The present study was carried out to evaluate the effect of morphine, cocaine 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 20mg/kg, or twice daily for 10 days in increasing doses of 20–100mg/kg. Cocaine was administered in a dose of 60mg/kg/day following the “binge” paradigm, every hour for 3h, one day (single treatment) or five days (chronic treatment). Ethanol was administered in drinking water at increasing concentrations of 1–6% v/v, for one month. As shown by receptor autoradiography, single morphine and cocaine administration did not influence the binding density of the selective ligand of δ2 receptors [³H]Ile^5,6deltorphin b, but single administration of cocaine decreased binding density of a highly selective antagonist of δ receptors, [³H]H-Tyr-TicΨ[CH₂-NH]Phe-Phe-OH. Repeated morphine administration decreased the receptor density after both ligands of the δ receptor in the nucleus accumbens after 3, 24 and 48h, and in the striatum after 24 and 48h. The density of [³H]Ile^5,6deltorphin b binding remained unchanged in both structures following repeated cocaine administration. After repeated cocaine administration either no changes (3h) or a decrease in the binding of [³H]H-Tyr-TicΨ[CH₂-NH]Phe-Phe-OH in the nucleus accumbens and striatum were observed after 24 and 48h. Ethanol did not influence the binding density of [³H]H-Tyr-TicΨ[CH₂-NH]Phe-Phe-OH and [³H]Ile^5,6deltorphin 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 [³H]Tyr-d-Ala-Gly-MePhe-Gly-ol following single or repeated morphine administration. At 3h after single or repeated “binge” cocaine administration, the binding of [³H]Tyr-d-Ala-Gly-MePhe-Gly-ol was not changed in either structure, but after 24h the density of μ opioid receptors was decreased in both structures. Ethanol given to rats in drinking water decreased the binding of [³H]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 μ receptor in both structures after 24, 48 and 96h. The above data indicate that repeated administration of morphine evokes a long-lasting down-regulation of the density of δ1 and δ2 opioid receptors, whereas cocaine affects in a similar way only the δ1 subtype in the nucleus accumbens, and to a lesser extent in the striatum. A long-term intake of ethanol solution down-regulates μ opioid receptors in both structures, but has no effect on any type of δ 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 play some role in maintaining the state of dependence.