Free-choice ethanol consumption under the influence of GABAergic drugs in rats

Background: Neurobiological mechanisms leading from controlled alcohol consumption to addiction are poorly understood. Among multiple neurotransmitters gamma-amino-butyric acid (GABA) is suggested to play a role. The present investigation studied effects of drugs interacting with the GABAergic system on the motivation of ethanol consumption. Methods: Fifty male PVG/OlaHsd rats were analyzed for free-choice ethanol drinking behavior without and with pre-exposure to drugs acting on the GABAergic system. For pretreatment, animals received the benzodiazepine agonists or antagonists diazepam, flumazenil, or Ro15-4513, or the GABA uptake inhibitor tiagabine via the drinking water for 4 weeks (day -21 until day 7). On day 0, two bottles containing 5% and 12% ethanol were added. On day 7, GABAergic drug exposure was discontinued and drug solutions were replaced by water. Between days 8 and 35, three alcohol deprivation periods of 1 to 3 days were randomly implemented. Results: The animals ingested substantial amounts of ethanol that was differentially affected by the GABAergic drugs. Diazepam increased and flumazenil decreased ethanol consumption significantly by about 30%. Without GABAergic drug pretreatment, a significant alcohol deprivation effect indicated by enhanced ethanol consumption after re-exposure to alcohol was observed after the third deprivation phase. The deprivation effect was prevented by pretreatment with diazepam or flumazenil, unaffected by Ro15-4513, and advanced by tiagabine. Conclusions: Modulation of GABAergic neurotransmission affects subsequent ethanol consumption and deprivation effects, Because enhancing of the GABAergic tone by the GABA uptake inhibitor tiagabine or by the benzodiazepine diazepam had different behavioral consequences, it seemed likely that the two drugs induce differential adaptive changes leading to distinct alterations in the motivation to consume alcohol.