Baclofen Blocks Expression and Sensitization of Anxiety‐Like Behavior in an Animal Model of Repeated Stress and Ethanol Withdrawal

RATS REPEATEDLY EXPOSED to 5-day cycles of ethanol in a liquid diet exhibit anxiety-like behavior following withdrawal from the third of 3 cycles (Overstreet et al., 2002). Furthermore, restraint stress substitutes for the first 2 cycles to sensitize anxiety during withdrawal from a future single cycle and elicits anxiety during abstinence (Breese et al., 2004, 2005a, 2005b). These protocols extend work with sensitized or “kindled” seizures in rats (e.g., McCown and Breese, 1990) and model sensitization of symptoms in human alcoholic individuals (Ballenger and Post, 1978; Malcolm et al., 2000; Sinha, 2001). This anxiety-like behavior (“anxiety”) in rats is manifest as a reduction in time spent in social interaction (SI), a deficit that can be prevented by pretreatment of the first 2 withdrawals by such drugs as the benzodiazepine (BZD) receptor antagonist flumazenil, the 5-HT1A receptor agonist buspirone, the 5-HT2C receptor antagonist SB242084, and the Type 1 corticotropin-releasing factor (CRF) antagonist CRA1000 (Knapp et al., 2005; Overstreet et al., 2003, 2004). These results suggest that such drugs may be useful for modifying emotional factors that may contribute to the development and/or maintenance of alcoholism. In the present investigation, several agents from drug classes with demonstrated clinical utility in human alcoholism or potential anxiety-modulating effects in animal models were tested for effects in the repeated ethanol sensitization protocol. Acamprosate, baclofen, and naloxone were selected in part because they or closely related compounds have been used clinically in alcoholic patients. Acamprosate has been widely used in Europe (and more recently the United States) to reduce relapse in alcoholic subjects, and some studies show it to be modestly effective (e.g., Garbutt et al., 1999; Pelc et al., 1997; Verheul et al., 2005; Wilde and Wagstaff, 1997). Baclofen, a GABAB receptor agonist, has shown promise in early, limited clinical trials (Addolorato et al., 2002; Flannery et al., 2004) and appears to have anxiolytic properties (e.g., Drake et al., 2003; Flannery et al., 2004). Initial studies of withdrawal from relatively intense and/or extended ethanol treatment regimens suggest acute actions of baclofen against withdrawal anxiety and accompanying physical symptoms as well (Colombo et al., 2000; File et al., 1991, 1992). Naloxone, an opiate antagonist, suppresses ethanol intake in rats (e.g., Overstreet et al., 1999). The related compound naltrexone has been widely used in the United States and is also modestly successful in reducing relapse/drinking in many studies (reviewed in Anton and Swift, 2003) but not others (Krystal et al., 2001). To explore possible mechanisms of an effect of acamprosate in this paradigm, several other compounds with actions against glutamate and/or N-methyl-d-aspartate (NMDA) receptors were investigated in the repeated ethanol sensitization protocol. While the mechanisms mediating acamprosate’s action in animal models and patients are not yet clear, it has been suggested that acamprosate may inhibit glutamatergic function (Harris et al., 2003; Littleton and Zieglgansberger, 2003; Mayer et al., 2002). Ifenprodil, lamotrigine, dizocilpine, {"type":"entrez-protein","attrs":{"text":"CGS19755","term_id":"875773122","term_text":"CGS19755"}}CGS19755, and 6-methyl-2-(phenylethynyl)pyridine (MPEP) were selected for the current studies because each antagonizes glutamatergic activity in a unique manner. Ifenprodil has a novel indirect inhibitor mechanism at the NMDA receptor (Snell et al., 2000). Lamotrigine is a novel antiseizure drug that regulates the release of glutamate (Messenheimer, 1995), while dizocilpine and {"type":"entrez-protein","attrs":{"text":"CGS19755","term_id":"875773122","term_text":"CGS19755"}}CGS19755 are noncompetitive and competitive blockers, respectively, of the NMDA receptor. 6-Methyl-2-(phenylethynyl)pyridine is an antagonist at the mGluR5 metabotropic glutamate receptor (Gasparini et al., 1999) and reportedly reduces ethanol drinking (Olive et al., 2005), cocaine reward (McGeehan and Olive, 2003) and anxiety in some models (Busse et al., 2004). If glutamatergic mechanisms participate in the adaptive changes associated with withdrawal from chronic ethanol and in the efficacy of acamprosate observed in the current experimental series and in clinical populations, then one would predict that 1 or more of these agents would counteract the reduced SI in ethanol-withdrawn rats. Diazepam and flumazenil were included in some experiments as positive controls based on previously reported results (Knapp et al., 2004, 2005).