Vous êtes sur la page 1sur 12

Photo by Jay Justice

Addiction: Making the

Connection Between Behavioral Changes and Neuronal Plasticity in Specific Pathways

The image evokes the alluring yet sinister nature of cocaine. By usurping neuronal pathways normally involved in motivated behavior, cocaine promotes "learning" of compulsive behavioral responses that underlie drug craving and addiction.

T here is an emerging consensus that drug addiction is a form of maladaptive learning. Drugs of abuse usurp the neuronal circuitry

involved in motivation and reward, leading to aberrant engagement of learning processes. As a result, drug-associated cues can trigger craving and compulsive drug-seeking behavior, and voluntary control over drug use is lost. Abused drugs can also modulate long-term potentiation (LTP) and long-term depression (LTD) in neuronal 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.

146

of addiction, particularly behavioral sensitization. 146 Marina E. Wolf Department of Neuroscience, The Chicago

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

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

Addiction and Neuronal Plasticity

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-

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

June 2002

Volume 2, Issue 3

147

148

Review

just beginning to understand how drugs of abuse modify their activity. Additionally, we will consider plasticity in the ventral tegmental area (VTA). Here, we are closer to making connections between plasticity and specific changes in neuronal activity that contribute to an animal model for addiction, behavioral sensitization.

NEURONAL PATHWAYS IMPORTANT IN ADDICTION

The nucleus accumbens (also termed ventral striatum) plays a central role in the neuronal circuits that are responsible for motivated, goal-directed behaviors—in other words, the type of behaviors that underlie compulsive drug-seeking in cocaine addicts (Figure 1). Goal-directed behaviors are produced by glutamate-containing projections that originate in limbic and cortical regions [most importantly, the basolateral amygdala (BLA), the hippocampus and the prefrontal cortex] and converge on a common postsynaptic target: the medium spiny neuron of the nucleus accumbens. The output of these nucleus accumbens neurons, conveyed through their projections to the ventral pallidum and ventral mesencephalon, is responsible for motor execution of these goal-directed behaviors. Thus, the nucleus accumbens serves as an interface between limbic and motor systems (21, 22), and ultimately, drug-seeking behavior depends on glutamate transmission in the nucleus accumbens (23, 24). Dopamine has long been the focus of addiction research because cocaine and other stimulants act initially by increasing the

release of dopamine in the brain, and because dopamine neurons participate in the elicitation of normal behaviors related to motivation and reward. Indeed, dopamine is readily integrated into glutamate-based models for addiction because glutamate- and dopamine-containing pathways converge in many brain regions, including the nucleus accumbens (Figure 1). Thus, the same nucleus accumbens neurons that receive limbic and cortical glutamate inputs also receive dopamine inputs from the VTA (25). Dopamine regulates interactions between glutamate inputs to nucleus accumbens neurons (26, 27), both by directly influencing synaptic transmission and by modulating voltage-dependent conductance (28), in a manner complicated by the ability of the same glutamate inputs to influence dopamine transmission (29). VTA dopamine neurons also project to limbic and cortical regions important for addiction, such as the prefrontal cortex and the amygdala. Dopamine transmission in these regions modulates the activity of addiction-related circuits (30) and is necessary for some types of drug-seeking behavior (31, 32, 33).

NUCLEUS ACCUMBENS GLUTAMATE AND DRUG-SEEKING BEHAVIOR

Animal models have been used extensively to study the circuits and neurotransmitters involved in drug-seeking behavior. Rats learn to associate drug availability with a stimulus (such as a flashing light or a particular environment), and will perform conditioned behaviors that are related to drug seeking when

presented subsequently with that stimulus. Rats can also learn to self-administer drugs

Glutamate

GABA

Dopamine

(e.g., by pressing a bar that delivers an intravenous drug infusion) in response to a priming injection of drug or a conditioned stimulus that was previously associated with drug availability. Different glutamate inputs to nucleus accumbens neurons have different functions in drug- seeking behavior. Projections from the BLA to the nucleus accumbens are important for learned associations between stimuli and drug reward, and for the

