The effect of repeated administration of morphine, cocaine and ethanol on mu and delta opioid receptor density in the nucleus accumbens and striatum of the rat

The present study was carried out to evaluate the effect of morphine, cocai ne and ethanol on the density of opioid receptors in the nucleus accumbens and striatum of rat brain. The animals were injected i.p. with morphine in a single dose 20 mg/kg, or twice daily for 10 days in increasing doses of 2 0-100 mg/kg. Cocaine was administered in a dose of 60 mg/kg/day following t he "binge" paradigm, every hour for 3 h, one day (single treatment) or five days (chronic treatment). Ethanol was administered in drinking water at in creasing concentrations of 1-6% v/v, for one month. As shown by receptor au toradiography, single morphine and cocaine administration did not influence the binding density of the selective ligand of delta 2 receptors [H-3]Ile( 5,6)deltorphin b, but single administration of cocaine decreased binding de nsity of a highly selective antagonist of delta receptors, [H-3]H-Tyr-Tic P si[CH2-NH]Phe-Phe-OH. Repeated morphine administration decreased the recept or density after both ligands of the delta receptor in the nucleus accumben s after 3, 24 and 48 h, and in the striatum after 24 and 48 h. The density of [H-3]Ile(5,6)deltorphin b binding remained unchanged in both structures following repeated cocaine administration. After repeated cocaine administr ation either no changes (3 h) or a decrease in the binding of [H-3]H-Tyr-Ti c Psi[CH2-NH]Phe-Phe-OH in the nucleus accumbens and striatum were observed after 24 and 48 h. Ethanol did not influence the binding density of [H-3]H -Tyr-Tic Psi[CH2-NH]Phe-Phe-OH and [H-3]Ile(5,6)deltorphin b in the nucleus accumbens and striatum at any time-point studied. In the nucleus accumbens and striatum, no changes were found in the binding density of [H-3]Tyr-D-A la-Gly-MePhe-Gly-ol following single or repeated morphine administration. A t 3 h after single or repeated "binge" cocaine administration, the binding of [H-3]Tyr-D-Ala-Gly-MePhe-Gly-ol was not changed in either structure, but after 24 h the density of mu opioid receptors was decreased in both struct ures. Ethanol given to rats in drinking water decreased the binding of [H-3 ]Tyr-D-Ala-Gly-MePhe-Gly-ol at the time of exposure to ethanol, yet in the nucleus accumbens only. Ethanol withdrawal decreased the density of the mu receptor in both structures after 24, 48 and 96 h. The above data indicate that repeated administration of morphine evokes a l ong-lasting down-regulation of the density of delta 1 and delta 2 opioid re ceptors, whereas cocaine affects in a similar way only the delta 1 subtype in the nucleus accumbens, and to a lesser extent in the striatum. A long-te rm intake of ethanol solution downregulates mu opioid receptors in both str uctures, but has no effect on any type of delta receptors. Thus changes in the particular opioid receptor depend on the type of drug used. Furthermore , the most profound changes are observed after late withdrawal, which may p lay some role in maintaining the state of dependence. (C) 1999 IBRO. Publis hed by Elsevier Science Ltd.