Ethanol and nicotine interaction within the posterior ventral tegmental area in male and female alcohol-preferring rats: evidence of synergy and differential gene activation in the nucleus accumbens shell

Ethanol and nicotine are frequently co-abused. The biological basis for the high co-morbidity rate is not known. Alcohol-preferring (P) rats will self-administer EtOH or nicotine directly into the posterior ventral tegmental area (pVTA). The current experiments examined whether sub-threshold concentrations of EtOH and nicotine would support the development of self-administration behaviors if the drugs were combined. Rats were implanted with a guide cannula aimed at the pVTA. Rats were randomly assigned to groups that self-administered sub-threshold concentrations of EtOH (50 mg%) or nicotine (1 mu M) or combinations of ethanol (25 or 50 mg%) and nicotine (0.5 or 1.0 mu M). Alterations in gene expression downstream projections areas (nucleus accumbens shell, AcbSh) were assessed following a single, acute exposure to EtOH (50 mg%), nicotine (1 mu M), or ethanol and nicotine (50 mg% + 1 mu M) directly into the pVTA. The results indicated that P rats would co-administer EtOH and nicotine directly into the pVTA at concentrations that did not support individual self-administration. EtOH and nicotine directly administered into the pVTA resulted in alterations in gene expression in the AcbSh (50.8-fold increase in brain-derived neurotrophic factor (BDNF), 2.4-fold decrease in glial cell line-derived neurotrophic factor (GDNF), 10.3-fold increase in vesicular glutamate transporter 1 (Vglut1)) that were not observed following microinjections of equivalent concentrations/doses of ethanol or nicotine. The data indicate that ethanol and nicotine act synergistically to produce reinforcement and alter gene expression within the mesolimbic dopamine system. The high rate of co-morbidity of alcoholism and nicotine dependence could be the result of the interactions of EtOH and nicotine within the mesolimbic dopamine system.