influence synaptic
animal models of drug seeking and relapse. Another challenge is events underlying LTP and LTD. But, can drug-induced changes in
to understand how drugs of abuse influence the cellular LTP and LTD account for the persistence of addiction? Based on
mechanisms governing synaptic plasticity. Two mechanisms that studies in the hippocampus, a model has been proposed in which
contribute to LTP are phosphorylation of AMPA receptors, which LTP and LTD trigger a series of sequential changes that lead to
increases their activity, and insertion of new AMPA receptors into alterations in the biochemical composition of the postsynaptic
synaptic sites (15, 17). Signaling through the D1 dopamine membrane, and ultimately to changes in the structure of dendritic
receptor may influence both processes. For example, in neurons of spines (20). By tapping into LTP and LTD, drugs of abuse could
the nucleus accumbens, acute stimulation of D1 dopamine influence these fundamental processes, accounting for the very
receptors increases the phosphorylation of AMPA receptors (81), long-lasting changes in brain structure and function that underlie
and there are compensatory changes in AMPA receptor addiction, which include changes in dendritic spines in the
phosphorylation in striatal neurons after chronic cocaine nucleus accumbens and prefrontal cortex (9, 10). It is also
administration (82). D1 dopamine receptors may also regulate important to look beyond LTP and LTD, as drugs may produce
AMPA receptor surface expression. For example, an increase in the neuroplasticity by regulating GABA-mediated inhibition in
density of AMPA receptor surface clusters on nucleus accumbens addition to glutamate-mediated excitation (77). Examining
neurons was observed after brief exposure to a D1 receptor agonist plasticity in neuronal circuits regulated by GABA is particularly
(83) (Figure 5). This exciting finding suggests a new mechanism important in light of recent work, which suggests that GABA-
that may enable dopamine receptors—when stimulated during based drugs may be useful for treating addiction (84).

References Res. 562, 164–168 (1991). 11. Cajal, S.R. “Histologie du Systeme
1. Gawin, F.H. and Kleber, H.D. Nerveux de L’Homme et des Vertebrès,”
6. Bonson, K.R., Grant, S.J., Contoreggi,
Abstinence symptomatology and Vol. II (Paris: Maloine), p. 993 (1911).
C.S., Links, M.J., Metcalfe, J., Weyl,
psychiatric diagnosis in cocaine H.L., Kurian, V., Ernst, M., and 12. Bliss, T.V.P. and Lømo, T. Long-lasting
abusers. Clinical observations. Arch. London, E.D. Neural systems and cue- potentiation of synaptic transmission in
Gen. Psychiatry 43, 107–113 (1986). induced cocaine craving. the dentate area of the anaesthetized
2. Ehrman, R.N., Robbins, S.J., Childress, Neuropsychopharmacol. 26, 376–386 rabbit following stimulation of the
A.R., and O’Brien, C.P. Conditioned (2002). perforant path. J. Physiol. 232,
responses to cocaine-related stimuli in 331–356 (1973).
7. Everitt, B.J. and Wolf, M.E.
cocaine abuse patients.
Psychomotor stimulant addiction: A 13. Bliss, T.V.P. and Gardner-Medwin, A.R.
Psychopharmacol. 107, 523–529
neural systems perspective. J. Long-lasting potentiation of synaptic
Neurosci.22, 3312–3320 (2002). transmission in the dentate area of the
3. Ciccocioppo, R., Sanna, P.P., and Weiss, unanaesthetized rabbit following
8. Hyman, S.E. and Malenka, R.C.
F. Cocaine-predictive stimulus induces stimulation of the perforant path. J.
Addiction and the brain: The
drug-seeking behavior and neural Physiol. 232, 357–374 (1973).
neurobiology of compulsion and its
activation in limbic brain regions after
multiple months of abstinence: persistence. Nat. Rev. Neurosci. 2, 14. Malenka, R.C. Synaptic plasticity in the
Reversal by D1 antagonists. Proc. Natl. 695–703 (2001). hippocampus: LTP and LTD. Cell 78,
Acad. Sci. U.S.A. 98, 1976–1981 535–538 (1994).
9. Robinson, T.E. and Kolb, B. Persistent
(2001). structural modifications in nucleus 15. Lee, H.-K., Barbarosie, M., Kameyama,
4. Karler, R., Calder, L.D., Chaudhry, I.A., accumbens and prefrontal cortex K., Bear, M.F., and Huganir, R.L.
and Turkanis, S.A. Blockade of “reverse neurons produced by previous Regulation of distinct AMPA receptor
tolerance” to cocaine and amphetamine experience with amphetamine. J. phosphorylation sites during
by MK-801. Life Sci. 45, 599–606 Neurosci. 17, 8491–8497 (1997). bidirectional synaptic plasticity. Nature
(1989). 405, 955–959 (2000).
10. Robinson, T.E., Gorny, G., Mitton, E.,
5. Wolf, M.E. and Khansa, M.R. Repeated and Kolb, B. Cocaine self- 16. Carroll, R.C., Beattie, E.C., von
administration of MK-801 produces administration alters the morphology of Zastrow, M., and Malenka, R.C. Role of
sensitization to its own locomotor dendrites and dendritic spines in the AMPA receptor endocytosis in synaptic
stimulant effects but blocks nucleus accumbens and neocortex. plasticity. Nat. Rev. Neurosci. 2,
sensitization to amphetamine. Brain Synapse 39, 257–266 (2001). 315–324 (2001).

