NEURONAL ADAPTATION TO AMPHETAMINE AND DOPAMINE - MOLECULAR MECHANISMS OF PRODYNORPHIN GENE-REGULATION IN RAT STRIATUM

Induction of prodynorphin gene expression by psychostimulant drugs may re present a compensatory adaptation to excessive dopamine stimulatio n and may contribute to the aversive aspects of withdrawal. We therefo re investigated the molecular mechanisms by which dopamine psychostimu lant drugs induce prodynorphin gene expression in vivo and in rat prim ary striatal cultures. We demonstrate that three recently described cA MP response elements (CREs), rather than a previously reported noncano nical AP-1 site, are critical for dopamine induction of the prodynorph in gene in striatal neurons. CRE-binding protein (CREB) binds to these CREs in striatal cell extracts and is phosphorylated on Ser-133 after dopamine stimulation in a D1 dopamine receptor-dependent manner. Surp risingly, following chronic administration of amphetamine, revels of p hosphorylated CREB are increased above basal in rat striatum in vivo, whereas c-fos mRNA is suppressed below basal levels. D1 receptor-media ted CREB phosphorylation appears to mediate adaptations to psychostimu lant drugs in the striatum.