Sensitization of Ventral Tegmental Area Dopamine Neurons to the Stimulating Effects of Ethanol

Background: Previous studies indicated that chronic alcohol drinking increased the sensitivity of the posterior ventral tegmental area (p‐VTA) to the reinforcing effects of ethanol. The current study tested the hypothesis that local exposure of the p‐VTA to ethanol would increase the sensitivity of dopamine (DA) neurons to the stimulating effects of ethanol. Methods: Experiment 1 examined the stimulating effects of ethanol in the p‐VTA after a 7‐day ethanol pretreatment in the p‐VTA. Adult female Wistar rats were pretreated with microinjections of 200 mg% ethanol or artificial cerebrospinal fluid (aCSF) into the p‐VTA once a day for 7 days. On the eighth day, rats received a challenge injection of ethanol (100, 200, or 300 mg%) or aCSF into the p‐VTA, and extracellular DA levels were measured in the nucleus accumbens (NAc) shell with microdialysis. Experiment 2 examined the stimulating effects of ethanol (200 mg%) after a 3‐ or 5‐day ethanol (200 mg%) pretreatment in the p‐VTA. Experiment 3 examined the stimulating effects of ethanol (200 mg%) 7 days after the last of the 7‐day ethanol (200 mg%) pretreatments in the p‐VTA. Results: Experiment 1: in both aCSF‐ and ethanol‐pretreated rats, the challenge microinjection of ethanol dose‐dependently increased DA release in the NAc shell, with significantly greater increases in ethanol‐pretreated groups. Experiment 2: the 5‐day, but not 3‐day, ethanol pretreatment protocol increased the response of p‐VTA dopamine neurons to the ethanol challenge. Experiment 3: the increased stimulating effects of ethanol were still evident after 7 days. Conclusions: The results indicate that repeated local ethanol exposure of the p‐VTA produced neuroadaptations in DA neurons projecting to the NAc shell, resulting in a persistent increase in the sensitivity of these neurons to the stimulating effects of ethanol.