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NEUROPHARMACOLOGY

Mice with Decreased Cerebral Dopamine Function following a Neurotoxic Dose of MDMA (3,4-Methylenedioxymethamphetamine, "Ecstasy") Exhibit Increased Ethanol Consumption and Preference

Departamento de Farmacologia, Facultad de Medicina (M.I., I.M., I.E., I.P., E.O., M.I.C.) and Instituto Pluridisciplinar (M.D.), Universidad Complutense, Madrid, Spain; and Facultad de Psicologia, Universidad Nacional de Educación a Distancia, Madrid, Spain (A.H.-M, O.O., E.A.)

MDMA (3,4-methylenedioxymethamphetamine, "ecstasy") administration to mice produces relatively selective long-term neurotoxic damage to dopaminergic pathways. There is strong evidence indicating that the dopamine system plays a key role in the rewarding effects of ethanol and modulates ethanol intake. Using a two-bottle free-choice paradigm, we examined the voluntary consumption and preference for ethanol in mice deficient in cerebral dopamine concentration and dopamine transporter density by previous repeated MDMA administration. The current study shows that mice pre-exposed to a neurotoxic dose of MDMA exhibited a higher consumption of and preference for ethanol compared with saline-treated animals. The D₁ receptor full agonist SKF81297 [(6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide)] attenuated the enhanced ethanol intake, an effect that was reversed by SCH23390 [((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], a D₁ receptor antagonist. MDMA-exposed mice also showed a reduced release of basal dopamine in the nucleus accumbens compared with saline-injected animals and a modest increase in D₁ receptor density in caudate-putamen and nucleus accumbens. Intraperitoneal administration of ethanol elevated extracellular dopamine release in the nucleus accumbens of saline-treated mice, but this effect was almost abolished in MDMA-treated mice. Differences between saline- and MDMA-treated animals did not appear to be secondary to changes in acute ethanol clearance. These results indicate that mice with reduced dopamine activity following a neurotoxic dose of MDMA exhibit increased ethanol consumption and preference and suggest that animals might need to consume more alcohol to reach the threshold for the rewarding effects of ethanol.

Address correspondence to: Maria Isabel Colado, Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain. E-mail: colado{at}med.ucm.es