It is well established that dopamine (DA) receptor activation causes marked changes in the release and biosynthesis of opioid peptides such as enkephalin (ENK) and dynorphin (DYN) in the striatum. The major objectives in this project are to: 1) examine the possible role that immediate early gene products (e.g., c-fos and related peptides) may play in mediating DA's actions on opioid peptide expression; and 2) explore how glutamatergic systems (e.g., descending cortico-striatal fibers) may interact with DA in the regulation of opioid peptide biosynthesis. DA-containing neurons with cell bodies in the substantial nigra and nerve terminals in the striatum appear to regulate ENK and DYN expression in opposing fashion, with increased DA activation generally leading to increased DYN and decreased ENK expression and decreased DA, causing decreased DYN and increased ENK expression. One explanation for DA's contrasting effects on DYN and ENK is that DA acts via two different DA receptor subtypes (D1 and D2, respectively), which may in turn be linked to different second and third messenger systems. This hypothesis is supported by recent data where we show that c-fos or fos-related antigens (fra) are co-localized with DYN, but not ENK, in striatal neurons. Daily treatment with the DA receptor agonist, apomorphine, caused similar small increases in DYN- and fos/fra- ir. These data support a role for fos/fra proteins in mediating DA's effects on DYN expression in the striatum. Pretreatment with MK-801, a NMDA glutamate receptor antagonist, abolished the apomorphine-induced increases in DYN- and fos/fra-ir, suggesting that glutamate and DA may converge in regulating DYN expression in the striatum. However, results from other experiments, where DA input to one side of the striatum was removed by unilateral injections of 6-hydroxydopamine (6-OHDA) in the substantia nigra, indicate a more complex relationship between DA, glutamate and fos/fra proteins in regulation of opioid biosynthesis. 6- OHDA caused a diffuse low level induction of fos/fra expression in the striatum, but had little effect on DYN-ir. Repeated apomorphine administration to 6-OHDA-treated animals produced 4-fold increase in DYN-ir as well as intense stimulation of fos/fra expression in the lesioned striatum. In contrast to its effects in non-lesioned animals, MK-801 did not reverse apomorphine's effects on fos/fra expression although it blocked the DYN increase. Factors other than fos/fra appear to be involved in nigrostriatal regulation of DYN (and ENK) expression.
