Regulation of Motivation to Self‐Administer Ethanol by mGluR5 in Alcohol‐Preferring (P) Rats

THE METABOTROPIC GLUTAMATE receptor sub-type1(mGluR1)and subtype 5 (mGluR5) belong to the Group I family of mGluRs. This family of receptors share common agonist pharmacological profiles and are coupled to similar signal transduction pathways (Conn and Pin, 1997). However, these receptor subtypes are abundant in different brain regions, with greater expression of mGluR5 in corticolimbic regions than mGluR1, which is highly abundant in the cerebellum (Romano et al., 1995; Shigemoto et al., 1992). Pharmacological antagonists of the Group I mGluRs show positive effects in models of nociception (Bhave et al., 2001; Sevostianova and Danysz, 2006) and anxiety (Spooren et al., 2000; Steckler et al., 2005a), and may possess neuroprotective properties (Baskys et al., 2005; Makarewicz et al., 2006); for reviews of Group I mGluR therapeutic potential, see (Bordi and Ugolini, 1999; Gasparini et al., 2002). There is a growing interest in the role of mGluR5 in drug taking behaviors, whereas mGluR1 has been less studied. For example, mGluR5 antagonism has been shown to attenuate self-administration of cocaine (Kenny et al., 2003; Lee et al., 2005; Tessari et al., 2004), nicotine (Kenny et al., 2003; Paterson et al., 2003; Tessari et al., 2004), as well as relapse to cocaine (Backstrom and Hyytia, 2006) and nicotine seeking (Tessari et al., 2004). mGluR5 antagonism has also been implicated in mediating ethanol reinforcement as the mGluR5 antagonist 6-methyl-2-(phenylethynyl) pyridine (MPEP) has been shown to reduce ethanol self-administration in mice (Hodge et al., 2006; Lominac et al., 2006), alcohol-preferring P rats (Schroeder et al., 2005), and Long Evans rats (Backstrom et al., 2004), and relapse to ethanol seeking (Backstrom et al., 2004; Schroeder et al., 2005). The findings of mGluR1 antagonism on ethanol self-administration are mixed with a reduction (Lominac et al., 2006), and no change (Hodge et al., 2006; Schroeder et al., 2005) in self-administration reported to date. In sum, glutamate activity at mGluR5, and perhaps mGluR1, appears to be an important factor mediating ethanol reinforcement. To further examine the role of Group I mGluRs in ethanol reinforcement, the present study examined ethanol self-administration under a progressive ratio (PR) schedule of reinforcement in selectively bred alcohol-preferring P rats (Li et al., 1979). Under PR schedules, the response requirement for reinforcer delivery increases systematically. The point at which the animal ceases to respond within a determined period is defined as the break point. Thus, the break point serves as an index of an animal’s motivation to work (e.g., respond) for the reinforcer (e.g., ethanol) and the reinforcing efficacy of the drug (for reviews, see Markou et al., 1993; Richardson and Roberts, 1996; Stafford et al., 1998). In the present work, the role of Group I receptors (mGluR1 and mGluR5) was examined on ethanol and sucrose reinforced responding under a PR schedule of reinforcement. First, P-rats were trained to self-administer 15% ethanol (v/v) with water concurrently available. The mGluR1 antagonist JNJ 16259685 (0 to 1 mg/kg) and the mGluR5 antagonist MPEP (0 to 10 mg/kg) were then tested for ethanol self-administration under a PR schedule of reinforcement. Second, to determine if antagonism of Group I mGluRs alters motivation to self-administer a nondrug rewarding substance, the rats were subsequently trained to self-administer sucrose (0.4%, w/v) with water concurrently available.The same dose ranges of JNJ 16259685 and MPEP were tested on sucrose self-administration under the same PR schedule of reinforcement. After each antagonist assessment on ethanol and sucrose reinforcement, the lowest effective dose of the antagonist that reduced ethanol and sucrose break point responding was examined for potential effects on locomotor activity.