Addiction and Neuronal Plasticity

17. Sheng, M. and Lee, S.H. AMPA 25. Floresco, S.B., Blaha, C.D., Yang, C.R. (2001).
receptor trafficking and the control of and Phillips, A.G. Modulation of
33. Grimm, J.W. and See, R.E. Dissociation
synaptic transmission. Cell 105, hippocampal and amygdalar-evoked
of primary and secondary reward-
825–828 (2001). activity of nucleus accumbens neurons
relevant limbic nuclei in an animal
by dopamine: Cellular mechanisms of
18. Martin, S.J., Grimwood, P.D., and model of relapse.
input selection. J. Neurosci. 21,
Morris, R.G.M. Synaptic plasticity and Neuropsychopharmacology 22, 473–479
2851–2860 (2001).
memory: An evaluation of the (2000).
hypothesis. Annu. Rev. Neurosci. 23, 26. Floresco, S.B., Blaha, C.D., Yang, C.R.,
34. Everitt, B.J., Dickinson, A.D., and
649–711 (2000). and Phillips, A.G. Dopamine D1 and
Robbins, T.W. The neuropsychological
NMDA receptors mediate potentiation
19. Wolf, M.E. Addiction and glutamate- basis of addictive behaviour. Brain Res.
of basolateral amygdala-evoked firing
dependent plasticity, in Glutamate and Rev. 36, 129–138 (2001).
of nucleus accumbens neurons. J.
Addiction (Herman, B.H., Frankenheim,
Neurosci. 21, 6370–7376 (2001). 35. Vorel, S.R., Liu, X., Hayes, R.J., Spector,
J., Litten, R., Sheridan, P.H., Weight, J.A., and Gardner E.L. Relapse to
F.F. and Zukin, S.R. eds), The Humana 27. Nicola, S.M., Surmeier, D.J., and
cocaine-seeking after hippocampal
Press, Inc. (in press). Malenka, R.C. Dopaminergic
theta burst stimulation. Science 292,
modulation of neuronal excitability in
20. Lüscher, C., Nicoll, R.A., Malenka, 1175–1178 (2001).
the striatum and nucleus accumbens.
R.C., and Muller, D. Synaptic plasticity Annu. Rev. Neurosci. 232, 185–215 36. Jentsch, J.D. and Taylor, J.R.
and dynamic modulation of the (2000). Impulsivity resulting from frontostriatal
postsynaptic membrane. Nat. Neurosci. dysfunction in drug abuse: Implications
3, 545–550 (2000). 28. Floresco, S.B., Todd, C.L. and Grace,
for the control of behavior by reward-
A.A. Glutamatergic afferents from the
21. Kelley, A.E. Neural integrative activities related stimuli. Psychopharmacology
hippocampus to the nucleus
of nucleus accumbens subregions in 146, 373–390 (1999).
accumbens regulate activity of ventral
relation to learning and motivation. tegmental area dopamine neurons. J. 37. O’Donnell, P. and Grace, A.A. Synaptic
Psychobiology 27, 198–213 (1999). Neurosci. 21, 4915–4922 (2001). interactions among excitatory afferents