Prefrontal Cortex Hippocampus Thalamus Nucleus Accumbens Ventral BLA Pallidum VTA Behavioral Output
Prefrontal
Cortex
Hippocampus
Thalamus
Nucleus
Accumbens
Ventral
BLA
Pallidum
VTA
Behavioral
Output

Figure 1. The neural circuitry involved in drug addiction. The nucleus accumbens, an interface between limbic and motor systems, plays a central role in this circuitry. Goal-directed behaviors are elicited by glutamate projections from limbic and 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 important for addiction, including nucleus accumbens and prefrontal cortex. Dopamine and glutamate inputs typically converge on common postsynaptic targets. BLA, basolateral amygdala; VTA, ventral tegmental area. [Based on (7).]

converge on common postsynaptic targets. BLA, basolateral amygdala; VTA, ventral tegmental area. [Based on (7) .]
converge on common postsynaptic targets. BLA, basolateral amygdala; VTA, ventral tegmental area. [Based on (7) .]
converge on common postsynaptic targets. BLA, basolateral amygdala; VTA, ventral tegmental area. [Based on (7) .]
converge on common postsynaptic targets. BLA, basolateral amygdala; VTA, ventral tegmental area. [Based on (7) .]

Addiction and Neuronal Plasticity

expression of motor behavior that is driven by motivationally relevant stimuli. These projections play a key role in drug-seeking behavior elicited by discrete cues that were previously paired with drug exposure (34, 35). On the other hand, drug-seeking behavior triggered by injection of a low priming dose of cocaine does not require the amygdala—perhaps because this involves a response to drug itself, rather than to a conditioned stimulus—but does require a circuit that includes the VTA, prefrontal cortex, nucleus accumbens, and ventral pallidum (31, 34). The hippocampus may be involved in conditioning to general contexts, such as a particular cage or room environment previously associated with drug availability. The direct and indirect connections of the hippocampus to the nucleus accumbens may enable such contextual cues to influence drug-seeking behavior (36), although the role of the hippocampus in cue-elicited craving has been studied far less extensively than that of the amygdala. The prefrontal cortex is implicated in executive control of behavioral output based on stimulus value and expected outcome, and plays an important role in animal models of addiction (37). Excitatory inputs from the prefrontal cortex, BLA, and hippocampus are integrated by dopamine to determine the net level of excitatory output to neurons in the nucleus accumbens (26, 38).

WHAT UNDERLIES THE TRANSITION TO ADDICTION?

The dopamine neurons that participate in motivation and reward have their cell bodies in the VTA and project to a number of limbic and cortical brain regions, including the nucleus accumbens. These dopamine neurons are activated by natural, rewarding stimuli such as food or sex, resulting in increased dopamine release in target

brain regions. Activation of dopamine- releasing neurons is important in predicting the likelihood of reward when an animal is presented with reward- related stimuli (39). Thus, one normal function of dopamine may be to help consolidate stimulus-response learning, so individuals acquire the habit of pursuing those stimuli that are both rewarding and necessary for survival. If the same neuronal circuits are involved in responding for “good rewards” such as food or sex, and “bad rewards” such as cocaine, why is it that cocaine, but usually not food or sex, leads to addiction? The answer is probably related to the fact that cocaine and amphetamines increase dopamine release in a more prolonged and

unregulated manner than natural stimuli, because these drugs interact with the dopamine transporter and interfere with the removal of dopamine from the synaptic cleft. Over the span of several repeated drug exposures, compensatory changes occur in dopamine-receptive neurons that presumably start a chain reaction of events that ultimately influences basic mechanisms of synaptic plasticity. Possible mechanisms involved in this process have been reviewed recently (19). The important point is that drugs of abuse usurp normal learning mechanisms and thereby “cement” behavioral responses related to drug-seeking behavior. In some people, this progresses to a form of habit-based learning so strong that it persists even in the face of tremendous adverse personal consequences (7). The behavioral changes that underlie the transition from drug experimentation to compulsive drug-seeking behavior may be due to synaptic plasticity in the neuronal circuits depicted in Figure 1. Based on what is known about the role of particular pathways in drug-seeking behavior, we can speculate about how plasticity in particular pathways might contribute to various aspects of addiction (Figure 2). For example, strengthening the synaptic connections between the amygdala and the nucleus accumbens may underlie the abnormally strong stimulus-reward learning that occurs in addiction, enabling drug-associated cues to elicit craving and relapse even after long periods of abstinence. This increase in conditioned control of behavior may be enhanced by sensitization of brain systems to the incentive-motivational effects of drugs, an effect that may underlie the transition from “wanting” to “craving”, and at least initially, may involve LTP in VTA dopamine neurons. Another important change may involve an increase in impulsive

