The purpose of this research is to further our understanding of the neuroeffector systems involved in the behavioral sensitization that develops following exposure to amphetamine and cocaine. The phenomenon is of interest because it represents a long-lasting, if not permanent, change in brain dopaminergic function that may be a critical factor in the problem of drug abuse. The results of previous studies suggest that sensitization is associated with qualitative changes in the systems that mediate the motor responses to the stimulants. Sensitization is affected by a wide range of drugs that implicate the participation of at least five neurotransmitter systems, but the loci of their actions in the brain relative to sensitization are not understood. There are, however, many potential brain loci of their actions because there are many brain nuclei that are known to be involved in mediating dopaminergic functions, which primarily involve nuclei of the basal ganglia. The role of various loci in the induction and expression of sensitization to stereotypy will be investigated in the mouse by the microinjection of drugs into specific areas of the basal ganglia and associated structures, such as the frontal cortex and the thalamus. In addition, the influence of sensitization on the role of the major dopamine receptor systems, D1 and D2 will be examined both systematically and in various brain loci with the functional role of different brain structures in the induction and expression of sensitization. The significance of this study derives from the importance of dopamine in brain function. It is a major neurotransmitter system involved in the problem of drug abuse, as well as in a variety of other disease states, such as parkinsonism and schizophrenia. The results of the proposed studies should enhance our understanding of the functions of the dopamine system in different brain areas and, in particular, how these functions are modified by exposure to drugs of abuse.
