Chronic Ethanol Drinking by Alcohol-Preferring Rats Increases the Sensitivity of the Posterior Ventral Tegmental Area to the Reinforcing Effects of Ethanol Zachary A. Rodd, Richard L. Bell, Victoria K. McQueen, Michelle R. Davids, Cathleen C. Hsu, James M. Murphy, Ting-Kai Li, Lawrence Lumeng, and William J. McBride Background: The ventral tegmental area (VTA) is involved in regulating ethanol drinking, and the posterior VTA seems to be a neuroanatomical substrate that mediates the reinforcing effects of ethanol in ethanol-naïve Wistar and ethanol-naïve alcohol-preferring (P) rats. The objective of this study was to test the hypothesis that chronic ethanol drinking increases the sensitivity of the posterior VTA to the reinforc- ing effects of ethanol. Methods: Two groups of female P rats (one given water as its sole source of fluid and the other given 24-hr free-choice access to 15% ethanol and water for at least 8 weeks) were stereotaxically implanted with guide cannulae aimed at the posterior VTA. One week after surgery, rats were placed in standard two-lever (active and inactive) operant chambers and connected to the microinfusion system. Depression of the active lever produced the infusion of 100 nl of artificial cerebrospinal fluid (CSF) or ethanol. The ethanol-naïve and chronic ethanol-drinking groups were assigned to subgroups to receive artificial CSF or 25, 50, 75, or 125 mg/dl of ethanol (n = 6 –9/dose/group) to self-infuse (FR1 schedule) during the 4-hr sessions given every other day. Results: Compared with the infusions of artificial CSF, the control group reliably (p  0.05) self-infused 75 and 125 mg/dl of ethanol but not the lower concentrations. The ethanol-drinking group had significantly (p  0.05) higher self-infusions of 50, 75, and 125 mg/dl of ethanol than artificial CSF during the four acquisition sessions; the number of infusions of all three doses was higher in the ethanol-drinking group than in the ethanol-naive group. Both groups decreased responding on the active lever when artificial CSF was substituted for ethanol, and both groups demonstrated robust reinstatement of responding on the active lever when ethanol was restored. Conclusions: Chronic ethanol drinking by P rats increased the sensitivity of the posterior VTA to the reinforcing effects of ethanol. Key words: Intracranial Self-Administration, Ethanol Reinforcement, Neuroadaptations, Sensitization, Ethanol Reward. T HE INTRACRANIAL SELF-ADMINISTRATION (ICSA) technique has been used to identify brain sites that are involved in mediating the reinforcing effects of drugs of abuse (for review, see McBride et al., 1999). The ventral tegmental area (VTA) has been shown to support the self-infusion of opioids (Bozarth and Wise, 1981; De- vine and Wise, 1994), acetaldehyde (Rodd-Henricks et al., 2002b), and a GABA A agonist (Ikemoto et al., 1998) or antagonist (Ikemoto et al., 1997b), depending on the VTA subregion. Gatto et al. (1994) were the first to demonstrate that the VTA also supported the self-infusion of ethanol. These investigators demonstrated that female alcohol- preferring (P) rats self-infused 75 to 200 mg/dl of ethanol into the VTA, whereas female alcohol-nonpreferring (NP) rats did not reliably self-infuse ethanol at any of the con- centrations tested. Moreover, P rats readily discriminated the active from the inactive lever and extinguished respond- ing on the active lever when artificial cerebrospinal fluid (CSF) was substituted for ethanol. These results not only indicated that the VTA was a neuroanatomical substrate me- diating the reinforcing effects of ethanol but also suggested that genetic factors might play a role in determining the reinforcing actions of ethanol within the VTA. In a subse- quent study, Rodd-Henricks et al. (2000) established that female Wistar rats self-infused 150 to 400 mg/dl of ethanol From the Institute of Psychiatric Research (ZAR, RLB, VKM, MRD, CCH, JMM, WJM), Departments of Psychiatry (ZAR, RLB, VKM, MRD, CCH, JMM, WJM), Medicine (LL), and Biochemistry (WJM), Indiana University School of Medicine, Indiana University; and Department of Psy- chology (JMM), Purdue School of Science, Indiana University-Purdue Uni- versity at Indianapolis, Indianapolis, Indiana. Received for publication August 10, 2004; accepted November 10, 2004. This study was supported in part by grants AA07611 and AA12262. Reprint requests: Dr. Zachary A. Rodd, Indiana University School of Medicine, Institute of Psychiatric Research, 791 Union Drive, Indianapolis, IN 46202-4887; Fax: 317-274-1365; E-mail: zrodd@iupui.edu. T-KL is currently affiliated with the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland. DOI: 10.1097/01.ALC.0000156127.30983.9D 0145-6008/05/2903-0358$03.00/0 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 29, No. 3 March 2005 358 Alcohol Clin Exp Res, Vol 29, No 3, 2005: pp 358–366