Some of the behavioral actions of psychomotor stimulants increase in intensity and duration with repetitive administration (behavioral sensitization) (1,2). Behavioral sensitization to psychomotor stimulants appears to be determined by two different but interactive processes or mechanisms. One mechanism is nonassociative in nature (i.e., does not depend on the stimulus context in which the drug is experienced) and is related predominantly to neurobiological adaptations that are induced by repetitive exposure to neuropharmacological agents. These would include alterations in receptor sensitivity and neurotransmitter release capacity, enhanced receptor upregulation, decreases in autoreceptor sensitivity (1,3,4), and cellular and molecular adaptations (5). The primary focus of research directed at identifying the neural adaptations that may underlie psychomotor stimulant-induced behavioral sensi-tization has been the meso-accumbens dopamine system because it has been shown to be involved in mediating the motoric effects of a variety of drugs (6). The principal findings do indeed support a role for the mesoaccumbens dopamine projections in the development and expression of behavioral sensiti-zation to psychomotor stimulants. First, behavioral sensitization is associated with enhanced in vivo and in vitro release of dopamine in the nucleus accumbens (3). Second, the response to D1 dopamine agonists is augmented in the nucleus accumbens of sensitized rats (7,8). Third, repeated administration of amphetamine directly onto dopamine cell bodies in the ventral tegmental area (VTA) produces behavioral sensitization to a systemic challenge (9-11). Based on such findings, the induction of sensi-tization has been conceptualized to occur in the VTA, where the psychomotor stimulant acts on dopamine cell bodies to trigger the sequence of cellular events that underlies the development of behavioral sensitization. The enhanced dopamine release and postsynaptic responsiveness to dopamine in the nucleus accumbens and striatum, on the other hand, is thought to mediate the expression of sen-sitization (3,12).

The second set of factors contributing to behavioral sensitization is associative in nature; that is, they are established through learning processes. Pavlov (13) was probably the first to recognize, for example, that drugs could act as unconditioned stimuli. In these early studies, it was found that discrete visual and auditory stimuli associated contiguously with injections of morphine or apomorphine developed, over time, the ability to elicit emesis in dogs when presented alone. Thus, such classical conditioning can confer to neutral stimuli the ability to elicit certain pharmacological actions of a drug. With regard to psychomotor stimulants, the conditioned response comes to resemble, to some degree, the unconditioned motoric effects produced by the drug itself (14).

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

An important contributing factor underlying the development of sensitization appears to be the acquisition of progressively increasing conditioned pharmacological effects, which add to the unchanging unconditioned response produced by the drug itself and the enhanced sensitivity caused by neuroadaptive changes in response to repetitive drug exposure. The importance of associative learning processes in the development of psychomotor stimulant-induced sensitization has also been noted by Anagnostaras and Robinson (15). The relative contribution of associative and nonassociative factors to sensitization would depend, of course, on the experimental setting and procedures employed. Not only is the study of drug-associated conditioned effects important for elucidating the mechanisms responsible for behavioral sensitization, but understanding such an associative process may also have relevance for revealing motivational mechanisms operational during addictive behaviors. We have previously proposed (16) that the classical conditioning of drug effects to environmental cues underlies the development of incentive motivation, which is probably the neurobehavioral substrate responsible for craving. Understanding the circuitry that mediates the conditioned drug effects may aid in the development of appropriate pharmacotherapeutic adjuncts for the treatment of drug addiction.

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