22. Groenewegen, H.J., Wright, C.I., Beijer, to nucleus accumbens neurons:
29. Rosenkranz, J.A. and Grace, A.A.
A.V., and Voorn, P. Convergence and Hippocampal gating of prefrontal
Dopamine attenuates prefrontal cortical
segregation of ventral striatal inputs cortical input. J. Neurosci. 15,
suppression of sensory inputs to the
and outputs. Ann. N.Y. Acad. Sci. 877, 3622–3639 (1995).
basolateral amygdala of rats. J. Neurosci.
49–64 (1999). 21, 4090–4103 (2001). 38. Schultz, W. and Dickinson, A.
22. Cornish, J.L. and Kalivas, P.W. Neuronal coding of prediction errors.
30. McFarland, K. and Kalivas, P.W. The
Glutamate transmission in the nucleus Annu. Rev. Neurosci. 21, 473–500
circuitry mediating cocaine-induced
accumbens mediates relapse in cocaine (2000).
reinstatement of drug-seeking behavior.
addiction. J. Neurosci. 20, RC89 (2000). J. Neurosci. 21, 8655–8663 (2001). 39. Otani, S., Auclair, N., Desce, J.-M.,
23. Di Ciano, P., Cardinal, R.N., Cowell, Roisin, M.-P., and Crépel, F. Dopamine
31. Ciccocioppo, R., Sanna, P.P., and Weiss,
R.A., Little, S.J., and Everitt B.J. receptors and groups I and II mGluRs
F. Cocaine-predictive stimulus induces
cooperate for long-term depression
Differential involvement of NMDA, drug-seeking behavior and neural
induction in rat prefrontal cortex
AMPA/kainate, and dopamine receptors activation in limbic brain regions after
through converging postsynaptic
in the nucleus accumbens core in the multiple months of abstinence:
activation of MAP kinases. J. Neurosci.
acquisition and performance of Reversal by D1 antagonists. Proc. Natl.
19, 9788–9802 (1999).
Pavlovian approach behavior. J. Acad. Sci. U.S.A. 98, 1976–1981
Neurosci. 21, 9471–9477 (2001). (2001). 40. Gurden, H., Takita, M. and Jay, T.M.
Essential role of D1 but not D2
24. Sesack, S.R. and Pickel, V.M. Prefrontal 32. See, R.E., Kruzich, P.J., and Grimm,
receptors in the NMDA receptor-
cortical efferents in the rat synapse on J.W. Dopamine, but not glutamate,
dependent long-term potentiation at
unlabeled neuronal targets of receptor blockade in the basolateral
hippocampal-prefrontal cortex synapses
catecholamine terminals in the nucleus amygdala attenuates conditioned
in vivo. J. Neurosci. 20, RC106 (2000).
accumbens septi and on dopamine reward in a rat model of relapse to
neurons in the ventral tegmental area. cocaine-seeking behavior. 41. Maren, S. Long-term potentiation in
J. Comp. Neurol. 320, 145–160 (1992). Psychopharmacology 154, 301–310 the amygdala: A mechanism for

