In humans the chronic use of psychomotor stimulant drugs frequently results in the development of a paranoid psychosis (eg. amphetamine psychosis), and even after years of abstainence former amphetamine (AMPH) users remain hypersensitive to the psychotogenic effects of subsequent AMPH treatment. In nonhuman animals the repeated administration of stimulants, such as AMPH, cocaine or methylphenidate, produces a progressive and enduring enhancement in many of the motor stimulant effects of these drugs - and this """"""""behavioral sensitization"""""""" is thought to represent an animal analogue AMPH psychosis. In vitro studies suggest that behavioral sensitization is at least in part due to enduring presynaptic changes in the releasability of dopamine (DA) from terminals located in the striatum and nucleus accumbens. However, it is not known if behavioral sensitization is accompanied by comparable changes in DA release in vivo. Therefore, the purpose of experiments proposed here is to rigorously test this hypothesis by use of intracerebral dialysis to simultaneously quantify regional DA release in vivo and behavior in freely moving rats previously exposed to AMPH, cocaine or methylphenidate. Specific experiments are designed to determine: (1) how changes in a variety of AMPH-induced behaviors (locomotin, stereotypy, rotation) are related to changes in striatal or nucleus accumbens DA release; and (2) how variables that influence the development of behavioral sensitization influence changes in regional brain DA release. Although most animals show behavioral sensitization when chronically exposed to stimulant drugs, there are vast individual differences in the susceptibility to sensitization. Therefore, another focus of experiments proposed here is to determine how individual variation in the development of behavioral sensitization (due to constitutional factors, such as sex and gonadal hormones) is related to individual variation in striatal and nucleus accubens DA release in vivo. These experiments will be important for understanding how the repeated use of stimulant drugs produces neuroplastic adaptations in neurochemnical systems to result in the emergence of new behavioral or cognitive responses; and how past experience with these agents can produce persistent changes in the response to subsequent exposure. Finally, studies on how biological and environmental factors interact to contribute to individual variation in the susceptibility to sensitization will be valuable in trying to understand individual variation in the psychotogenic effects of stimulants.
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