Marina E Wolf PhD

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Addiction may be defined as the gradual evolution from casual or controlled use into a compulsive pattern of drug-seeking and drug-taking behavior. Even after abstinence is achieved, patients remain vulnerable to episodes of craving and relapse triggered by stimuli previously associated with the availability of drug or the act of drug-taking (1). This transition fits the definition of neuroplasticity, defined as the ability of the nervous system to modify its response to a stimulus based on prior experience. However, it is an exceptionally powerful and persistent form of plasticity. Episodic craving persists for years in humans (2), and animal studies show that conditioned responses to cocaine-related stimuli are highly resistant to extinction (3).

Monoamine transporters are the immediate target in brain of psychostimulants like cocaine and amphetamine, and this interaction is becoming increasingly well characterized. However, it remains a mystery how an initial elevation of monoamine levels leads to changes in the nervous system that persist for years. This problem will be the focus of this chapter. We will emphasize studies related to behavioral sensitization, a glutamate-dependent form of drug-induced plasticity that provides a useful model for some aspects of addiction. An overview of sensitization is therefore provided, but it is not comprehensive (for other reviews, see refs. 4 and 5).


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. The relevance of sensitization to addiction has been discussed (6-9). Key points are as follows: (1) sensitization occurs to the reinforcing effects of psychostimulants, not just locomotor effects, (2) sensitization is influenced by the same factors that influence addiction (e.g., stress, conditioning, drug priming), (3) sensitization is accompanied by profound cellular and molecular adaptations in the mesocorticolimbic circuits that are fundamentally involved in motivation and reward and that are implicated in addiction in humans, and (4) like addiction, sensitization is very persistent, e. g., amphetamine sensitization can last up to a year in rats, a species that lives only 1-2 yr (10). Thus, behavioral sensitization provides an animal model for the induction of persistent changes, at both cellular and behavioral levels, in the neural circuitry of motivation and reward as a result of chronic exposure to drugs of abuse.

In retrospect, there are many logical reasons to focus on glutamate in addiction research. An obvious reason is that addiction fits the definition of plasticity, and glutamate is implicated in nearly every

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

form of plasticity. A second reason is that glutamate neurons are well placed, anatomically, to govern the output of dopamine (DA) systems. They provide the major source of excitatory drive to DA cell bodies in the midbrain, whereas target cells in DA projection areas, such as the nucleus accumbens (NAc), receive convergent inputs from DA and glutamate nerve terminals (e.g., ref. 11). Finally, human imaging studies implicate glutamate-rich cortical and limbic brain regions in cocaine-conditioned responses (12-17). As relapse is the major problem in treating cocaine addicts and may be triggered by drug-conditioned cues, it is likely that plasticity in glutamate projections mediating drug-conditioned responses plays a key role in addiction.

Historically, however, the impetus for studying glutamate's role in addiction came from studies of behavioral sensitization. It was first demonstrated in 1989 that the development of behavioral sensitization in rats and mice was prevented if each amphetamine or cocaine injection in a chronic regimen was preceded by systemic injection of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (18). Since then, many studies have demonstrated similar effects with different classes of NMDA receptor antagonists and with a-amino-3-hydroxy-5-isoazole propionic acid (AMPA) and metabotropic glutamate receptor antagonists (4). A key observation is that coadministration of glutamate receptor antagonists with psychostimulants also prevents the ability of prior drug exposure to promote drug self-administration, demonstrating that sensitization to drug reinforcing effects is also a glutamate-dependent process (e.g., ref. 19; reviewed in ref. 4). Another important observation is that glutamate antagonist treatments that prevent behavioral sensitization also prevent the development of neurochemical and electrophysiological adaptations that normally accompany sensitization (e.g., ref. 20; reviewed in ref. 4). This indicates that glutamate receptor stimulation is a necessary step in the cascade of cellular changes leading to sensitization. An encouraging finding, from a therapeutic perspective, is that manipulations of glutamate transmission can reverse behavioral sensitization (21,22). Some glutamatergic drugs, particularly MK-801, may influence sensitization in part through mechanisms related to state-dependent learning (23-25). However, such effects cannot account for the ability of many classes of glutamate receptor antagonists to prevent the development of behavioral sensitization and associated neuroadaptations (26,27).

Microinjection studies indicate that glutamate receptor antagonists are probably acting in the A9/A10 region, which contains DA cell bodies, to prevent the development of sensitization (28-31). We have hypothesized that glutamate receptor antagonists prevent sensitization by attenuating excitatory drive to midbrain DA neurons (4). Supporting this hypothesis, the development of sensitization is associated with a transient increase in excitatory drive to DA neurons (4), whereas it is prevented by lesions of the prefrontal cortex, an important source of glutamate-containing projections to the ventral tegmental area (VTA) (20,30,32; but see ref. 33). These findings suggest that sensitization may involve drug-induced plasticity at excitatory synapses between glutamate terminals originating in the pre-frontal cortex and VTA DA neurons. The simplest version of this model is that drugs of abuse promote long-term potentiation (LTP) at these synapses, increasing excitatory drive to DA neurons and thus influencing transmission in limbic and cortical DA projection areas. Exciting new data support the possible importance of this mechanism (Section 3). However, recent anatomical studies have shown that prefrontal cortex terminals synapse on meso-accumbens GABA neurons rather than meso-accubens DA neurons (34), suggesting that the route of communication between prefrontal cortex and mesoaccubens DA neurons may be indirect. Other findings suggest that alterations in GABA transmission in the VTA may contribute to sensitization (see ref. 35).

In the remainder of this chapter we will address three topics: (1) basic mechanisms by which drugs of abuse may "tap into" cellular mechanisms governing plasticity at excitatory synapses, (2) the role of such plasticity in the induction of sensitization in the VTA, and (3) the role of such plasticity in long-term adaptations within the NAc. We are focusing on VTA and NAc because these are critical brain regions for induction and expression of sensitization, respectively; however, both phases of sensitization actually require complex circuitry (4).

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