Prefrontal Cortex Drug-related cues Loss of drive behavior inhibitory control BLA Nucleus Accumbens VTA
Prefrontal
Cortex
Drug-related cues
Loss of
drive behavior
inhibitory control
BLA
Nucleus
Accumbens
VTA
Sensitization
(wanting craving)

Compulsive drug-seeking and drug-taking behavior

Figure 2. Possible relationships between neuronal plasticity in particular pathways and behavioral changes that lead to addiction. Several types of behavioral changes may contribute to compulsive drug- seeking and drug-taking behavior in addicts. Alterations in transmission between the BLA and the nucleus accumbens may strengthen stimulus-reward learning, increasing the ability of drug-related cues 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”. Alterations in transmission between the prefrontal cortex and limbic targets, including nucleus accumbens, may lead to impairment of inhibitory control mechanisms that normally govern reward- seeking behavior. Ultimately, drug-seeking behavior depends on glutamate transmission in the nucleus accumbens. BLA, basolateral amygdala; VTA, ventral tegmental area. [Based on (37).]

June 2002

Volume 2, Issue 3

149

150

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

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, 5759). Robinson and Berridge have developed an incentive- sensitization theory of addiction (60, 61) that remains one of the

Robinson and Berridge have developed an incentive- sensitization theory of addiction (60 , 61) that remains
Robinson and Berridge have developed an incentive- sensitization theory of addiction (60 , 61) that remains
Robinson and Berridge have developed an incentive- sensitization theory of addiction (60 , 61) that remains
Robinson and Berridge have developed an incentive- sensitization theory of addiction (60 , 61) that remains

Addiction and Neuronal Plasticity

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

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

June 2002

Volume 2, Issue 3

151

152

Review

debate (19). Dopamine receptor stimulation may also increase the excitability of midbrain dopamine neurons by reducing inhibitory effects of metabotropic glutamate receptors (67). 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. Unfortunately, this hypothesis is not consistent with recent anatomical findings. Sesack and colleagues have shown that prefrontal cortex neurons do not make excitatory synapses on 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 findings are consistent with this anatomical arrangement (69). 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 cortex is necessary for cocaine-induced adaptations occurring in the nucleus accumbens (70), and there is evidence for changes in both glutamate and dopamine transmission in the prefrontal cortex shortly after discontinuing repeated cocaine or amphetamine administration (7). However, this proposed site for LTP (site 1 in Figure 3) is not consistent with evidence that AMPA receptor transmission is enhanced in those VTA dopamine neurons that project to nucleus accumbens (64). Another possibility is that VTA dopamine neurons projecting to nucleus accumbens are excited by glutamate (and cholinergic) projections from the laterodorsal tegmentum (LDT) and neighboring mesopontine nuclei (71). Thus, the LTP important for initiating sensitization might occur at synapses between the LDT and VTA dopamine neurons projecting to nucleus accumbens (site 2 in Figure 3). Although promising, this hypothesis raises questions about how the prefrontal cortex is brought into the circuit. The prefrontal cortex projects to the LDT, and it has been proposed that this indirect route to the VTA enables the prefrontal cortex to exert excitatory effects on midbrain dopamine neurons (72). This hypothesis is consistent with experiments showing that the prefrontal cortex activates VTA dopamine neurons through polysynaptic pathways rather than through a direct monosynaptic projection (73) (Figure 4). However,

Glutamate GABA Prefrontal Dopamine Cortex Nucleus Accumbens VTA 1 2 LDT
Glutamate
GABA
Prefrontal
Dopamine
Cortex
Nucleus
Accumbens
VTA
1
2
LDT

