title: Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors.
abstract: It was previously demonstrated that the central nicotinic acetylcholine receptor antagonist mecamylamine perfused in the ventral tegmental area (VTA) counteracts the elevation of extracellular dopamine levels in the nucleus accumbens after systemic ethanol, as measured by in vivo microdialysis. In the present study we investigated the effect of different concentrations of ethanol perfused locally in the VTA or in the nucleus accumbens on extracellular accumbal dopamine levels. Ethanol (10-1000 mM) perfused in the VTA did not influence dopamine output in the nucleus accumbens. However, ethanol (300 mM) perfused in the nucleus accumbens increased accumbal dopamine levels to approximately the same extent (30%) as observed after systemic ethanol, whereas ethanol (1000 mM) decreased the dopamine output by approximately 50%. Next, the hypothesis that endogenous acetylcholine is required for the increased accumbal dopamine levels after ethanol was challenged. It was shown that in animals pre-treated with vesamicol, a potent inhibitor of vesicular acetylcholine storage, ethanol (300 mM) in the nucleus accumbens failed to elevate extracellular accumbal dopamine levels. Similarly, in animals perfused with mecamylamine in the VTA, but not in the nucleus accumbens, ethanol in the nucleus accumbens (300 mM) failed to increase accumbal dopamine levels. However, whereas dihydro-beta-erythroidine (antagonist for the nicotinic receptor subtype alpha4beta2) perfused in the VTA prevented the increase in accumbal dopamine after systemic nicotine, the antagonist was unable to prevent the dopamine elevating effects of ethanol. Finally, to investigate whether mecamylamine exerts its antagonizing effect of ethanol induced accumbal dopamine levels through an interaction with the NMDA receptor MK-801, the effects of the prototypic NMDA receptor antagonist were examined and compared to those of mecamylamine. After perfusion in the VTA, MK-801 enhanced accumbal dopamine levels by itself but did not antagonize the enhancing effect of ethanol. The present set of experiments indicate that the mesolimbic dopamine activating effects of ethanol may be due to an indirect rather than direct activation of ventral tegmental nicotinic acetylcholine receptors of a subtype composition different from the alpha4beta2. Furthermore, it is argued that the primary site of action of ethanol in its accumbal dopamine elevating effect may be located to the nucleus accumbens or nearby regions.
authors.affiliation: Department of Pharmacology, Institute of Physiology and Pharmacology, Göteborg University, P.O. Box 431, SE-405 30 Göteborg, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Ericson
authors.forename: Anna
authors.initials: A
authors.lastname: Molander
authors.forename: Elin
authors.initials: E
authors.lastname: Löf
authors.forename: Jörgen A
authors.initials: JA
authors.lastname: Engel
authors.forename: Bo
authors.initials: B
authors.lastname: Söderpalm
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D017551:Microdialysis; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011978:Receptors, Nicotinic / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C427403:alpha(4)beta(4) nicotinic receptor; D000431:Ethanol; D008464:Mecamylamine; D004298:Dopamine