Effects of CRF1-Receptor and Opioid-Receptor Antagonists on Dependence-Induced Increases in Alcohol Drinking by Alcohol-Preferring (P) Rats

Alcohol-preferring (P) rats have been bred over many generations to be highly prone to voluntary consumption of alcohol (Lumeng et al., 1977). P rats voluntarily drink amounts of alcohol sufficient to achieve pharmacologically significant blood-alcohol levels (BALs; Li et al., 1979; Lumeng and Li, 1986), and they also self-administer alcohol via nonoral routes (e.g., intracranially; Gatto et al., 1994). P rats do not consume alcohol simply for its taste, smell, or caloric properties (Bice and Kiefer, 1990; Lankford et al., 1991), and they work for alcohol in an operant situation even when water and food are concurrently available (Murphy et al., 1989). Following free-choice alcohol drinking, P rats exhibit both functional (Gatto et al., 1987) and metabolic tolerance (Lumeng and Li, 1986) and eventually exhibit signs of physical dependence following long periods of alcohol access (Kampov-Polevoy et al., 2000; Waller et al., 1982). P rats also exhibit additional increases in alcohol intake when made dependent via chronic intermittent exposure to alcohol vapor (Gilpin et al., 2008, see previous article in this issue). It is generally accepted that the relative contributions of the positive and negative reinforcing effects of alcohol to the motivation for alcohol-drinking behavior change significantly across the various stages of the addiction cycle. Alcohol-drinking behavior by organisms not dependent on alcohol is likely motivated in large part by the positive reinforcing (i.e. pleasant) effects of alcohol (Altshuler et al., 1980). Alcohol-preferring P rats provide an excellent animal model of these motivational aspects of alcohol self-administration behavior, mainly for the reasons described above. Conversely, chronic exposure to high doses of alcohol (e.g., via alcohol vapor exposure) produces somatic and affective symptoms indicative of an alcohol dependence syndrome, defined in large part by the aversive symptoms that manifest upon discontinuation of alcohol exposure. The negative affective state produced by the absence of alcohol in dependent animals is hypothesized to provide the unconditioned stimulus for negative reinforcing properties of alcohol, and it is further hypothesized that these negative reinforcing effects eventually become the primary motivational force driving alcohol consumption in the dependent organism (Koob, 2003). Brain corticotropin-releasing factor (CRF) systems play a major role in the affective-like disturbances associated with alcohol dependence (Heilig and Koob, 2007; Valdez and Koob, 2004). Withdrawal from chronic alcohol exposure produces increases in anxiety-like behavior that are blocked by CRF antagonists and, more specifically, by antagonists of the CRF1-receptor subtype (Baldwin et al., 1991; Overstreet et al., 2004). Increased alcohol consumption associated with acute withdrawal from chronic alcohol is also blocked by CRF1 antagonists in dependent animals (Chu et al., 2007; Funk et al., 2007; Gehlert et al., 2007; Sabino et al., 2006). More specifically, the small molecule CRF1-receptor antagonist used in the present study, MPZP (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5a]pyrimidin-7-amine), attenuates dependence-induced increases in alcohol drinking in Wistar rats (Richardson et al., 2008). Brain CRF systems are also involved in alcohol-related behaviors in rats selectively bred for high alcohol preference. Rats selectively bred for high and low alcohol preference exhibit innate differences in brain CRF levels (Hwang et al., 2004; Richter et al., 2000). Pharmacology studies have shown that CRF1-receptor antagonists suppress alcohol drinking by rats selectively bred for high alcohol preference under a variety of experimental conditions (Hansson et al., 2006; Overstreet et al., 2007; Sabino et al., 2006). Brain opioid systems are heavily implicated in alcohol-drinking behavior (for reviews, see Froehlich and Li, 1994; Gianoulakis, 2004). Naltrexone, classified as a general opioid receptor antagonist (but with highest affinity at the μ-opioid receptor at low doses), blocks craving and relapse drinking in humans (Volpicelli et al., 1992) and has been approved as a pharmacological treatment for alcoholism. Very low doses of naltrexone are effective in suppressing operant alcohol responding by nondependent outbred rats (Walker and Koob, 2007), and even lower doses are effective in Sardinian-preferring (sP) rats (Sabino et al., 2006). In direct contrast to CRF antagonists, naltrexone may actually be more effective in suppressing alcohol drinking by nondependent rats relative to dependent rats (Walker and Koob, 2007). The primary purpose of the present investigation was to examine the contributions of brain CRF and opioid systems to dependence-induced changes in the reinforcing effects of alcohol in genetically selected P rats. It was hypothesized that naltrexone would suppress alcohol drinking similarly in alcohol-dependent and nondependent rats, a finding that would indicate a role for brain opioid systems in the regulation of baseline alcohol-drinking behavior by P rats, but not in dependence-induced enhancement of alcohol consumption by those animals. Conversely, it was hypothesized that the CRF1-receptor antagonist (MPZP) would suppress dependence-induced, but not baseline, alcohol drinking by P rats.