Figure 3. Possible sites for LTP in the ventral tegmental area during the induction of behavioral sensitization. The VTA contains dopamine neurons that project to nucleus accumbens (mesoaccumbens dopamine neurons) and dopamine neurons that project to prefrontal cortex (mesoprefrontal dopamine neurons). Likewise, the VTA contains mesoaccumbens GABA neurons and mesoprefrontal GABA neurons. VTA dopamine and GABA neurons also innervate other brain regions not shown in the diagram. Glutamate projections from the prefrontal cortex synapse on mesoaccumbens GABA neurons but not mesoaccumbens DA neurons, and on mesoprefrontal DA neurons but not mesoprefrontal GABA neurons (68). Some evidence suggests that prefrontal cortex also communicates with mesoaccumbens dopamine neurons indirectly, via projections to the LDT. The LDT sends both glutamate and cholinergic projections to mesoaccumbens dopamine neurons (71). The cholinergic fibers are not shown in the diagram. Based on this anatomy and other evidence, two possible sites are proposed for cocaine-induced LTP leading to the initiation of behavioral sensitization. Site 1: Excitatory synapses between prefrontal cortical projections and mesoprefrontal dopamine neurons. Site 2: Excitatory synapses between LDT projections and mesoaccumbens dopamine neurons. VTA, ventral tegmental area; LDT, laterodorsal tegmentum. [Based on (68).]

even this indirect route is not consistent with all findings, as a recent study showed that stimulation of the prefrontal cortex at physiologically relevant frequencies actually inhibits dopamine release in the nucleus accumbens (74). Of course, the prefrontal

relevant frequencies actually inhibits dopamine release in the nucleus accumbens (74) . Of course, the prefrontal
relevant frequencies actually inhibits dopamine release in the nucleus accumbens (74) . Of course, the prefrontal
relevant frequencies actually inhibits dopamine release in the nucleus accumbens (74) . Of course, the prefrontal
relevant frequencies actually inhibits dopamine release in the nucleus accumbens (74) . Of course, the prefrontal

Addiction and Neuronal Plasticity

Prefrontal

Cortex Nucleus Accumbens Glutamate Ventral Laterodorsal GABA Tegmental Area Tegmentum Dopamine (VTA) (LDT)
Cortex
Nucleus
Accumbens
Glutamate
Ventral
Laterodorsal
GABA
Tegmental Area
Tegmentum
Dopamine
(VTA)
(LDT)

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 the LDT (cholinergic inputs not shown). See legend to Figure 3 for more details.

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).

through interconnections between these regions (Figure 1). Figure 5. Dopamine regulates cell surface AMPA receptor

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).

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, GABA B 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

154

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).

based drugs may be useful for treating addiction (84) . References 1. Gawin, F.H. and Kleber,

References

1.

Gawin, F.H. and Kleber, H.D. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations. Arch. Gen. Psychiatry 43, 107–113 (1986).

2.

Ehrman, R.N., Robbins, S.J., Childress, A.R., and O’Brien, C.P. Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacol. 107, 523–529

(1992).

3.

Ciccocioppo, R., Sanna, P.P., and Weiss, F. Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence:

Reversal by D1 antagonists. Proc. Natl. Acad. Sci. U.S.A. 98, 1976–1981

(2001).

4.

Karler, R., Calder, L.D., Chaudhry, I.A., and Turkanis, S.A. Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801. Life Sci. 45, 599–606

(1989).

5.

Wolf, M.E. and Khansa, M.R. Repeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine. Brain

Res. 562, 164–168 (1991).

6. Bonson, K.R., Grant, S.J., Contoreggi, C.S., Links, M.J., Metcalfe, J., Weyl, H.L., Kurian, V., Ernst, M., and London, E.D. Neural systems and cue- induced cocaine craving. Neuropsychopharmacol. 26, 376–386

(2002).

7. Everitt, B.J. and Wolf, M.E. Psychomotor stimulant addiction: A neural systems perspective. J. Neurosci.22, 3312–3320 (2002).