June 2002
Volume 2, Issue 3 155

emotional learning and memory. Trends sensitized rats. Neurosci. Lett. 268, glutamatergic transmission in the
Neurosci. 22, 561–567 (1999). 81–84 (1999). induction and expression of behavioral
sensitization: A critical review of
42. Pennartz, C.M.A., Ameerun, R.F., 50. Thomas, M.F., Beurrier, C., Bonci, A.,
preclinical studies. Psychopharmacology
Groenewegen, H.J., and Lopes da Silva, and Malenka, R. Long-term depression
151, 99–120 (2000).
F.H. Synaptic plasticity in an in vitro in the nucleus accumbens: A neural
slice preparation of the rat nucleus correlate of behavioral sensitization to 58. Nestler, E.J. Molecular basis of long-
accumbens. Eur. J. Neurosci. 5, 107–117 cocaine. Nat. Neurosci. 4, 1217–1223 term plasticity underlying addiction.
(1993). (2001). Nat. Rev. Neurosci. 2, 119–128 (2001).

43. Boeijinga, P.H., Mulder, A.B., Pennartz, 51. West, A.R. and Grace, A.A. Opposite 59. Robinson, T.E. and Berridge, K.C. The
C.M.A., Manshanden, I., and Lopes da influences of endogenous D1 and D2 neural basis of drug craving: An
Silva, F.H. Responses of the nucleus receptor activation on activity states incentive-sensitization theory of
accumbens following fornix/fimbria and electrophysiological properties of addiction. Brain Res. Rev. 18, 247–291
stimulation in the rat. Identification striatal neurons: Studies combining in (1993).
and long-term potentiation of mono- vivo intracellular recordings and
60. Robinson, T.E. and Berridge, K.C. The
and polysynaptic pathways. reverse microdialysis. J. Neurosci. 22,
psychology and neurobiology of
Neuroscience 53, 1049–1058 (1993). 294–304 (2002).
addiction: An incentive-sensitization
44. Kombian, S.B. and Malenka, R.C. 52. Strakowski, S.M. and Sax, K.W., view. Addiction 95, S91–S117 (2000).
Simultaneous LTP of non-NMDA- and Progressive behavioral response to
61. Wyvell, C.L. and Berridge, K.C.
LTD of NMDA-receptor-mediated repeated d-amphetamine challenge:
Incentive sensitization by previous
responses in the nucleus accumbens. Further evidence for sensitization in
amphetamine exposure: Increased cue-
Nature 368, 242–246 (1994). humans. Biol. Psych. 44, 1171–1177
triggered “wanting” for sucrose reward.
45. Thomas, M.J., Malenka, R.C., and J. Neurosci. 21, 7831–7840 (2001).
Bonci, A. Modulation of long-term 53. Robinson, T.E., Browman, K.E.,
62. Zhang, X.-F., Hu, X.-T., White, F.J., and
depression by dopamine in the Crombag, H.S., and Badiani, A.
Wolf, M.E. Increased responsiveness of
mesolimbic system. J. Neurosci. 20, Modulation of the induction or
ventral tegmental area dopamine
5581–5586 (2000). expression of psychostimulant
neurons to glutamate after repeated
sensitization by the circumstances
46. Calabresi, P., Centonze, D., Gubellini, administration of cocaine or
surrounding drug administration.
P., Marfia, G.A., Pisani, A., Sancesario, amphetamine is transient and
Neurosci. Biobehav. Rev. 22, 347–354
G., and Bernardi, G. Synaptic selectively involves AMPA receptors. J.
transmission in the striatum: From Pharmacol. Exp. Ther. 281, 699–706
plasticity to neurodegeneration. Prog. 54. Shaham, Y., Erb, S., and Stewart, J. (1997).
Neurobiol. 61, 231–265 (2000). Stress-induced relapse to heroin and
63. Giorgetti, M., Hotsenpiller, G., Ward,
cocaine seeking in rats: A review. Brain
47. Li, Y. and Kauer, J. Effects of P., Teppen, T., and Wolf, M.E.
Res. Rev. 33, 13–33 (2000).
amphetamine on long-term Amphetamine-induced plasticity of
potentiation in the nucleus accumbens. 55. Paulson, P.E., Camp, D.M., and AMPA receptors in the ventral
Soc. Neurosci. Abstr. 26, 1398 (2000). Robinson, T.E. The time course of tegmental area: Effects on extracellular
transient behavioral depression and levels of dopamine and glutamate in
48. Yamamoto, Y., Nakanishi, H., Takai, N.,
persistent behavioral sensitization in freely moving rats. J. Neurosci. 21,
Shimazoe, T., Watanabe, S., and Kita,
relation to regional monoamine 6362–6369 (2001).
H. Expression of N-methyl-D-aspartate
concentrations during amphetamine
receptor-dependent long-term 64. Ungless, M.A., Whistler, J.L., Malenka,
withdrawal in rats. Psychopharmacol.
potentiation in the neostriatal neurons R.C., and Bonci, A. Single cocaine
103, 480–492 (1991).
in an in vitro slice after ethanol exposure in vivo induces long-term
withdrawal of the rat. Neuroscience 91, 56. Wolf, M.E. The role of excitatory amino potentiation in dopamine neurons.
59–68 (1999). acids in behavioral sensitization to Nature 411, 583–587 (2001).
psychomotor stimulants. Prog.
49. Nishioku, T., Shimazoe, T., Yamamoto, 65. Jones, S., Kornblum, J.L., and Kauer,
Neurobiol. 54, 679–720 (1998).
Y., Nakanishi, H., and Watanabe, S. J.A. Amphetamine blocks long-term
Expression of long-term potentiation of 57. Vanderschuren, L.J. and Kalivas, P.W. synaptic depression in the ventral
the striatum in methamphetamine- Alterations in dopaminergic and tegmental area. J. Neurosci. 20,

