Ethanol and central nicotinic acetylcholine receptors : a behavioral and neurochemical study in rodents

Abstract

ETHANOL AND CENTRAL NICOTINIC ACETYLCHOLINE RECEPTORS. <P>A behavioral and neurochemical study in rodents. pp. 1-61., Institute of Physiology and Pharmacology, Department of Phannacology, Göteborg University, Medieinaregatan 7, S-413 90 Göteborg, Sweden.<BR>Smoking and alcoholism cause severe health problems. Furthermore, smoking and drinking covary positively. Ethanol and nicotine, like other drugs of abuse, activate the iiiesocortieolimbic dopamine system, that originates in the ventral segmental area (VTA) and projects mainly to the nucleus accumbens and the frontal cortex. In experimental animals, drug-induced activation of this system appears to be associated both with the reinforcing and the locomotor stimulatory properties of dependence producing drugs. Nicotine activates the mesocortieolimbic dopamine system by stimulating nicotinie acetylcholine receptors (nAChR) in the VTA and/or presynaptically in the nucleus accumbens. It is, however, not clear how ethanol activates this system.<BR>In the present study, nicotine increased or antagonized ethanol-induced hyper-locomotion in mice, depending on the ethanol dose. Mecamylarnine, a centrally acting nAChR antagonist, but not hexamethonium, a nAChR antagonist that does not enter the brain, partially counteracted ethanol-induced hyperlocomotion. Mecamylamine also counteracted ethanol-induced increases in mouse brain dopamine turnover and catecholamine synthesis rate in the rat limbie forebrain. Ethanol increased dopamine overflow in the rat nucleus accumbens. This effect was blocked by mecamylamine but not by hexamethonium. Furtherinore, ethanol-induced accumbal dopamine overflow was abolished after local perfusion mecamylamine or hexamethonium in the VTA but not after mecamylamine perfusion in the nucleus accumbens. Systemic mecamylan-iine, but not hexamethonium, reduced voluntary ethanol intake in ethanol high- but not not low- preferring rats. Subchronic nicotine treatment, which produced behavioral sensitization to nicotine, increased ethanol intake and preference in medium- and low-but not high-preferring rats. This treatment also inereased measures of doparnine release in the limbic forebrain after acute nicotine or ethanol in rats and enhanced ethanol-induced hyperlocomotion and dopamine turnover in mice, suggesting a cross-sensitization between nicotine and ethanol.<BR>In summary, the mesolimbic dopamine activating and the reinforcing properties of ethanol appears to involve central nAChR, preferrably those located in the VTA. Furthermore, cross-sensitization between nicotine and ethanol may develop, an effect that could contribute to the co-abuse of these compounds. It is also suggested that antagonists at central nAChR may be useful in the treatment of alcoholism.