THE ROLE OF DOPAMINERGIC SYSTEMS IN OPIOID RECEPTOR DESENSITIZATION IN NUCLEUS-ACCUMBENS AND CAUDATE-PUTAMEN OF RAT AFTER CHRONIC MORPHINE TREATMENT

Morphine treatment of rats (60-70 mg/kg/day, 7 days) reduced delta opi oid receptor-mediated inhibition of adenylyl cyclase activity in cauda te putamen without any change in regulation by mu receptors. Earlier s tudies suggested that dopamine D-1 and mu opioid receptors that regula te adenylyl cyclase are expressed preferentially by striato-nigral neu rons, whereas adenosine A(2a) and delta(1) opioid receptors are expres sed preferentially by striato-pallidal neurons. Chronic morphine treat ment also resulted in a reduction of dopamine D-2 receptor-mediated in hibition of A(2a) receptor-stimulated adenylyl cyclase. Treatment with a D-2 receptor antagonist (eticlopride; 1 mg/kg/day) for 7 days reduc ed D-1 receptor stimulation of adenylyl cyclase. In contrast, chronic treatment with a D-1 receptor antagonist ethyl-1-phenyl-2,3,4,5-tetrah ydro-1H-3-benzazepine HCL (SCH 23390; 2.5 mg/kg/day) resulted in a red uction of delta(1) and delta(2) opioid inhibition of adenylyl cyclase, with no change in the inhibitory activity of a mu agonist. The inhibi tory activity of the D-2 agonist quinelorane against adenosine A(2a)-a ctivated enzyme was also reduced by this treatment. Thus chronic D-1 b lockade, like chronic morphine treatment, appears to cause a selective impairment of the regulation of adenylyl cyclase in A(2a) receptor-ex pressing striato-pallidal neurons. D-2 receptor activation appears to play an important role in the desensitization of delta receptors, beca use concurrent administration of the D-2 antagonist eticlopride with m orphine prevented the densitization of delta and D-2 receptors. Simila r results were obtained in nucleus accumbens, which suggests a role fo r D-2 receptor desensitization in the adaptive response of this brain region to chronic morphine.