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

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 selfadministration; 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 non-drug reward, sucrose. Male alcohol-preferring inbred (iP) rats were trained to self-administer ethanol (15% v/v) vs. water on a concurrent schedule of reinforcement, and the effect of the mGlu1 receptor antagonist JNJ16259685 (0.1 -1.0 mg/kg IP) was evaluated on self-administration. The rats were then trained to self-administer sucrose (0.4% w/v) vs. water, and the same dose range of JNJ16259685 was tested. Locomotor activity was tested in a separate assessment to evaluate potential non-specific 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 non-drug reward (i.e., sucrose).

Glutamate Signaling in Alcohol Abuse and Dependence

“…Indeed, systemic pretreatment with the JNJ compound dose-dependently reduced alcohol-reinforced responding in rats on both a fixed ratio and a progressive ratio schedule of reinforcement. Notably, in both studies, the minimally effective JNJ 16259685 dose that reduced ethanol self-administration also impaired locomotor activity but did not influence the self-administration of sucrose (Besheer et al, 2008a(Besheer et al, , 2008b. Although Lominac et al (2006) failed to detect any effect of mGlu1 receptor inhibition upon spontaneous locomotion, CPCCOEt potentiated the sedative/hypnotic effects of ethanol.…”

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

“…The mGluR5 antagonists MPEP and MTEP reduce the selfadministration of addictive substances (i.e. nicotine, amphetamine, cocaine, morphine or alcohol) in rats and mice (Hodge et al, 2006;Kenny et al, 2003;Martin-Fardon et al, 2009;Osborne and Olive, 2008;Paterson et al, 2003;Schroeder et al, 2005), and the mGluR1 antagonist (3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685) ameliorates the behavioral effects of cocaine and methamphetamine in squirrel monkeys and alcohol intake in rats (Achat-Mendes et al, 2012;Besheer et al, 2008). Other mGluR1 antagonists such as NAM-EMQMCM and CPCCOEt either did not change (Schroeder et al, 2005) or reduced ethanol (Lominac et al, 2006) self-administration in rodents.…”

Antagonism of Metabotropic Glutamate 1 Receptors Attenuates Behavioral Effects of Cocaine and Methamphetamine in Squirrel Monkeys

“…There appear to be no other published reports investigating the direct role of the mGluR1subtype in cocaine's reinforcing effects, but mGluR1 signaling has been implicated in the reinforcing effects of other drugs of abuse (Olive, 2009 for review). In a previous study in rats, for example, JNJ16259685 pretreatment significantly decreased the break point at which ethanol was self-administered under a progressive ratio schedule (Besheer et al, 2008).…”

“…The available preclinical evidence sug-gests, however, that mGluR1 activity can modulate some behavioral effects of drugs of abuse in rodents. For example, the pharmacological inhibition of mGluR1 can attenuate ethanolinduced place preference and ethanol self-administration (Lominac et al, 2006;Besheer et al, 2008). Regarding psychostimulants, the inhibition of mGluR1 activity blocked cocaineinduced psychomotor sensitization (Dravolina et al, 2006;Kotlinska and Bochenski, 2011) and methamphetamine-induced hyperlocomotion (Satow et al, 2008), and amphetamine-induced locomotor activity was greater in mGluR1 knockout mice compared with their wild-type littermates (Mao et al, 2001).…”