Dopamine (DA) receptor activation causes marked changes in the release and biosynthesis of opioid peptides such as enekephalin and dynorphin, in the srtiatum. The major objective in this project is to examine the possible role that immediste early gene products (fos- and jun-relates proteins) play in mediating DA's actions on opioid peptide expression. DA-containing neurons with cell bodies in the substanti nigra and nerve terminals in the striatum appear to regulate enekephalin and dynorphin expression in opposing fashion, (e.g.increased DA activation generally leading to increased dynorphin and decreased expression). It is thought that DA's contrasting effects on dynorphin and enekephalin expression are mediated by two different DA receptor subtypes, D1 and D2, respectively, which are linked to different second and third messanger systems. Previously, we found that the DA agonist, apomorphine (APO) induced the expression c-fos or fos-related antigens (fra) in dynorphin, but not enekephalin, neurons in the striatum. Since APO also increased dynorphin-ir concentrations, this suggested a possible role for fos/fra proteins in mediating DA's effects on dynorphin expression in the striatum. In studies where the DA input to one side of the srtiatum was removed by unilateral injections of 6-hydroxydopamine (6-OHDA) into the substania nigra, repeated APO administration caused large increases in dynorphin-ir peptide and mRNA levels. Increased dynorphin expression was accompanied by intense stimulation of fos/fra expression, in particular a 35 kDa FRA, in the lesioned striatum as well as increased binding to the AP-1 DNA element. Administration of the specific D1 receptor agonist, SKF 38393, had similar effects to those seen with APO, while a D2 agonist (quinpirole) had no effect, indicating that D1 receptor activation is responsible for the induction of dynorphin biosynthesis. In another set of studies, the short term regulation of dynorphin expresion was examined following the acute administrarion of the stimulant drug, methamphetamine (METH). The pattern of time-dependent changes in dynorphin-ir peptide and mRNA levels suggets that dynorphin release and biosynthesis was stimulated by a single injection of METH. Again, the increased dynorphin ewxpression was accompanied by elevated levels of the fos/fra-ir peptides, particulary a 35 and 46 kDa FRA. These data suggest that the short- and long-term induction of dynorphin by D1 receptor activation may be mediated by a 35 kDa FRA protein.
