Role of Glutamate and Nitric Oxide in the Acquisition and Expression of Cocaine-Induced Conditioned Increases in Locomotor Activity

Abstract

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 sensitization has been the meso-accumbens dopamine system because it has been shown to be involved in mediating the motorie 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 sensitization 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 Dl 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 sensitization 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 sensitization (3,12).