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 microM maximally inhibited dopamine release. Withdrawal from chronic (4 days) treatment with U69,593 (1 microM) induced a long-lasting (at least 7 days) increase (30-50%) in [3H]dopamine release induced by 25 mM K+ from cultured rat mesencephalic neurons without causing functional kappa-opioid receptor desensitization. Incubation of these cultured neurons with the glucocorticoid agonist, dexamethasone (3 nM), had no effect on basal or 25 mM K(+)-induced dopamine release, whereas the steroid completely blocked the development of opiate-induced neuronal supersensitivity to depolarization. This blockade was found to be concentration-dependent, with an EC50 of about 0.3 nM and was not associated with changes in corticotropin-releasing factor (CRF) receptor, dopamine D2 autoreceptor or kappa-opioid receptor functioning. Therefore, opioid and glucocorticoid receptors appear to be co-localized in dopaminergic neurons of rat ventral mesencephalon and interact in a functionally antagonistic manner. Interestingly, the mineralocorticoid agonist, aldosterone (5 nM), itself increased K(+)-stimulated [3H]dopamine release by about 25%, consistent with the putative role of mineralocorticoid 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 effect similar to that of dexamethasone. Thus, whereas mineralocorticoid receptors that are already activated at low plasma corticosterone levels may uphold neuronal sensitivity to depolarizing stimuli, activation of glucocorticoid receptors by higher plasma corticosterone levels may prevent the development of neuronal supersensitivity, e.g. following chronic activation of kappa-opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)