Addiction and Neuronal Plasticity

5575–5580 (2000). prefrontal cortex at physiologically Greengard, P. Effects of chronic

relevant frequencies inhibits dopamine exposure to cocaine are regulated by
66. Paladini, C.A., Fiorillo, C.D.,
release in the nucleus accumbens. J. the neuronal protein Cdk5. Nature
Morikawa, H., and Williams, J.T.
Neurochem. 78, 920–923 (2001). 410, 376–380 (2001).
Amphetamine selectively blocks
inhibitory glutamate transmission in 74. Cornish, J.L., Nakamura, M., and 82. Chao, S.Z., Peterson, D.A., and Wolf,
dopamine neurons. Nat. Neurosci. 4, Kalivas, P.W. Dopamine-independent M.E. Dopamine and glutamate
275–281 (2001). locomotion following blockade of N- receptors regulate surface expression of
methyl-D-aspartate receptors in the GluR1 in postnatal nucleus accumbens
67. Carr, D.B. and Sesack, S.R. Projections
ventral tegmental area. J. Pharmacol. cultures. Soc. Neurosci. Abstr. 26, 789
from the rat prefrontal cortex to the
Exp. Ther. 298, 226–233 (2001). (2000).
ventral tegmental area: Target
specificity in the synaptic associations 75. Bonci, A. and Malenka, R.C. Properties 83. Dewey, S.L., Morgan, A.E., Ashby Jr.,
with mesoaccumbens and mesocortical and plasticity of excitatory synapses on C.R., Horan, B., Kushner, S.A., Logan,
neurons. J. Neurosci. 20, 3864–3873 dopaminergic and GABAergic cells in J., Volkow, N.D., Fowler, J.S., Gardner,
(2000). the ventral tegmental area. J. Neurosci. E.L. and Brodie, J.D. A novel strategy
19, 3723–3730 (1999). for the treatment of cocaine addiction.
68. Takahata, R. and Moghaddam, B.
Synapse 30, 119–129 (1998).
Target-specific glutamatergic regulation 76. Giorgetti, M., Hotsenpiller, G., Froestl,
of dopamine neurons in the ventral W., and Wolf, M.E. In vivo modulation
tegmental area. J. Neurochem. 75, of ventral tegmental area dopamine and
1775–1778 (2000). glutamate efflux by local GABAB
receptors is altered after repeated
69. Li, Y., Hu, X.-T., Berney, T.G.,
amphetamine treatment. Neuroscience
Vartanian, A.J., Stine, C., Wolf, M.E.,
109, 585–595 (2002).
and White, F.J. Both glutamate receptor
antagonists and prefrontal cortex 77. Beretta, N., Paolucci, E., Bernardi, G.,
lesions prevent the induction of and Mercuri, N.B. Glutamate receptor
cocaine sensitization and associated stimulation induces a persistent
neuroadaptations. Synapse 34,169–180 rhythmicity of the GABAergic inputs to
(1999). rat midbrain dopaminergiic neurons.
Eur. J. Neurosci. 14, 777–784 (2001).
70. Forster, G.L. and Blaha, C.D.
Laterodorsal tegmental stimulation 78. Onn, S.P. and Grace, A.A.
elicits dopamine efflux in the rat Amphetamine withdrawal alters
nucleus accumbens by activation of bistable states and cellular coupling in
acetylcholine and glutamate receptors rat prefrontal cortex and nucleus
in the ventral tegmental area. Eur. J. accumbens neurons recorded in vivo. J. Marina E. Wolf, PhD, is a Professor and is
Neurosci. 12, 3596–3604 (2000). Neurosci. 20, 2332–2345 (2000). the acting-chair in the Department of
Neuroscience at the Finch University of
71. Lokwan, S.J.A., Overton, P.G., Berry, 79. Kim, J.-H. and Vezina, P. Metabotropic
Health Sciences, Chicago Medical School.
M.S., and Clark, D. Stimulation of the glutamate receptors are necessary for
Please address correspondence to MEW. E-
pedunculopontine tegmental nucleus in sensitization by amphetamine.
mail:; Fax
the rat produces burst firing in A9 Neuroreport 9, 403–306 (1998).
dopaminergic neurons. Neuroscience 92,
80. Chao, S.Z., Lu, W., Lee, H.-K., Huganir,
245–254 (1999).
R.L., and Wolf, M.E. D1 dopamine
72. Tong, Z.-Y., Overton, P.G., and Clark, receptor stimulation increases GluR1
D. Stimulation of the prefrontal cortex phosphorylation in postnatal nucleus
in the rat induces patterns of activity in accumbens cultures. J. Neurochem., in
midbrain dopaminergic neurons which press (2002).
resemble natural burst events. Synapse
81. Bibb, J.A., Chen, J., Taylor, J.R.,
22, 195–208 (1996).
Svenningsson, P., Nishi, A., Snyder,
73. Jackson, M.E., Frost, A.S. and G.L., Yan, Z., Sagawa, Z.K., Ouimet,
Moghaddam, B. Stimulation of C.C., Nairn, A.C., Nestler, E.J., and

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