D-Penicillamine prevents ethanol and acetaldehyde-induced increase in mesolimbic dopaminergic neuronal activity

Acetaldehyde (ACD) is the main metabolite of ethanol (EtOH); recent evidence suggests that ACD may significantly contribute to EtOH rewarding properties (1). Previous research in our laboratory has shown that ACD stimulates ventral tegmental area (VTA) dopaminergic neurons activity and that pretreatment with 4-methyl-pyrazole (4MP, an inhibitor of alcohol-dehydrogenase), prevented EtOH-induced increase in neuronal firing (2) leaving ACD-induced effects unmodified. To further characterize the contribution of ACD to the stimulating properties of EtOH, we studied the effects of ACD and EtOH on VTA dopaminergic cells using single unit extracellular recordings coupled with antidromic identification from the NAcb in rats pretreated with D-penicillamine (DP), an effective ACD-chelating agent (3). Administration of ACD (5-40 mg/kg i.v.) dose-dependently increased the firing rate, spikes/burst, and burst firing of VTA neurons. EtOH (250-1000 mg/kg i.v.) administration produced similar increments in the same electrophysiological parameters. In animals pretreated with DP (50 mg/kg intraperitoneal, 30' before drug challenge), EtOH (250- 1000 mg/kg i.v.) and ACD (5-40 mg/kg i.v.) effects on the firing rate, spikes/burst, and burst firing were drastically reduced. These observations add further evidence to the idea that EtOH increases in vivo electrophysiological activity of Nacb- projecting VTA dopaminergic neurons via ACD. Our results further suggest that ACD, by increasing DA neuronal activity in the VTA, significantly contributes to the centrally mediated positive motivational properties of ethanol and may bear important theoretical consequences on pharmacological therapies of alcohol abuse and alcoholism. (1) Quertemont et al., (2004). Trends Pharmacol Sci;25(3):130-4. (2) Foddai et al., (2004) Neuropsychopharmacology;29(3):530-6. (3) Font et al., (2006) Psychopharmacology (Berl);184(1):56-64