8. Hyman, S.E. and Malenka, R.C. Addiction and the brain: The neurobiology of compulsion and its persistence. Nat. Rev. Neurosci. 2, 695–703 (2001).

9. Robinson, T.E. and Kolb, B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J. Neurosci. 17, 8491–8497 (1997).

10. Robinson, T.E., Gorny, G., Mitton, E., and Kolb, B. Cocaine self- administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse 39, 257–266 (2001).

11. Cajal, S.R. “Histologie du Systeme Nerveux de L’Homme et des Vertebrès,” Vol. II (Paris: Maloine), p. 993 (1911).

12. Bliss, T.V.P. and Lømo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356 (1973).

13. Bliss, T.V.P. and Gardner-Medwin, A.R. Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 357–374 (1973).

14. Malenka, R.C. Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78, 535–538 (1994).

15. Lee, H.-K., Barbarosie, M., Kameyama, K., Bear, M.F., and Huganir, R.L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).

16. Carroll, R.C., Beattie, E.C., von Zastrow, M., and Malenka, R.C. Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2, 315–324 (2001).

and Malenka, R.C. Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2 ,
and Malenka, R.C. Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2 ,
and Malenka, R.C. Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2 ,
and Malenka, R.C. Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2 ,

Addiction and Neuronal Plasticity

17.

Sheng, M. and Lee, S.H. AMPA receptor trafficking and the control of synaptic transmission. Cell 105, 825–828 (2001).

18.

Martin, S.J., Grimwood, P.D., and Morris, R.G.M. Synaptic plasticity and memory: An evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).

19.

Wolf, M.E. Addiction and glutamate- dependent plasticity, in Glutamate and Addiction (Herman, B.H., Frankenheim, J., Litten, R., Sheridan, P.H., Weight, F.F. and Zukin, S.R. eds), The Humana Press, Inc. (in press).

20.

Lüscher, C., Nicoll, R.A., Malenka, R.C., and Muller, D. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nat. Neurosci. 3, 545–550 (2000).

21.

Kelley, A.E. Neural integrative activities of nucleus accumbens subregions in relation to learning and motivation. Psychobiology 27, 198–213 (1999).

22.

Groenewegen, H.J., Wright, C.I., Beijer, A.V., and Voorn, P. Convergence and segregation of ventral striatal inputs and outputs. Ann. N.Y. Acad. Sci. 877, 49–64 (1999).

22.

Cornish, J.L. and Kalivas, P.W. Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J. Neurosci. 20, RC89 (2000).

23.

Di Ciano, P., Cardinal, R.N., Cowell, R.A., Little, S.J., and Everitt B.J. Differential involvement of NMDA, AMPA/kainate, and dopamine receptors in the nucleus accumbens core in the acquisition and performance of Pavlovian approach behavior. J. Neurosci. 21, 9471–9477 (2001).

24.

Sesack, S.R. and Pickel, V.M. Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J. Comp. Neurol. 320, 145–160 (1992).

25. Floresco, S.B., Blaha, C.D., Yang, C.R. and Phillips, A.G. Modulation of hippocampal and amygdalar-evoked activity of nucleus accumbens neurons by dopamine: Cellular mechanisms of input selection. J. Neurosci. 21, 2851–2860 (2001).

26. Floresco, S.B., Blaha, C.D., Yang, C.R., and Phillips, A.G. Dopamine D1 and NMDA receptors mediate potentiation of basolateral amygdala-evoked firing of nucleus accumbens neurons. J. Neurosci. 21, 6370–7376 (2001).

27. Nicola, S.M., Surmeier, D.J., and Malenka, R.C. Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens. Annu. Rev. Neurosci. 232, 185–215

(2000).

28. Floresco, S.B., Todd, C.L. and Grace, A.A. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J. Neurosci. 21, 4915–4922 (2001).

29. Rosenkranz, J.A. and Grace, A.A. Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats. J. Neurosci. 21, 4090–4103 (2001).

30. McFarland, K. and Kalivas, P.W. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J. Neurosci. 21, 8655–8663 (2001).

31. Ciccocioppo, R., Sanna, P.P., and Weiss, F. Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence:

Reversal by D1 antagonists. Proc. Natl. Acad. Sci. U.S.A. 98, 1976–1981

(2001).

