Glucocorticoid receptor activation potentiates the morphine-induced adaptive increase in dopamine D-1 receptor efficacy in γ-aminobutyric acid neurons of rat striatum/nucleus accumbens

The present study was designed to evaluate the hypothesis that enhanced corticosterone levels may facilitate the enduring neuroadaptive effects in the brain caused by drugs of abuse. Treatment of primary neuronal cultures of the rat striatal complex (striatum/nucleus accumbens, consisting for more than 90% of γ-aminobutyric acid neurons) with 10 μM morphine for 2 hr to 3 days, enhanced the maximal stimulatory effect of the dopamine D-1 receptor agonist SKF38393 on adenylyl cyclase activity. This adaptive increase in D-1 receptor efficacy upon long-term mu-opioid receptor activation was about doubled after simultaneous or previous exposure of the neurons to the glucocorticoid receptor agonist dexamethasone (EC₅₀ about 2 nM). A similar facilitation of the effect of morphine was observed upon exposure of the neurons to relatively high (nanomolar) concentrations of corticosterone, whereas the mineralocorticoid receptor agonist aldosterone appeared to be ineffective in this respect, indicating the involvement of glucocorticoid receptors. Interestingly, whereas morphine exposure also enhanced isoprenaline-stimulated adenylyl cyclase activity, this increase of beta adrenoceptor efficacy was not at all affected by dexamethasone. In both morphine-treated and untreated neurons, low concentrations (<.3 nM) of corticosterone or aldosterone, but not dexamethasone, caused a slight (about 20%) reduction of dopamine D-1 receptor-stimulated adenylyl cyclase activity, indicating the involvement of mineralocorticoid receptors. These data show that the morphine-induced adaptive increase of postsynaptic dopamine D-1 receptor efficacy (also observed in striatal slices of rats weeks after repeated treatment with morphine or cocaine) is strongly enhanced after previous or simultaneous glucocorticoid receptor activation. Activation of these glucocorticoid receptors in efferent neurons of the striatum and nucleus accumbens by corticosterone may play a pivotal role in stress- and drug-induced behavioral (cross) sensitization and the acquisition and maintenance of drug abuse.