We have used amphetamine (AMPH)-induced rotational behavior as an index of mesostriatal dopamine (DA) activity. In preliminary studies we found that a single injection of a relatively small dose of AMPH (1.25 mg/kg) greatly enhanced (nearly doubled) the rotational behavior produced by a subsequent injection of AMPH given 3-4 weeks later. This long-lasting facilitation of rotational behavior occurred only in intact female, ovariectomized female and castrated male rats; not in intact males. We have hypothesized that an androgen (probably testosterone) suppresses the development of this form of neuroplasticity. Another factor which influenced sensitization was the stability of an endogenous asymmetry in the nigrostriatal DA system. We have evidence that these long-lasting behavioral changes produced by AMPH are due to long-term changes in striatal DA release. A month after a single pretreatment with AMPH the AMPH-stimulated release of DA from striatal tissue in vitro was significantly enhanced, relative to saline pretreated controls. The studies proposed here are designed to: 1) further characterize the phenomenon of long-term changes in rotational behavior produced by 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-term changes in the mesostriatal DA system are involved in the development of behavioral sensitization by using an in vitro perifusion system to study endogenous DA release; and 4) 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 sensitization is thought to provide an animal model of the neurochemical changes which underlie amphetamine psychosis and/or paranoid schizophrenia in man. Lastly, the fact that the single administration of psychostimulant drugs may result in long-term physiological alterations is of obvious practical concern in psychotherapeutics.
