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

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

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
availability.
Different
Ventral glutamate inputs to
BLA
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

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 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
Cortex
increased dopamine release in target
brain regions. Activation of dopamine- Drug-related cues Loss of
releasing neurons is important in drive behavior inhibitory control
BLA
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. (wanting
craving)
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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 Review
behavior owing to the loss of inhibitory control mechanisms. The
prefrontal cortex is responsible for cognitive functions related to
working memory and planning. Normally, descending projections
from the prefrontal cortex (to the nucleus accumbens, amygdala
and other brain regions) exert inhibitory control over reward-
seeking behaviors. Recent evidence, from both rat and human
studies, indicates that chronic cocaine exposure impairs these
inhibitory control mechanisms. Decreased inhibitory control,
combined with enhanced responsiveness to drug-related cues and
sensitization of “drug wanting”, may explain the compulsive
nature of drug-seeking behavior in addicts (7, 35, 37).
Does intensification of stimulus-reward associations reflect
LTP in pathways between BLA and nucleus accumbens? Does loss
of inhibitory control reflect LTD in pathways between prefrontal
cortex and its limbic targets? While it is not yet possible to answer
these questions, recent studies have made significant progress
towards characterizing LTP and LTD in reward-related brain
regions, including the prefrontal cortex (40, 41) and amygdala
(42). The remainder of this article will consider the role in
addiction of synaptic plasticity in the nucleus accumbens and the
VTA.
SYNAPTIC PLASTICITY IN THE NUCLEUS
ACCUMBENS
Both LTP and LTD are produced in the nucleus accumbens in
response to repetitive stimulation of projections from the
prefrontal cortex (43). LTP is also produced by repetitive
stimulation of hippocampal projections to the nucleus accumbens
(44). NMDA receptor activation is required for both LTP and LTD
in nucleus accumbens neurons (43, 45, 46). While LTP may be
modulated by dopamine, LTD is not affected by application of
dopamine (46). It is notable that the properties of LTP and LTD in
the nucleus acumbens (ventral striatum) differ from those in
dorsal striatum (8, 19), where these processes have been better
characterized (47).
Neurons in the nucleus accumbens are normally quiescent,
and their activation requires synchronous stimulation of multiple
excitatory inputs (38). Therefore, any drug-induced change that
either enhances or depresses their response to a particular input
will have a very significant influence on their activity. Recent
studies suggest that two kinds of changes may occur. First,
modulatory effects of stimulants (or dopamine itself) on LTP may
be altered after repeated drug administration. Li and Kauer
reported that the application of amphetamine blocked the
induction of LTP in nucleus accumbens slices prepared from
control rats, whereas amphetamine did not block LTP in slices
prepared from rats pretreated with amphetamine for six days (48).
A relative shift towards LTP that may be attributable to loss of D2
receptor-mediated inhibitory effects has also been reported in
striatal slices prepared from rats chronically treated with
methamphetamine or ethanol (49, 50). Thus, the response of
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nucleus accumbens or striatal neurons to drug challenge might be
different after repeated drug exposure because inhibitory
mechanisms are dampened. The second kind of change may
involve an alteration in the strength of particular synaptic
connections that long outlasts the period of drug administration.
For example, nucleus accumbens slices prepared from mice two
weeks after discontinuing repeated cocaine treatment exhibited
LTD at excitatory synapses between cortical afferents and nucleus
accumbens neurons (51). This observation is consistent with
previous work indicating that the nucleus accumbens is less
excitable after chronic stimulant exposure (19), and suggests that
decreases in the cortical regulation of nucleus accumbens neuronal
activity could be related to the loss of inhibitory control that is
implicated in addiction and thought to involve prefrontal cortex
dysfunction (37). Loss of inhibitory control at the level of the
prefrontal cortex may also contribute to the expression of
behavioral sensitization (7).
These are exciting findings; nonetheless, we are a long way
from understanding the relationship between LTP or LTD in a
particular pathway and a specific behavioral change in animal
models or human studies of addictive behavior. Part of the
difficulty is that we do not yet understand how dopamine and
glutamate work together to determine the output of nucleus
accumbens neurons under normal conditions (28, 52), let alone
after chronic drug administration. In contrast, we are closer to
understanding how plasticity in the VTA may contribute to
behavioral sensitization, an animal model of addiction.
GLUTAMATE AND BEHAVIORAL
SENSITIZATION
Behavioral sensitization refers to the progressive enhancement of
species-specific behavioral responses that occurs during repeated
drug administration and persists even after long periods of
withdrawal. Sensitization occurs in humans (53), but most studies
have focused on sensitization of locomotor activity in rodents.
There is compelling evidence that locomotor sensitization provides
a useful model for sensitization of drug craving. Both depend on
VTA dopamine neurons projecting to limbic and cortical regions
(Figure 1). Prior exposure to cocaine or amphetamine, resulting in
locomotor sensitization, promotes drug self-administration and
enhances stimulus-reward learning and responding for
conditioned reward (7). Finally, both sensitization in rats and drug
craving in humans are strongly modulated by environmental
stimuli, conditioning and stress (54, 55). Once established,
sensitization is very long-lasting—amphetamine sensitization can
last up to a year in rats, a species that lives only one or two years
(56)—and is accompanied by dramatic changes in addiction-
related neuronal circuits at molecular, cellular, and systems levels
(7, 57–59).
Robinson and Berridge have developed an incentive-
sensitization theory of addiction (60, 61) that remains one of the

