Nicotinic mechanisms in ethanol reinforcement. A neurochemical and behavioral study

Abstract

Both smoking and alcohol consumption are known to cause severe health problems and there is an extensive co-abuse of tobacco and ethanol. The reinforcing properties of drugs of abuse may involve the brain mesolimbic dopamine system, that originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens. Whereas the mechanisms of action of e.g. psychostimulants in their mesolimbic dopamine activating effects are fairly well known, those of ethanol are not. It has, however, previously been suggested that nicotinic acetylcholine receptors (nAChR) are involved. In the present thesis, nicotinic mechanisms in the reinforcing and accumbal dopamine enhancing effects of ethanol have been further investigated. Voluntary ethanol intake in ethanol high-preferring Wistar rats was found to elevate accumbal dopamine output by approximately 40%, as measured by in vivo microdialysis. Furthermore, ventral tegmental perfusion of the nAChR antagonist, mecamylamine, switched the ethanol high-preferring rats into low-preferring ones and prevented the ensuing accumbal dopamine output. Next, the effect of ethanol applied locally in the mesolimbic dopamine system was investigated. Tegmental ethanol perfusion (10-1000 mM) did not alter the accumbal dopamine output, whereas accumbal ethanol perfusion (300 mM), elevated the dopamine output in the nucleus accumbens to approximately the same extent as observed after systemic ethanol administration. Tegmental perfusion with mecamylamine, but not DHßE, a nAChR antagonist selective for the a4ß2 subtype composition, completely antagonized the ethanol-induced elevation of accumbal dopamine levels, as did pharmacological (vesamicol) depletion of extracellular acetylcholine. In line with previous observations, subchronic intermittent nicotine enhanced ethanol intake/preference in low- and medium-preferring Wistar rats, as well as nicotine-induced locomotor stimulation and disinhibition. Whereas co-pretreatment with the tertiary nAChR antagonist mecamylamine, but not with the quarternary compound hexamethonium, prevented induction of sensitization to the locomotor stimulatory effects of nicotine, both drugs failed to antagonize the development of an enhanced ethanol consummatory and nicotine-induced disinhibitory behavior after subchronic nicotine. On the contrary, both blockers by themselves mimicked the effect of nicotine on the latter behaviors.It is suggested that ethanol interferes with an accumbal mechanism that secondarily increases endogenous acetylcholine release in the VTA and thereby activates nAChR subtypes (different from the a4ß2), resulting in enhanced mesolimbic dopamine neuronal activity and release, of importance also to the reinforcing properties of ethanol. The enhanced ethanol intake after repeated nicotine administration may primarily derive from adaptations in response to intermittent peripheral nAChR blockade and appears to relate to the development of nicotine-induced disinhibitory behavior rather than locomotor sensitization. The results indicate new receptor populations and mechanisms, the antagonism of or interference with could be expected to reduce/control alcohol intake also in humans.