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
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.
References (45)
- et al.
Context-specific enhancement of glutamate transmission by cocaine
Neuropsychopharmacology
(2000) The expression of both amphetamine-conditioned place preference and pentylenetetrazol-conditioned place aversion is attenuated by the NMDA receptor antagonist (+/−)-CPP
Drug Alcohol Depend.
(1996)- et al.
Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats
Pharmacol. Biochem. Behav.
(2002) - et al.
A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior
Neuroscience
(1999) - et al.
Effect of dopamine receptor antagonists on renewal of cocaine seeking by reexposure to drug-associated contextual cues
Neuropsychopharmacology
(2002) - et al.
Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior
Neuropsychopharmacology
(2001) - et al.
Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat
Neuropsychopharmacology
(1999) - et al.
Systemic administration of the potent mGlu8 receptor agonist (S)-3,4-DCPG induces c-Fos in stress-related brain regions in wild-type, but not mGlu8 receptor knockout mice
Neuropharmacology
(2003) - et al.
AMPA-receptors are involved in the expression of amphetamine-induced behavioural sensitisation, but not in the expression of amphetamine-induced conditioned activity in mice
Neuropharmacology
(1998) - et al.
Anticonvulsant activity of 3,4-dicarboxyphenylglycines in DBA/2 mice
Neuropharmacology
(2001)
Reduction of excitatory transmission in the retino-collicular pathway via selective activation of mGlu8 receptors by DCPG
Neuropharmacology
(S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord
Neuropharmacology
Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats
Psychopharmacology
Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer
J. Neurosci.
A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking
J. Neurosci.
Attenuation of cocaine-seeking behaviour by the AMPA/kainate receptor antagonist CNQX in rats
Psychopharmacology
Ionotropic glutamate receptor antagonists modulate cue-induced reinstatement of ethanol-seeking behavior
Alcohol., Clin. Exp. Res.
The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats
J. Pharmacol. Exp. Ther.
Tolerance to the motor impairment, but not to the reversal of PCP-induced motor activities by oral administration of the mGlu2/3 receptor agonist, LY379268
Naunyn-Schmiedeberg's Arch. Pharmacol.
Long-lasting resistance to extinction of response reinstatement induced by ethanol-related stimuli: role of genetic ethanol preference
Alcohol., Clin. Exp. Res.
Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men
J. Abnorm. Psychology
Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction
J. Neurosci.
Cited by (115)
Roles of metabotropic glutamate receptor 8 in neuropsychiatric and neurological disorders
2023, International Review of NeurobiologyTargeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases
2022, Pharmacology and TherapeuticsClinical investigations of compounds targeting metabotropic glutamate receptors
2022, Pharmacology Biochemistry and BehaviorAlcohol: Neurobiology of Addiction
2021, Alcohol: Neurobiology of Addiction