most influential in the field. A key element of this theory is that
“liking” and “wanting” are produced by distinct neuronal
mechanisms, and it is “wanting” that intensifies with repeated drug
use. In other words, repeated drug exposure does not increase the
pleasure produced by a drug, but does increase craving. According
to this theory, addictive drugs produce long-lasting adaptations in
brain systems mediating incentive-motivational effects, leading to
sensitization of these systems to drugs and, importantly, to cues
that trigger pursuit of rewarding stimuli (62). Sensitization of
incentive-motivational effects would promote compulsive behavior,
perhaps by contributing to the enhanced stimulus-reward learning
discussed above in relation to projections from the amygdala to
the nucleus accumbens (Figure 2). In fact, although we will focus
on VTA below, the amygdala might also participate in the
induction of sensitization (57).
SYNAPTIC PLASTICITY IN THE VTA
The circuitry involved in sensitization is complex, because
sensitization represents a cascade of events involving different
brain regions and different transmitter systems at different
withdrawal times. However, microinjection studies have
established that the initiation of sensitization to cocaine or
amphetamine occurs in the VTA. Thus, direct injection of
amphetamine into the VTA has no acute effect on locomotor
activity, but repeated intra-VTA administration results in a
sensitized locomotor response to systemic injections of
amphetamine, cocaine, or morphine. In contrast, sensitization is
expressed in the nucleus accumbens, because direct injection of
amphetamine into nucleus accumbens is sufficient to elicit a
sensitized response in rats that received repeated systemic or intra-
VTA injections (57, 58).
The anatomical separation of sites for initiation and for
expression implies a “transfer” of sensitization from the VTA to the
nucleus accumbens, presumably as a result of changes in the firing
rate or pattern of dopamine neurons projecting from VTA to
nucleus accumbens. Indeed, the firing rate of VTA dopamine
neurons is increased for several days after discontinuing repeated
administration of cocaine or amphetamine. Firing rates then
normalize within a week or so. This transient activation of
dopamine-releasing neurons is believed to be a key step in the
development of long-lasting behavioral sensitization. The
mechanism underlying the activation may involve increased
glutamate transmission in the VTA during drug administration and
the early withdrawal period. This idea is consistent with studies
showing that the development of sensitization is prevented by
blocking glutamate transmission in the VTA, or by lesioning the
prefrontal cortex, which sends glutamate projections to the VTA
(57, 58).
One way to account for these findings is to propose that
repeated drug administration results in LTP at synapses between
glutamate nerve terminals and VTA dopamine neurons, leading to
Addiction and Neuronal Plasticity
a transient increase in the firing rate of dopamine neurons (57).
This, in turn, would increase dopamine release in the nucleus
accumbens and other addiction-related brain regions that are the
targets of dopamine projections (including prefrontal cortex,
amygdala and hippocampus). Drug-induced changes in dopamine
release may be one of the triggers for the persistent
electrophysiological and neurochemical changes observed in these
regions after discontinuing drug use (57, 58).
Once it has developed, LTP is expressed as an enhancement
of postsynaptic AMPA receptor transmission. Thus, if the initiation
of behavioral sensitization is associated with LTP at glutamate
synapses on VTA dopamine neurons, and if LTP is responsible for
transient activation of dopamine cell firing during early
withdrawal, then dopamine neurons in sensitized rats should
exhibit increased responsiveness to AMPA at early withdrawal
times, but not at later times. This prediction has been confirmed
in two ways. First, VTA dopamine neurons recorded from chronic
cocaine- or amphetamine-pretreated rats are more responsive to
the excitatory effects of AMPA (63). Second, intra-VTA
administration of AMPA produces a greater increase in nucleus
accumbens dopamine levels in rats previously treated with
amphetamine (64). The latter study suggests that the enhancement
of AMPA receptor transmission occurs in those VTA dopamine
neurons that project to the nucleus accumbens. In both studies,
no change in responsiveness to NMDA was observed and the
increased responsiveness to AMPA was evident in rats tested three
days after discontinuing drug administration but not at later times
when dopamine cell firing rates have normalized.
But can a drug regimen that produces sensitization in a whole
animal influence synaptic plasticity in the VTA? In prepared
midbrain slices from control mice and from mice injected the day
before with a single injection of saline or cocaine, the cocaine
treatment—which produces “one-shot” behavioral sensitization—
produced an enhancement of AMPA receptor transmission in VTA
dopamine neurons that was attributable to LTP (65). Cocaine-
induced LTP was observed in slices prepared five days, but not ten
days, after cocaine injection. Thus, cocaine-induced LTP is a
transient phenomenon, similar to the enhancement of AMPA
receptor transmission detected in vivo (63, 64). Furthermore, LTP
was blocked by an NMDA receptor antagonist, as was
sensitization. These findings argue strongly for linkage between
cocaine-induced LTP and sensitization.
How do dopamine-releasing psychomotor stimulants promote
LTP in the VTA? Amphetamine or dopamine, acting through D2
dopamine receptors, can block the induction of LTD in midbrain
dopamine neurons, through a mechanism that may involve
inhibition of high threshold calcium channels (46, 66). Inhibiting
LTD through cocaine-dependent stimulation of dopamine
receptors may increase neuronal excitability and thus promote LTP.
LTP may also be promoted by stimulant-induced increases in
glutamate levels in the VTA, although exactly how cocaine and
amphetamine modulate VTA glutamate levels is a matter of some
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 Review