32. See, R.E., Kruzich, P.J., and Grimm, J.W. Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior. Psychopharmacology 154, 301–310

(2001).

33. Grimm, J.W. and See, R.E. Dissociation of primary and secondary reward- relevant limbic nuclei in an animal model of relapse. Neuropsychopharmacology 22, 473–479

(2000).

34. Everitt, B.J., Dickinson, A.D., and Robbins, T.W. The neuropsychological basis of addictive behaviour. Brain Res. Rev. 36, 129–138 (2001).

35. Vorel, S.R., Liu, X., Hayes, R.J., Spector, J.A., and Gardner E.L. Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science 292, 1175–1178 (2001).

36. Jentsch, J.D. and Taylor, J.R. Impulsivity resulting from frontostriatal dysfunction in drug abuse: Implications for the control of behavior by reward- related stimuli. Psychopharmacology 146, 373–390 (1999).

37. O’Donnell, P. and Grace, A.A. Synaptic interactions among excitatory afferents to nucleus accumbens neurons:

Hippocampal gating of prefrontal cortical input. J. Neurosci. 15, 3622–3639 (1995).

38. Schultz, W. and Dickinson, A. Neuronal coding of prediction errors. Annu. Rev. Neurosci. 21, 473–500

(2000).

39. Otani, S., Auclair, N., Desce, J.-M., Roisin, M.-P., and Crépel, F. Dopamine receptors and groups I and II mGluRs cooperate for long-term depression induction in rat prefrontal cortex through converging postsynaptic activation of MAP kinases. J. Neurosci. 19, 9788–9802 (1999).

40. Gurden, H., Takita, M. and Jay, T.M. Essential role of D1 but not D2 receptors in the NMDA receptor- dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo. J. Neurosci. 20, RC106 (2000).

41. Maren, S. Long-term potentiation in the amygdala: A mechanism for

June 2002

Volume 2, Issue 3

155

156

Review

emotional learning and memory. Trends Neurosci. 22, 561–567 (1999).

42. Pennartz, C.M.A., Ameerun, R.F., Groenewegen, H.J., and Lopes da Silva, F.H. Synaptic plasticity in an in vitro slice preparation of the rat nucleus accumbens. Eur. J. Neurosci. 5, 107–117

(1993).

43. Boeijinga, P.H., Mulder, A.B., Pennartz, C.M.A., Manshanden, I., and Lopes da Silva, F.H. Responses of the nucleus accumbens following fornix/fimbria stimulation in the rat. Identification and long-term potentiation of mono- and polysynaptic pathways. Neuroscience 53, 1049–1058 (1993).

44. Kombian, S.B. and Malenka, R.C. Simultaneous LTP of non-NMDA- and LTD of NMDA-receptor-mediated responses in the nucleus accumbens. Nature 368, 242–246 (1994).

45. Thomas, M.J., Malenka, R.C., and Bonci, A. Modulation of long-term depression by dopamine in the mesolimbic system. J. Neurosci. 20, 5581–5586 (2000).

46. Calabresi, P., Centonze, D., Gubellini,

P.,

Marfia, G.A., Pisani, A., Sancesario,

G.,

and Bernardi, G. Synaptic

transmission in the striatum: From plasticity to neurodegeneration. Prog. Neurobiol. 61, 231–265 (2000).

47. Li, Y. and Kauer, J. Effects of amphetamine on long-term potentiation in the nucleus accumbens. Soc. Neurosci. Abstr. 26, 1398 (2000).

48. Yamamoto, Y., Nakanishi, H., Takai, N., Shimazoe, T., Watanabe, S., and Kita,

H. Expression of N-methyl-D-aspartate

receptor-dependent long-term potentiation in the neostriatal neurons in an in vitro slice after ethanol withdrawal of the rat. Neuroscience 91, 59–68 (1999).

49. Nishioku, T., Shimazoe, T., Yamamoto,

Y., Nakanishi, H., and Watanabe, S.

Expression of long-term potentiation of the striatum in methamphetamine-

sensitized rats. Neurosci. Lett. 268, 81–84 (1999).

