It is well established that the repeated administration of stimulant drugs (e.g. amphetamine) results in a progressively enhanced behavioral response to subsequent injections. This phenomenon of 'reverse tolerance', or sensitization, has generated considerable interest because it is thought to provide an animal analogue of amphetamine (AMPH) psychosis in humans. However, a single injection of AMPH may also produce a long-lasting change in brain activity. In preliminary studies using AMPH-induced rotational behavior as an index of mesostriatal dopamine (DA) activity we found that a single injection of a low dose (1.25 mg/kg) of AMPH greatly enhanced the rotational behavior produced by a second injection of AMPH given 3-4 weeks later in intact female, ovariectomized female and castrated male rats. Intact males did not show as robust a change. This behavioral sensitization may be due to changes in DA release, since it is accompanied by a long-lasting enhancement in AMPH-stimulated endogenous DA release from striatal tissue in vitro. The studies proposed here are disigned to: (1) further characterize the phenomenon of long-term changes in rotational behavior produced by a single or repeated injections of AMPH: (2) examine the role of gonadal steroid hormones in modulating this form of neural plasticity; (3) further explore the possibility that long-lasting changes in DA release from terminals in a variety of brain regions are involved in the development of behavioral sensitization; (4) determine whether similar long-lasting changes in brain activity are produced by other stimulant drugs; and (5) determine whether a single injection of AMPH will produce comparable changes in other behaviors thought to be mediated by brain DA systems. We believe the proposed studies integrating both in vivo and in vitro approaches will increase our understanding of the basic neurobiological mechanisms involved in neuroplasticity. The studies are of clinical interest since they may provide some insight as to the neurochemical changes underlying AMPH psychosis. Lastly, the fact that the single administration of psychostimulant drugs may result in long-term physiological alterations should be of obvious practical concern in psychotherapeutics.
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