Dependence-induced alcohol drinking by alcohol-preferring (P) rats and outbred Wistar rats.

An alcohol vapor inhalation procedure has been validated for its ability to produce somatic (Rogers et al., 1979) and motivational (Roberts et al., 1996, 2000) aspects of alcohol dependence that parallel those seen in humans. This animal model was initially developed to address some of the methodological concerns with liquid diet and intragastric intubation procedures (Rogers et al., 1979). The model has since been refined to include daily 10-hour withdrawal periods between daily 14-hour alcohol vapor exposure periods; this exposure schedule accelerates and accentuates the development of increased alcohol drinking induced by dependence (O'Dell et al., 2004). There are multiple rodent lines that have been selectively bred for high and low alcohol preference, including the alcohol-preferring/-nonpreferring (P/NP) lines (Lumeng et al., 1977). Rats with high and low alcohol preference have been bred over generations in order to produce lines that are either highly prone or highly resistant to voluntary consumption of alcohol. High alcohol-drinking lines are characterized not only by their voluntary intake of high amounts of alcohol (>5 g ethanol/kg body weight/d), but also their preference for alcohol in the presence of other solutions (Murphy et al., 2002). P rats do not consume alcohol simply for its taste (Bice and Kiefer, 1990), smell, or caloric properties, as they consume alcohol even in the presence of other palatable solutions (Lankford et al., 1991). P rats also self-administer alcohol via nonoral routes (e.g., intracranially; Gatto et al., 1994) and work for a wide range of alcohol concentrations in an operant situation, even when water and food are concurrently available (Murphy et al., 1989). P rats also voluntarily drink amounts of alcohol sufficient to achieve blood–alcohol levels (BALs) that are known to be reinforcing in rodents (Li et al., 1979; Lumeng and Li, 1986). Finally, following free-choice alcohol drinking, P rats exhibit both functional (Gatto et al., 1987) and metabolic tolerance (Lumeng and Li, 1986) and, following many weeks of access, they exhibit signs of physical dependence (Kampov-Polevoy et al., 2000; Waller et al., 1982). The primary purpose of the present investigation was to test the hypothesis that P rats will self-administer higher levels of alcohol following dependence induction via chronic alcohol vapor exposure. In order to determine the effects of genetic susceptibility to high alcohol preference on the motivational aspects of alcohol dependence, a control group of genetically heterogeneous Wistar rats was trained and tested in parallel with P rats. Wistar rats are the parent line from which P rats were initially derived. A variety of parametric manipulations were employed to determine the effects of this genetic susceptibility on dependence-induced drinking during both acute withdrawal and protracted abstinence. Such gene-environment interactions have not been adequately explored to this point. A second goal of this study was to determine the long-lasting effects of alcohol dependence on alcohol-drinking behavior in P and Wistar rats. The motivational factors that drive relapse alcohol drinking in humans last well into protracted abstinence (Hershon, 1977; Voltaire-Carlsson et al., 1996). Many alcohol vapor studies have examined dependence-induced drinking in animals allowed to self-administer alcohol during acute withdrawal (2 to 12 hours), usually following approximately 4 weeks of alcohol vapor inhalation (Funk et al., 2006, 2007; O'Dell et al., 2004; Richardson et al., 2008; Roberts et al., 1996; Walker and Koob, 2007). Recently, it was shown that longer periods (≥8 weeks) of chronic intermittent alcohol vapor exposure produce dependence-induced increases in alcohol drinking that persist well into the abstinence period (Sommer et al., 2008), in agreement with an earlier study that showed protracted elevations in alcohol responding following a shorter period of vapor exposure (∼3 weeks; Roberts et al., 2000). Examination of drinking during protracted abstinence allows for complete dissociation of the somatic and motivational aspects of alcohol dependence, as well as separation of their respective effects on dependence-induced increases in alcohol drinking. The main hypothesis for the current study was that alcohol vapor inhalation would produce increases in alcohol self-administration behavior in all rats, and that these increases would be larger and last longer in selectively bred P rats than in genetically heterogeneous Wistar rats. Therefore, it was hypothesized that selective breeding for high alcohol preference (i.e., enrichment of genes that underlie alcohol preference) and dependence induced by alcohol vapor inhalation would produce a greater enhancement of alcohol-drinking behavior than either procedure alone. A secondary hypothesis was that the interaction effect of these 2 models, one genetic and the other environmental, would produce increases in alcohol drinking that last well into protracted abstinence.