Drug challenges reveal differences in mediation of stress facilitation of voluntary alcohol drinking and withdrawal-induced anxiety in alcohol-preferring P rats.

Stress has been implicated in precipitating relapse in alcoholics (Breese et al., 2005; Sinha, 2001), but the relationship between stress and alcohol intake in both animals and humans has been and remains controversial (e.g., Champagne and Kirouac, 1987; Lynch et al., 1999; Pohorecky, 1990, 1991) despite the apparent simplicity of the tension reduction hypothesis (e.g., Kalodner et al., 1989; Young et al., 1990). Some of these discrepancies may relate to differences in animal strains, types of stressors, or other procedural variables. For example, Lynch et al. (1999) reported that restraint stress resulted in increased voluntary alcohol consumption in Wistar rats, while Chester et al., 2004) reported a decrease in voluntary alcohol drinking in the alcohol-preferring P rats or the high alcohol drinking (HAD) rats during the application of stress. Both groups reported increased drinking after termination of stress (Chester et al., 2004; Lynch et al., 1999). Thus, stress may have biphasic effects on alcohol intake depending upon the time at which measurements are made. Footshock-induced stress resulted in a reduction in alcohol drinking in adolescent Sprague–Dawley (SD) rats (Brunell and Spear, 2005), but increased alcohol intake in a variety of alcohol-preferring rat lines, including the alcohol-preferring (P) and HAD rats (Vengeliene et al., 2003). On the other hand, repeated swim stress increased alcohol intake only in Wistar rats, not the alcohol-preferring rat lines (Vengeliene et al., 2003). Of particular relevance to the present study is the report by Funk et al. (2004). They applied repeated footshock or social defeat during 2-week deprivation periods and reported that the elevated alcohol drinking associated with the alcohol-deprivation effect (ADE) was enhanced in the stress groups. The present study shows that acute restraint stress during withdrawal from alcohol can have a similar effect in P rats. Stress has also been implicated in the induction of anxiety-like behavior (Breese et al., 2004; Valdez et al., 2002). Indeed, it has been shown that exposure to restraint stress for 60 min is comparable to an episode of withdrawal from 5 days exposure to alcohol, with both procedures sensitizing rats to the anxiety-like behavior observed during withdrawal from a final episode of alcohol exposure (Breese et al., 2004; Overstreet et al., 2002). These studies have been carried out in SD rats on a forced alcohol diet. Because these rats do not drink substantial amounts of alcohol voluntarily, it was not possible to explore the relationship between stress, voluntary alcohol drinking, and subsequent withdrawal-induced anxiety-like behavior. By using a modified repeated withdrawal protocol (Overstreet et al., 2002, 2003, 2004) in the alcohol-preferring P rats, it was possible to explore the relationship between these variables, as reported in the current communication and described briefly in a previous report (Breese et al., 2004). Another well-characterized phenomenon in the P rat is the ADE, where the rats exhibit increased drinking of and preference for alcohol following a period of deprivation (Holter et al., 1998; McKinzie et al., 1998; Rodd-Henricks et al., 2000a,b; Sinclair and Li, 1989; Spanagel and Holter, 1999, 2000). These studies often employ long-term exposure to water and alcohol solutions and have relatively long (2 weeks) deprivation periods. The present communication includes P rats that have been subjected to quite brief (5-day) exposures to water and alcohol and even briefer (2 days) deprivation (withdrawal) periods. The elevated alcohol intake and withdrawal-induced anxiety under these conditions are quite remarkable (see Breese et al., 2004). While others have reported both an increase in alcohol drinking and anxiety-like behavior in out-bred rats, the rats had access to alcohol for nearly 1 year (Holter et al., 1998; Spanagel and Holter, 1999), not just 15 days. The increase in withdrawal-induced anxiety-like behavior in SD rats has been blocked or reduced by treatments with specific pharmacological actions during the early withdrawal periods (Breese et al., 2004; Knapp et al., 2005; Overstreet et al., 2003, 2004) despite the fact that the drug treatments were given nearly a week before the behavioral test. Among the compounds that counteracted the withdrawal-induced anxiety were flumazenil, a benzodiazepine (BZD) receptor antagonist, buspirone, a 5-HT1A receptor partial agonist, and CP154,526, a corticotropin-releasing factor type 1 (CRF1) receptor antagonist. These compounds were, therefore, examined in the P rats subjected to multiple cycles of alcohol exposure and withdrawal/deprivation and stress. In addition, the following drugs known to affect alcohol intake or the ADE were tested: naloxone, an opiate receptor antagonist, reduces alcohol intake (Overstreet et al., 1999), while haloperidol, a dopamine receptor antagonist, reduces the ADE (Salimov et al., 2000) and olanzapine, an atypical antipsychotic that blocks both dopamine and serotonin receptors, reduces alcohol consumption and craving in humans (Hutchison et al., 2006). The findings of this study, which greatly extend the results previously reported (Breese et al., 2004), suggest a close but imperfect link between the elevated voluntary drinking induced by stress and the withdrawal-induced anxiety-like behavior.