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
LDT
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

152

Prefrontal
Cortex
Nucleus
Accumbens
Glutamate Ventral
GABA Tegmental Area
Dopamine (VTA)
cortex could be brought into the circuit later, after changes have
occurred in the pathway from LDT to VTA to nucleus accumbens,
through interconnections between these regions (Figure 1).
Figure 5. Dopamine regulates cell surface AMPA receptor expression.
Insertion and removal of AMPA receptors from synaptic sites is important
for LTP and LTD (16,17). In cultured nucleus accumbens neurons, D1
dopamine receptor stimulation increased the density of AMPA receptor
puncta on the cell surface, suggesting a mechanism by which dopamine
might influence LTP and LTD (83). Primary cultures were prepared from
nucleus accumbens of postnatal day one rats. AMPA receptors on the cell
surface were visualized by incubating live cells (twenty-one days in vitro)
with antibody that recognizes the extracellular portion of the AMPA
receptor subunit GluR1, fixing cultures, and then incubating with
fluorescent secondary antibody. To quantify GluR1 surface expression, a
standard length of neurite was defined using a circle 25 M in diameter
and the number of cell surface GluR1 puncta on a single neurite within
the circle was counted using MetaMorph Imaging software. Left panel:
Control conditions. Right panel: Incubation with the D1 agonist SKF
81297 (1 M, for fifteen minutes) increased the density of surface GluR1
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
receptor stimulation increased phosphorylation of GluR1 at the protein
kinase A site, suggesting another way that dopamine may influence basic
mechanisms of synaptic plasticity (81).
Addiction and Neuronal Plasticity
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
DA neurons. Mesoaccumbens
dopamine neurons also receive
glutamate and cholinergic inputs from
Laterodorsal the LDT (cholinergic inputs not
Tegmentum shown). See legend to Figure 3 for
(LDT) more details.
A cornerstone of the above hypotheses is that the induction
of sensitization is prevented by blocking NMDA receptors in the
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
minutes) co-activation of group I metabotropic and NMDA
glutamate receptors in the ventral midbrain produced a long-
lasting (greater than one hour) enhancement in the rhythmicity of
GABAergic inhibitory synaptic activity (78). This effect involved
direct electrical coupling of neurons through gap junctions (78), a
phenomenon that is altered by chronic amphetamine treatment in
other brain regions (79). A role for this mechanism in sensitization
would account for the fact that the development of sensitization is
inhibited by administration of either NMDA or metabotropic
glutamate receptor antagonists into the VTA (80). Alterations in
inhibitory tone, which controls basal firing characteristics of VTA
dopamine neurons, would be expected to have major effects on
the response of these neurons to excitatory inputs (29).
FUTURE DIRECTIONS
The demonstration that drugs of abuse alter LTP and LTD in
reward-related neuronal pathways is a very exciting development.
June 2002
Volume 2, Issue 3 153
 Review

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

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