This proposal focuses scientifically on the psychomotor stimulants, amphetamine and cocaine, which are among the most reinforcing drugs known. Their rewarding properties are mediated, to a great extent, by facilitation of the action of dopamine in the ventral striatum, especially the nucleus accumbens. However, acute activation of """"""""brain reward"""""""" circuitry does not, by itself, explain drug dependence. Dependence develops only after a drug has been administered at an adequate dose, frequency, and chronicity; once established the state of dependence may be very long-lived. It has been hypothesized that the slow-onset, long-term changes in neural functioning responsible for psychostimulant dependence are caused, at least in part, by drug-induced regulation of gene expression. In primary striatal cultures and in dorsal and ventral striatum in vivo , the candidate proposes to study the molecular mechanisms by which dopamine and psychostimulants regulate the interaction of CREB and AP-1 family transcription factors with target genes, including the prodynorphin gene, and consequences of that regulation for brain function.