50. Thomas, M.F., Beurrier, C., Bonci, A., and Malenka, R. Long-term depression in the nucleus accumbens: A neural correlate of behavioral sensitization to cocaine. Nat. Neurosci. 4, 1217–1223

(2001).

51. West, A.R. and Grace, A.A. Opposite influences of endogenous D1 and D2 receptor activation on activity states and electrophysiological properties of striatal neurons: Studies combining in vivo intracellular recordings and reverse microdialysis. J. Neurosci. 22, 294–304 (2002).

52. Strakowski, S.M. and Sax, K.W., Progressive behavioral response to repeated d-amphetamine challenge:

Further evidence for sensitization in humans. Biol. Psych. 44, 1171–1177

(1998).

53. Robinson, T.E., Browman, K.E., Crombag, H.S., and Badiani, A. Modulation of the induction or expression of psychostimulant sensitization by the circumstances surrounding drug administration. Neurosci. Biobehav. Rev. 22, 347–354

(1998).

54. Shaham, Y., Erb, S., and Stewart, J. Stress-induced relapse to heroin and cocaine seeking in rats: A review. Brain Res. Rev. 33, 13–33 (2000).

55. Paulson, P.E., Camp, D.M., and Robinson, T.E. The time course of transient behavioral depression and persistent behavioral sensitization in relation to regional monoamine concentrations during amphetamine withdrawal in rats. Psychopharmacol. 103, 480–492 (1991).

56. Wolf, M.E. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog. Neurobiol. 54, 679–720 (1998).

57. Vanderschuren, L.J. and Kalivas, P.W. Alterations in dopaminergic and

glutamatergic transmission in the induction and expression of behavioral sensitization: A critical review of preclinical studies. Psychopharmacology 151, 99–120 (2000).

58. Nestler, E.J. Molecular basis of long- term plasticity underlying addiction. Nat. Rev. Neurosci. 2, 119–128 (2001).

59. Robinson, T.E. and Berridge, K.C. The neural basis of drug craving: An incentive-sensitization theory of addiction. Brain Res. Rev. 18, 247–291

(1993).

60. Robinson, T.E. and Berridge, K.C. The psychology and neurobiology of addiction: An incentive-sensitization view. Addiction 95, S91–S117 (2000).

61. Wyvell, C.L. and Berridge, K.C. Incentive sensitization by previous amphetamine exposure: Increased cue- triggered “wanting” for sucrose reward. J. Neurosci. 21, 7831–7840 (2001).

62. Zhang, X.-F., Hu, X.-T., White, F.J., and Wolf, M.E. Increased responsiveness of ventral tegmental area dopamine neurons to glutamate after repeated administration of cocaine or amphetamine is transient and selectively involves AMPA receptors. J. Pharmacol. Exp. Ther. 281, 699–706

(1997).

63. Giorgetti, M., Hotsenpiller, G., Ward, P., Teppen, T., and Wolf, M.E. Amphetamine-induced plasticity of AMPA receptors in the ventral tegmental area: Effects on extracellular levels of dopamine and glutamate in freely moving rats. J. Neurosci. 21, 6362–6369 (2001).

64. Ungless, M.A., Whistler, J.L., Malenka, R.C., and Bonci, A. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001).

65. Jones, S., Kornblum, J.L., and Kauer, J.A. Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J. Neurosci. 20,

J.L., and Kauer, J.A. Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J. Neurosci.
J.L., and Kauer, J.A. Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J. Neurosci.
J.L., and Kauer, J.A. Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J. Neurosci.
J.L., and Kauer, J.A. Amphetamine blocks long-term synaptic depression in the ventral tegmental area. J. Neurosci.

Addiction and Neuronal Plasticity

5575–5580 (2000).

66. Paladini, C.A., Fiorillo, C.D., Morikawa, H., and Williams, J.T. Amphetamine selectively blocks inhibitory glutamate transmission in dopamine neurons. Nat. Neurosci. 4, 275–281 (2001).

67. Carr, D.B. and Sesack, S.R. Projections from the rat prefrontal cortex to the ventral tegmental area: Target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J. Neurosci. 20, 3864–3873

(2000).

