The abuse of amphetamine-like psychostimulants is a global medical and social problem. The rewarding property of psychostimulants is linked, at least in part, to the capacity of these drugs to increase extracellular dopamine in the basal forebrain, notably in the nucleus accumbens. Despite the advances in our understanding of the cellular and molecular actions of psychostimulants, effective pharmcological treatments for amphetamine and cocaine addiction remain elusive. One paradigm, known as behavioral sensitization, models psychostimulant-induced adaptations in the addict brain by assessing changes in rodent neuronal function and behavior following repeated, daily injections of cocaine. Recent data suggests that the neurotrophins promote neural plasticity in the mesoaccumbens dopamine system and may contribute to behavioral sensitization. This grant proposal will expand on these initial findings by assessing potential cellular and molecular mechanisms whereby neurtrophins and neurotrophin-stimulated second messenger systems influence the ability of psychostimulants to promote behavioral sensitization. These experiments will assess: i) the effects of repeated intra-cranial microinjections of neurotrophins on the behavioral activation induced by a subsequent challenge injection of cocaine, ii) changes in neurotrophin mRNA in the mesolimbic/nigrostriatal dopamine system following acute and repeated cocaine, and iii) alterations in extracellular neurotrophins and dopamine in the cell body and terminal regions of mesotelencephalic dopamine projections. Further characterization of the role of the neurotrophins in the behavioral plasticity associated with repeated cocaine injections will provide valuable new information that may be relevant to the pharmacological treatment of the intense drug craving associated with pscyhostimulant withdrawal.
