GLUCOCORTICOID RECEPTOR ACTIVATION POTENTIATES THE MORPHINE-INDUCED ADAPTIVE INCREASE IN DOPAMINE D-1 RECEPTOR EFFICACY IN GAMMA-AMINOBUTYRIC-ACID NEURONS OF RAT STRIATUM NUCLEUS ACCUMBENS/

The present study was designed to evaluate the hypothesis that enhance d corticosterone levels may facilitate the enduring neuroadaptive effe cts in the brain caused by drugs of abuse. Treatment of primary neuron al cultures of the rat striatal complex (striatum/nucleus accumbens, c onsisting for more than 90% of gamma-aminobutyric acid neurons) with 1 0 mu M morphine for 2 hr to 3 days, enhanced the maximal stimulatory e ffect of the dopamine D-1 receptor agonist SKF38393 on adenylyl cyclas e activity. This adaptive increase in D-1 receptor efficacy upon long- term mu-opioid receptor activation was about doubled after simultaneou s or previous exposure of the neurons to the glucocorticoid receptor a gonist dexamethasone (EC(5)0 about 2 nM). A similar facilitation of th e effect of morphine was observed upon exposure of the neurons to rela tively high (nanomolar) concentrations of corticosterone, whereas the mineralocorticoid receptor agonist aldosterone appeared to be ineffect ive in this respect, indicating the involvement of glucocorticoid rece ptors. Interestingly, whereas morphine exposure also enhanced isoprena line-stimulated adenylyl cyclase activity, this increase of beta adren oceptor efficacy was not at all affected by dexamethasone. In both mor phine-treated and untreated neurons, low concentrations (< .3 nM) of c orticosterone or aldosterone, but not dexamethasone, caused a slight ( about 20%) reduction of dopamine D-1 receptor-stimulated adenylyl cycl ase activity, indicating the involvement of mineralocorticoid receptor s. These data show that the morphine-induced adaptive increase of post synaptic dopamine D-1 receptor efficacy (also observed in striatal sli ces of rats weeks after repeated treatment with morphine or cocaine) i s strongly enhanced after previous or simultaneous glucocorticoid rece ptor activation. Activation of these glucocorticoid receptors in effer ent neurons of the striatum and nucleus accumbens by corticosterone ma y play a pivotal role in stress- and drug-induced behavioral (cross) s ensitization and the acquisition and maintenance of drug abuse.