GLUCOCORTICOID AND MINERALOCORTICOID RECEPTORS DIFFERENTIALLY MODULATE CULTURED DOPAMINERGIC-NEURONS OF RAT VENTRAL MESENCEPHALON

Activation of kappa-opioid receptors by U69,593 in a concentration of 1 mu M maximally inhibited dopamine release. Withdrawal from chronic ( 4 days) treatment with U69,593 (1 mu M) induced a long-lasting (at lea st 7 days) increase (30-50%) in [H-3]dopamine release induced by 25 mM K+ from cultured rat mesencephalic neurons without causing functional kappa-opioid receptor desensitization. Incubation of these cultured n eurons with the glucocorticoid agonist, dexamethasone (3 nM), had no e ffect on basal or 25 mM K+-induced dopamine release, whereas the stero id completely blocked the development of opiate-induced neuronal super sensitivity to depolarization. This blockade was found to be concentra tion-dependent, with an EC(50) of about 0.3 nM and was not associated with changes in corticotropin-releasing factor (CRF) receptor, dopamin e D-2 autoreceptor or kappa-opioid receptor functioning. Therefore, op ioid and glucocorticoid receptors appear to be co-localized in dopamin ergic neurons of rat ventral mesencephalon and interact in a functiona lly antagonistic manner. Interestingly, the mineralocorticoid agonist, aldosterone (5 nM), itself increased K+-stimulated [H-3]dopamine rele ase by about 25%, consistent with the putative role of mineralocortico id receptors in maintaining neuronal excitability. Moreover, whereas 1 nM corticosterone appeared to mimic the dopamine release-facilitating effect of aldosterone, 30 nM corticosterone displayed a modulatory ef fect similar to that of dexamethasone. Thus, whereas mineralocorticoid receptors that are already activated at low plasma corticosterone lev els may uphold neuronal sensitivity to depolarizing stimuli, activatio n of glucocorticoid receptors by higher plasma corticosterone levels m ay prevent the development of neuronal supersensitivity, e.g. followin g chronic activation of kappa-opioid receptors. It is suggested that t hese corticosteroid receptor-mediated effects play an important role i n long-lasting behavioral sensitization caused by stress and drugs of abuse.