Long-lasting effects of chronic mu-opioid intake on the signal transmission via dopamine D1 receptors in the limbic forebrain of drug deprived rats.

Rats orally self-administered the potent and selective mu-opioid receptor agonist etonitazene for 8 weeks (free choice between three opioid solutions and water resulting in low drug intake, or forced intake of a single drug solution resulting in high opioid consumption). The signal transmission in membranes of the limbic forebrain (nucleus accumbens and olfactory tubercle) was studied during acute withdrawal (2 days of abstinence) and after 6 weeks of drug deprivation. Binding experiments with the dopamine (DA) D1 receptor antagonist [3H]SCH23390 revealed in the high consuming rats an increased binding density (Bmax) by 19% during withdrawal and a decreased Bmax by 17% after long-term abstinence compared with drug-naive controls (each P < 0.05). The addition of 500 nM DA reduced the [3H]SCH23390 binding affinity (Kd increased by 60-105%) and density (by 15-23%) in each of the five groups (P < 0.001). During acute withdrawal, the portion of Bmax inhibited by DA increased by 83% in the high consuming rats vs. the controls (P < 0.05). Full concentration-response curves of adenylyl cyclase (AC) stimulation by the DA D1 receptor agonist dihydrexidine and of inhibition of forskolin stimulated AC activity by the GTP analogue guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) were performed: the former revealed a reduced maximum efficacy (Emax decreased by 23-37%), P < 0.001), the latter a reduced effective concentration (EC50 decreased by 60-103%, P < 0.05), in each etonitazene-experienced group vs. the controls.