Elsevier

Alcohol

Volume 42, Issue 1, February 2008, Pages 13-20
Alcohol

Article
Effects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats

https://doi.org/10.1016/j.alcohol.2007.11.001Get rights and content

Abstract

The Group I family of metabotropic glutamate receptors includes subtype 1 (mGlu1) and subtype 5 (mGlu5) receptors. This family of receptors has generated interest as potential targets for different areas of therapeutic development, including intervention for alcohol and drug abuse. Most of this interest is driven by findings showing involvement of mGlu5 receptors in the regulation of drug self-administration; however, studies examining the role of mGlu1 receptors in drug self-administration are limited. The purpose of this work was to examine the role of mGlu1-receptor antagonism in the maintenance of ethanol self-administration and the self-administration of an alternate nondrug reward, sucrose. Male alcohol-preferring inbred rats were trained to self-administer ethanol (15% vol/vol) versus water on a concurrent schedule of reinforcement, and the effect of the mGlu1-receptor antagonist JNJ16259685 (0.1–1.0 mg/kg intraperitoneal [IP]) was evaluated on self-administration. The rats were then trained to self-administer sucrose (0.4% wt/vol) versus water, and the same dose range of JNJ16259685 was tested. Locomotor activity was tested in a separate assessment to evaluate potential nonspecific motor effects of the antagonist. Ethanol self-administration was dose dependently reduced by JNJ16259685. This reduction was likely due to a motor impairment as the lowest effective dose (0.1 mg/kg) significantly reduced locomotor behavior. Sucrose self-administration was reduced by the highest JNJ16259685 dose (1.0 mg/kg), and this reduction was also likely due to a motor impairment. Interestingly, ethanol self-administration was more sensitive to mGlu1-receptor antagonism than sucrose self-administration as lower JNJ16259685 doses reduced ethanol-reinforced responding and motor behavior. Together, these results suggest that mGlu1 receptors do not play a specific role in modulating ethanol self-administration or the self-administration of an alternate nondrug reward (i.e., sucrose).

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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