Sensitization of ventral tegmental area dopamine neurons to the stimulating effects of ethanol.

The Mesolimbic Dopamine (DA) system projects from DA neurons in the midbrain ventral tegmental area (VTA) to several limbic forebrain regions, mainly the nucleus accumbens (NAc) (Oades and Halliday, 1987). A number of studies have associated this pathway with mediating the reinforcing and rewarding effects of drugs of abuse, including ethanol (Gonzales et al., 2004; Koob, 1992; Koob et al., 1998; McBride et al., 1999; Wise, 1996). Electrophysiological and neurochemical studies indicate that ethanol activates the mesolimbic DA system. Ethanol increased the firing rates of VTA DA neurons both in vivo (Foddai et al., 2004; Gessa et al., 1985) and in vitro (Brodie et al., 1990, 1999). Studies using the in vivo microdialysis technique demonstrated that experimenter-administered ethanol increased extracellular DA levels in the VTA (Campbell et al., 1996; Kohl et al., 1998) and NAc (Campbell and McBride, 1995; Imperato and Di Chiara, 1986; Yoshimoto et al., 1991). Operant self-administration of ethanol was also shown to enhance NAc DA levels (Gonzales and Weiss, 1998; Melendez et al., 2002; Weiss et al., 1993, 1996), although recent findings (Doyon et al., 2004, 2005) suggested that the increase of NAc DA levels after self-administration might not be due solely to the local pharmacological effects of ethanol. A number of studies testing the effects of dopaminergic agents on alcohol drinking in animals also suggest an association between the mesolimbic DA system and alcohol drinking. Nonspecific blockade of DA receptors, either globally or locally within the NAc, decreased oral ethanol intake and operant responding for ethanol (Rassnick et al., 1992; Samson et al., 1993). Specific activation of VTA D2 autoreceptors also decreased voluntary oral ethanol intake and operant responding (Hodge et al., 1993; Nowak et al., 2000). Furthermore, physiologically relevant concentrations of ethanol were self-infused directly into the posterior VTA (p-VTA) (Gatto et al., 1994; Rodd-Henricks et al., 2000), suggesting this region is a neuroanatomical substrate for the reinforcing effects of ethanol. Subsequent studies indicated that activation of p-VTA DA neurons is involved in the local reinforcing effects of ethanol (Rodd et al., 2004, 2005c). Systemic ethanol pre-exposure in rodents produces neuroadaptations within the mesolimbic system. Repeated intermittent exposure to ethanol increased the responsiveness of VTA DA neurons to the excitation of a subsequent ethanol challenge in vitro (Brodie, 2002), elevated basal extracellular DA concentrations in the NAc (Smith and Weiss, 1999), decreased DA D2 autoreceptor function in the NAc (Engleman et al., 2003), and increased ethanol intake (Camarini and Hodge, 2004). Chronic ethanol exposure, via liquid diet, vapor chamber or continuous access, increased operant responding for ethanol (Schulteis et al., 1996) and subsequent voluntary oral ethanol intake (Lopez and Becker, 2005; Melis et al., 2002). Furthermore, chronic alcohol drinking and exposure to repeated deprivations enhanced the reinforcing effects of ethanol in the p-VTA (Rodd et al., 2005a,2005b). However, it remains unknown, given the global effects with systemic ethanol exposure, whether ethanol-induced neuroadaptations were initiated within the VTA, NAc, or even other brain regions modulating the activity of the mesolimbic system. The electrolytic microinfusion transducer (EMIT) system (Bozarth and Wise, 1980; Goeders and Smith, 1987) has been used to test the local reinforcing effects of ethanol within the VTA (Gatto et al., 1994; Rodd et al., 2004, 2005c; Rodd-Henricks et al., 2000), and in a preliminary study to test the local stimulating effects of ethanol in the VTA on DA release in the NAc. In the later study, pulse injections of ethanol into the p-VTA increased DA release in the NAc shell. The use of the EMIT system provided a feasible approach to investigate the effects of direct ethanol exposure of the p-VTA on subsequent ethanol effects on VTA DA neurons. The hypothesis to be tested in the current study was that direct repeated exposure of the p-VTA to ethanol would produce neuroadaptations that would increase the sensitivity of VTA DA neurons to the stimulating effects of ethanol. Rats were given microinjections of ethanol into the p-VTA over multiple days, then microdialysis was conducted, during which rats received challenge injections of ethanol into the p-VTA. The change in extracellular DA levels in the NAc shell was used as an index of the local stimulating effects of ethanol within the p-VTA.