Neural Substrates Of Cocaine Abuse

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A critical issue for the understanding of drug dependence is what neurochemical changes occur during the various phases of the course of addiction. Psychostimulant dependence has been a major focus of investigation, especially following the cocaine epidemic of the 1980s. Despite early misconceptions that considered cocaine as a recreational drug devoid of abuse and addictive potential, the recent cocaine epidemic has revealed the harmful consequences of cocaine use and its high abuse liability. Therefore, much experimental attention has been devoted over the past two decades to the search for the neural substrates responsible for cocaine abuse.

With the use of experimental models of intravenous drug self-administration, it has become clear that cocaine and other psychostimulant drugs such as amphetamine are readily self-administered by various species of laboratory animals (1). The acute reinforcing properties of psychostimulant drugs appear to depend on dopamine neurotransmission within areas of the limbic forebrain (2-4). In particular, the nucleus accumbens of the ventral striatum seems a critical structure for the maintenance of cocaine self-administration. The nucleus accumbens is the main projection area of the dopamine neurons originating within the mesencephalic ventral tegmental area (A10) and is critically involved in motivated behavior (5,6). Neurochemical studies have shown that dopamine outflow in the nucleus accumbens is increased after administration of cocaine (7), and an increase in nucleus accumbens dopamine concentration was shown in rats self-administering cocaine by microdialysis studies (8-10). Furthermore, behavioral evidence suggests that lesions of the dopamine terminals within the nucleus accumbens extinguished cocaine self-administration (11), and competitive antagonism at the dopamine receptor site within the same region reduced the reinforcing properties of cocaine (12).

Understanding the neurochemical determinants underlying the acute reinforcing properties of cocaine still leaves several unanswered questions regarding the intimate mechanisms leading to the development of the full cocaine dependence syndrome. The natural history of drug dependence consists of different phases (13). Although the positive reinforcing effects of cocaine as well as of other abused drugs are likely to represent critical factors in the initiation of drug self-administration (14), during this phase important neurochemical events are thought to occur within critical brain sites to contribute to the increased motivation to seek drugs that characterizes compulsive use (13).

Indeed, with more prolonged drug exposure, the period of acquisition of drug intake in rats self-administering cocaine intravenously is followed by a period of maintenance of a relatively low and stable level of intake or by escalation to higher levels of intake (15). This seems to depend on the duration of daily access to drug self-administration (15). This transition from moderate to excessive drug intake

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

is particularly significant because it is considered the first step leading to the loss of control, which represents the cardinal feature of the addictive process.

In addition to the issue of uncontrollable use, relapse into drug-seeking behavior following a period of abstinence has recently received much dedicated attention because it is believed to represent one of the major factors leading to the perpetuation of the addictive cycle. In this respect, extinction procedures provide a measure of the motivational properties of drugs as reflected by the persistence of drug-seeking behavior in the absence of the drug. However, extinction procedures also provide a powerful means of assessing the incentive-motivational properties of drug-paired stimuli or noncontingent drug administration in reinstating responding (16,17).

The long-lasting adaptive changes occurring in response to drug exposure are therefore thought to play a key role in the addictive cycle and they may represent the basis for clinically relevant phenomena, including drug craving and conditioned reinforcement. The intimate neurobiological mechanisms underlying such forms of neuroadaptation within critical neural sites remain obscure. However, there is now such evidence suggesting that neurochemical effectors other than dopamine may play a critical role, and a growing body of evidence accumulated over the last few years has indicated that excitatory amino acids may be relevant in this respect.

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