ENKEPHALIN REGULATES ACUTE D-2 DOPAMINE-RECEPTOR ANTAGONIST-INDUCED IMMEDIATE-EARLY GENE-EXPRESSION IN STRIATAL NEURONS

Projection neurons of the striatum release opioid peptides in addition to GABA. Our previous studies showed that the opioid peptide dynorphi n regulates that subtype of projection neurons which sends axons to th e substantia nigra/entopeduncular nucleus, as indicated by an inhibito ry action of dynorphin/agonists on D-1 dopamine receptor-mediated imme diate-early gene induction in these neurons. The other subtype of stri atal projection neurons projects to the globus pallidus and contains t he opioid peptide enkephalin. Here, we investigated whether enkephalin regulates the function of striatopallidal neurons, by analysing opioi d effects on immediate-early gene induction by D-1 dopamine receptor b lockade that occurs in these neurons. Thus, the effects of systemic an d intrastriatal administration of various opioid receptor agonists and antagonists on immediate-early gene expression (c-fos, zif 268) induc ed by the D-2 receptor antagonist eticlopride were examined with in si tu hybridization histochemistry. Intrastriatal infusion of enkephalin (delta and mu), but not dynorphin (kappa), receptor agonists suppresse d immediate-early gene induction by eticlopride in a dose-dependent ma nner. This suppression was blocked by the opioid receptor antagonist n aloxone, confirming the involvement oi opioid receptors. Repeated trea tment with D-2 receptor antagonists produces increased enkephalin expr ession and diminished immediate-early gene inducibility in striatopall idal neurons, as well as behavioral effects that are attenuated compar ed to those of acute treatment (e.g., reduced akinesia). Naloxone reve rsed such behavioral recovery (i.e. reinstated akinesia), but did not significantly affect suppressed immediate-early gene induction. Our re sults indicate that enkephalin acts, via mu and delta receptors in the striatum, to inhibit acute effects of D-2 receptor blockade in striat opallidal neurons. Moreover, the present findings suggest that increas ed enkephalin expression after repealed D-2 receptor antagonist treatm ent is an adaptive response that counteracts functional consequences o f D-2 receptor blockade, but is not involved in suppressed immediate-e arly gene induction. Together with our earlier findings of the role of dynorphin, these results indicate that opioid peptides in the striatu m serve as negative feedback systems to regulate the striatal output p athways in which they are expressed. (C) 1998 IBRO. Published by Elsev ier Science Ltd.