ArticleEffects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats
Introduction
The Group I family of metabotropic glutamate receptors is made up of subtype 1 (mGlu1) and subtype 5 (mGlu5). These receptor subtypes stimulate phospholipase C and phosphoinositide hydrolysis (Abe et al., 1992, Houamed et al., 1991) and share common agonist pharmacological profiles (Conn and Pin, 1997). Group I mGlu receptors are widely expressed throughout the brain as determined from in situ hybridization and immunohistochemical work (for review see Ferraguti and Shigemoto, 2006). For example, mGlu1 receptors show intense expression in the cerebellum, and are also abundant in other regions such as the lateral septum, ventral pallidum, and thalamic nuclei (Hubert et al., 2001, Lavreysen et al., 2004a, Martin et al., 1992). mGlu5 receptors show intense expression in corticolimbic regions such as the nucleus accumbens, lateral septum, striatum, and hippocampus (Abe et al., 1992, Romano et al., 1995, Shigemoto et al., 1993).
Group I metabotropic glutamate receptors have generated interest as potential targets for different areas of therapeutic development (for reviews see Bordi and Ugolini, 1999, Gasparini et al., 2002). For example, antagonists of the Group I mGlu receptors show anxiolytic properties (Spooren et al., 2000, Steckler et al., 2005a), positive effects in models of nociception (Bhave et al., 2001, Sevostianova and Danysz, 2006), and may possess neuroprotective properties (Makarewicz et al., 2006, Szydlowska et al., 2007). In addition, mGlu5 receptors may be a viable target for therapeutic interventions in drug abuse as mGlu5 receptors have been shown to modulate cocaine, nicotine, and ethanol reinforcement (Bespalov et al., 2005, Hodge et al., 2006, Paterson et al., 2003, Tessari et al., 2004) and drug seeking behavior in reinstatement models (Backstrom et al., 2004, Backstrom and Hyytia, 2006, Bespalov et al., 2005, Schroeder et al., 2005).
In relation to drug reinforcement, studies examining the role of mGlu1 receptors are very limited. Antagonism of mGlu1 receptors with EMQMCM has been shown to reduce both cue-induced reinstatement and nicotine priming—induced reinstatement in rats trained to self-administer nicotine (Dravolina et al., 2007). In regard to ethanol reinforcement, the data published to date have shown mixed results. Work from our laboratory has shown no effect of mGlu1-receptor antagonism by 7 (Hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) on ethanol self-administration in alcohol-preferring (P) rats and in mice (Hodge et al., 2006, Schroeder et al., 2005). In contrast, others have shown that CPCCOEt reduced ethanol self-administration in mice (Lominac et al., 2006). These studies do not conclusively suggest a role for mGlu1 receptors in ethanol reinforcement, and thus, further study is warranted.
Therefore, the goal of the present work was to further characterize the role of mGlu1 receptors in ethanol reinforcement using the recently available mGlu1-receptor antagonist 3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl) (cis-4-methoxycyclohexyl) methone (JNJ16259685). JNJ16259685 is a potent noncompetitive mGlu1-receptor antagonist (Ki = 0.34 nM) that displays >1,000-fold selectivity over mGlu5 receptors in a Ca2+ mobilization assay (Lavreysen et al., 2004b). JNJ16259685 also displays no agonist, antagonist, or allosteric activity at mGlu2, mGlu3, mGlu4, or mGlu6 receptors (Lavreysen et al., 2004b). JNJ16259685 is centrally active after systemic administration and has been shown to modulate learning and memory, and anxiety, at doses ranging from 0.63 to 10 mg/kg (Steckler et al., 2005a, Steckler et al., 2005b). Thus, examining the effects of a highly potent, selective, and behaviorally active mGlu1 antagonist has the potential to further elucidate the role of these receptors in ethanol reinforcement.
In addition, the mGlu1-receptor antagonist was also tested on sucrose reinforcement as a measure of reinforcer specificity. Finally, locomotor assessments were conducted to assess potential motor disturbances by mGlu1-receptor antagonism alone and to address possible pharmacological interactions with ethanol.
Section snippets
Subjects
Male alcohol-preferring inbred rats (n = 10) were derived from a line provided by Indiana University. This stock of inbred P rats (5B substrain) was derived from breeders of the selected line of P rats originally provided in 1999 by Indiana University (courtesy of Dr. T.K. Li) and has been bred on-site at the University of North Carolina at Chapel Hill. The rats were housed in pairs in Plexiglas cages with water and food available continuously unless otherwise mentioned. The colony room was
Ethanol reinforcement and motor activity
Average baseline data (mean ± S.E.M.) for the 2 days preceding testing of JNJ16259685 on ethanol self-administration was as follows: ethanol responses (30.75 ± 3.50), water responses (7.45 ± 1.45), and ethanol intake (0.65 ± 0.07 g/kg). JNJ16259685 significantly reduced total session responding for ethanol (15% vol/vol) reinforcement (Fig. 1A). The two-way RM ANOVA showed a significant main effect of lever with greater responses on the ethanol lever [F(1, 9) = 117.01; P < .001], a main effect of JNJ16259685
Discussion
In the present work, blockade of mGlu1 receptors with JNJ16259685 reduced ethanol self-administration at doses (0.1 and 0.3 mg/kg JNJ16259685) that did not alter sucrose self-administration. These data pattern suggest that ethanol-reinforced responding is more sensitive to mGlu1-receptor antagonism than sucrose-reinforced responding. However, the doses of the mGlu1-receptor antagonist that reduced ethanol and sucrose self-administration also reduced locomotor activity, suggesting that the
Acknowledgments
This work was supported by Grants AA016009 to J.B. and AA014983 and AA011605 to C.W.H. from the National Institute on Alcohol Abuse and Alcoholism and by the Bowles Center for Alcohol Studies. The authors would like to thank Dr. David H. Overstreet for breeding and providing the P rats.
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