68. Takahata, R. and Moghaddam, B. Target-specific glutamatergic regulation of dopamine neurons in the ventral tegmental area. J. Neurochem. 75, 1775–1778 (2000).

69. Li, Y., Hu, X.-T., Berney, T.G., Vartanian, A.J., Stine, C., Wolf, M.E., and White, F.J. Both glutamate receptor antagonists and prefrontal cortex lesions prevent the induction of cocaine sensitization and associated neuroadaptations. Synapse 34,169–180

(1999).

70. Forster, G.L. and Blaha, C.D. Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area. Eur. J. Neurosci. 12, 3596–3604 (2000).

71. Lokwan, S.J.A., Overton, P.G., Berry, M.S., and Clark, D. Stimulation of the pedunculopontine tegmental nucleus in the rat produces burst firing in A9 dopaminergic neurons. Neuroscience 92, 245–254 (1999).

72. Tong, Z.-Y., Overton, P.G., and Clark, D. Stimulation of the prefrontal cortex in the rat induces patterns of activity in midbrain dopaminergic neurons which resemble natural burst events. Synapse 22, 195–208 (1996).

73. Jackson, M.E., Frost, A.S. and Moghaddam, B. Stimulation of

prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens. J. Neurochem. 78, 920–923 (2001).

74. Cornish, J.L., Nakamura, M., and Kalivas, P.W. Dopamine-independent locomotion following blockade of N- methyl-D-aspartate receptors in the ventral tegmental area. J. Pharmacol. Exp. Ther. 298, 226–233 (2001).

75. Bonci, A. and Malenka, R.C. Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J. Neurosci. 19, 3723–3730 (1999).

76. Giorgetti, M., Hotsenpiller, G., Froestl, W., and Wolf, M.E. In vivo modulation of ventral tegmental area dopamine and glutamate efflux by local GABA B receptors is altered after repeated amphetamine treatment. Neuroscience 109, 585–595 (2002).

77. Beretta, N., Paolucci, E., Bernardi, G., and Mercuri, N.B. Glutamate receptor stimulation induces a persistent rhythmicity of the GABAergic inputs to rat midbrain dopaminergiic neurons. Eur. J. Neurosci. 14, 777–784 (2001).

78. Onn, S.P. and Grace, A.A. Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo. J. Neurosci. 20, 2332–2345 (2000).

79. Kim, J.-H. and Vezina, P. Metabotropic glutamate receptors are necessary for sensitization by amphetamine. Neuroreport 9, 403–306 (1998).

80. Chao, S.Z., Lu, W., Lee, H.-K., Huganir, R.L., and Wolf, M.E. D1 dopamine receptor stimulation increases GluR1 phosphorylation in postnatal nucleus accumbens cultures. J. Neurochem., in press (2002).

81. Bibb, J.A., Chen, J., Taylor, J.R., Svenningsson, P., Nishi, A., Snyder, G.L., Yan, Z., Sagawa, Z.K., Ouimet, C.C., Nairn, A.C., Nestler, E.J., and

Greengard, P. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380 (2001).

82. Chao, S.Z., Peterson, D.A., and Wolf, M.E. Dopamine and glutamate receptors regulate surface expression of GluR1 in postnatal nucleus accumbens cultures. Soc. Neurosci. Abstr. 26, 789

(2000).

83. Dewey, S.L., Morgan, A.E., Ashby Jr., C.R., Horan, B., Kushner, S.A., Logan, J., Volkow, N.D., Fowler, J.S., Gardner, E.L. and Brodie, J.D. A novel strategy for the treatment of cocaine addiction. Synapse 30, 119–129 (1998).

of cocaine addiction. Synapse 30 , 119–129 (1998). Marina E. Wolf, PhD, is a Professor and

Marina E. Wolf, PhD, is a Professor and is the acting-chair in the Department of Neuroscience at the Finch University of Health Sciences, Chicago Medical School. Please address correspondence to MEW. E- mail: marina.wolf@finchcms.edu; Fax

(847)-578-3428

June 2002

Volume 2, Issue 3

157