Suppression of alcohol self-administration and cue-induced reinstatement of alcohol seeking by the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG

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Abstract

Glutamatergic neurotransmission has been suggested to modulate cue-induced drug-seeking behavior. Here we examined the effects of metabotropic glutamate receptor agonists on alcohol self-administration and cue-induced reinstatement. Rats were trained to self-administer 10% w/v ethanol under an FR1 schedule of reinforcement during 30-min sessions. In the reinstatement experiments, ethanol and a non-rewarding quinine solution (available on alternating days) were paired with olfactory stimuli (S+/S) as well as light (CS+) or tone (CS) stimuli. Following extinction training, reinstatement of responding was induced by the ethanol-associated stimuli (S+/CS+). The mGlu2/3 receptor agonist LY379268 (0, 1, 3 and 5 mg/kg i.p.) and the mGlu8 receptor agonist (S)-3,4-DCPG (0, 5, 10 and 15 mg/kg i.p.) attenuated alcohol self-administration and reinstatement at doses that decreased also spontaneous locomotor activity. The results suggest that metabotropic glutamate receptors may have a role in the modulation of alcohol seeking and self-administration. However, further studies with ligands with fewer motor-suppressant side effects are needed.

Introduction

Discrete or contextual stimuli that have been repeatedly paired with the availability and pharmacological effects of alcohol can induce craving in abstinent users. For example, exposure to ethanol odor or the presentation of an alcoholic beverage increases subjective reports of craving and the desire to drink (Cooney et al., 1997, Greeley et al., 1993, Schneider et al., 2001). Although a priming dose of alcohol increases the probability of further alcohol consumption (de Wit and Chutuape, 1993), a correlation between craving and subsequent drug use has not been established (Tiffany and Carter, 1998). However, the activation of certain brain areas by alcohol-associated stimuli has been shown to predict subsequent relapse in abstinent alcoholics (Grüsser et al., 2004). Similar to humans, alcohol-seeking behavior in laboratory animals is influenced by alcohol cues, as extinguished alcohol seeking has been demonstrated to be reinstated reliably by alcohol-associated visual or olfactory stimuli (Ciccocioppo et al., 2001, Katner et al., 1999, Nie and Janak, 2003).

Evidence is accumulating for the role of glutamate transmission in processing of drug-associated stimuli. Presentation of drug-associated stimuli increases accumbal dopamine and glutamate levels in laboratory animals (Hotsenpiller et al., 2001, Ito et al., 2000, Katner and Weiss, 1999, Weiss et al., 2000). These alterations in transmitter levels are probably coupled to drug-seeking behavior because stimulus-induced drug seeking is attenuated by intra-accumbal injections of dopamine or glutamate receptor antagonists (Di Ciano and Everitt, 2001, Samson and Chappell, 2004). Also when administered systemically, D1 and D2 type dopamine antagonists as well as NMDA and AMPA/kainate glutamate receptor antagonists are effective in suppressing drug seeking (Alleweireldt et al., 2002, Bäckström and Hyytiä, 2004, Crombag et al., 2002, Liu and Weiss, 2002). Glutamate receptor antagonists decrease also the expression of conditioned place preference (Bespalov, 1996, Kotlinska and Biala, 2000, Popik et al., 2003), behavioral sensitization and conditioned locomotor activity (Hotsenpiller et al., 2001, Jackson et al., 1998, Mead and Stephens, 1998), suggesting that antagonizing the actions of stimulus-induced glutamate release at postsynaptic receptors attenuates the expression of conditioned drug-related behaviors. Alternatively, it could be hypothesized that reduction of stimulus-evoked glutamate release through presynaptic metabotropic glutamate receptors could also be possible.

Metabotropic glutamate (mGlu) receptors are divided into three groups, mGluI–mGluIII, based on signal transduction pathways and sequence homology (Schoepp, 2001). Group I is comprised of mGlu1 and mGlu5 receptors, group II of mGlu2 and mGlu3 receptors and group III of mGlu4 and mGlu6-8 receptors (Schoepp, 2001). mGlu1/5 receptors are predominantly postsynaptic, whereas mGlu2/3 receptor agonists have been shown to reduce glutamate release via a presynaptic mechanism (Schoepp, 2001). Similar to group II agonists, group III agonists can negatively modulate glutamate transmission (Pothecary et al., 2002, Thomas et al., 2001).

The present study aimed at clarifying whether cue-induced reinstatement of alcohol-seeking behavior and alcohol self-administration in rats could be attenuated by pretreatment with group II/III metabotropic glutamate receptor agonists. LY379268 is a selective group II, mGlu2/3 receptor agonist that is centrally active following systemic administration (Monn et al., 1999). It has previously been shown to attenuate cocaine and heroin seeking triggered by discriminative stimuli and contextual cues, respectively, and cocaine self-administration (Baptista et al., 2004, Bossert et al., 2004). (S)-3,4-DCPG was chosen because it has been described as a potent group III, mGlu8 receptor agonist that reduces excitatory transmission during excessive glutamate release, presumably through a presynaptic action (Pothecary et al., 2002, Thomas et al., 2001), and reaches the brain at relevant concentrations after systemic administration (Linden et al., 2003).

Section snippets

Animals

Fifty-six male Long–Evans rats (HsdBlu:LE, Harlan Sprague Dawley, Indianapolis, IN) weighing 160–200 g upon arrival were used. Rats were housed in pairs in Eurostandard Type IV cages (transparent polycarbonate, dimensions 595 × 380 × 200 mm) in a temperature and humidity controlled room under a 12-h light–dark cycle (lights on at 4 p.m.). Water and pellet food (RM1, SDS, Witham, UK) were available ad libitum in the home cage except during initial training (see below). All behavioral testing was

Experiment 1: effects of mGlu receptor agonists on ethanol self-administration

Rats were allowed 28 sessions of self-administration with the 10% w/v ethanol solution before the agonist pretreatments. During the last three sessions, the average number of responses (± S.E.M.) was 26.7 ± 1.9 on the active lever and 4.2 ± 1.5 on the inactive lever for the subjects participating in this experiment. This corresponded to an average ethanol intake of 0.59 ± 0.04 g/kg.

Both the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG suppressed ethanol

Discussion

In the present study, we examined the effects of two mGlu receptor agonists, the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG, on alcohol self-administration and cue-induced reinstatement of alcohol seeking. Alcohol self-administration reflects mainly the unconditioned, primary reinforcing effects of alcohol, whereas the cue-induced reinstatement model measures the potency of alcohol-associated environmental cues to reinstate extinguished behavior and thus

Acknowledgements

The authors would like to thank Dr. Schoepp from Eli Lilly for the generous donation of LY379268. This study was supported by a grant from the Finnish Foundation for Alcohol Studies to P.B.

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