Metabotropic glutamate 5 receptors regulate sensitivity to ethanol in mice

Abstract

The metabotropic glutamate receptor 5 (mGlu5) has been implicated in ethanol-and drug-seeking behaviours in rodent studies. Here we examine a number of ethanol-related behavioural assays in mice lacking mGlu5 and wild-type littermates. In a two-bottle free-choice paradigm, mGlu5-deficient mice consumed less ethanol with a reduced preference compared to wild-type mice. Indeed, mGlu5-deficienct mice were ethanol-avoiding at both concentrations of ethanol proffered (5 % and 10 % v/v). However, there was no difference in the rate of hepatic ethanol and acetaldehyde metabolism between genotypes and consumption of saccharin was similar. In a conditioned place preference study, mGlu5-deficient mice displayed a place preference for ethanol when conditioned with a low dose (1 g/kg), a phenomenon not observed in wild-type littermates, suggesting increased sensitivity to the rewarding effects of ethanol in mutant mice. Finally, mGlu5-deficient mice were more sensitive to ethanol-induced hypnosis at a high dose (3.5 g/kg) of ethanol. Thus, while mGlu5-deficient mice consume less ethanol (with a reduced preference) than wild-type mice, this is not apparently related to impaired hepatic metabolism or a lack of reward from ethanol. Rather, we provide evidence that deletion of the mGlu5 receptor increases sensitivity to centrally mediated effects of ethanol.

Glutamate Signaling in Alcohol Abuse and Dependence

“…Intriguingly, the alcohol behavioral phenotype of GRM5 KO mice is remarkably similar to that exhibited by mice with null mutations of the major Group 1 mGluR scaffolding protein Homer2 (Szumlinski et al, 2005) and by mice with null mutations of one of the downstream effectors of Group 1 mGluR activation PKCε (Olive et al, 2005). Moreover, in both GRM5 and Homer2 KO mice, the dose-response function for ethanol-induced conditioned place preference is shifted leftwards (Bird, Kirchhoff, Djouma, & Lawrence, 2008;Szumlinski et al, 2005; but see McGeehan & Olive, 2003), suggesting that the alcohol aversion exhibited by these mutant animals reflects a hyper-sensitivity to alcohol, thereby implicating a signaling pathway involving mGlu5 receptors, Homer proteins, and PKCε in regulating behavioral sensitivity to alcohol. In some support for this assertion, mice with a point mutation in mGlu5 receptors that prevents Homer scaffolding also exhibit blunted binge alcohol intake under limited-access procedures, although these mutants do not differ from WT controls regarding their alcohol intake under continuous-access procedures (Cozzoli et al, 2009(Cozzoli et al, , 2012.…”

“…Bird & Lawrence, 2009;. For one, mGlu5 receptor-null mutant mice exhibit reduced voluntary ethanol consumption and are more sensitive to the sedative/hypnotic or intoxicating effects of ethanol (Bird, Kirchhoff, Djouma, & Lawrence, 2008;Downing, Marks, Larson, & Johnson, 2010;Blednov & Harris, 2008). Intriguingly, the alcohol behavioral phenotype of GRM5 KO mice is remarkably similar to that exhibited by mice with null mutations of the major Group 1 mGluR scaffolding protein Homer2 (Szumlinski et al, 2005) and by mice with null mutations of one of the downstream effectors of Group 1 mGluR activation PKCε (Olive et al, 2005).…”

CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants

“…was administered to CREB1 DARPP-32Cre/loxlox mice and littermate controls to induce loss of righting reflex (LORR, Bird et al 2008). Once the righting reflex was lost, mice were oriented supinely and the time taken for the mice to recover was recorded.…”

Chronic intermittent toluene inhalation initiated during adolescence in rats does not alter voluntary consumption of ethanol in adulthood

“…The endogenous activity of hepatic ADH was determined for each animal by the nicotinamide adenine dinucleotide-induced increase in absorbance at 340 nm on a microplate spectrophotometer (BioeRad Benchmark Plus; BioeRad Laboratories, CA, USA) as previously described (Bird, Kirchhoff, Djouma, & Lawrence, 2008;Lodge & Lawrence, 2003). In brief, the assay was performed in duplicate at 37 C in a final volume of 1.25 mL glycine buffer (0.1 M glycine; pH 10) containing 2.4 mM of beNADþ and a volume of cytosolic fraction equivalent to 1 mg protein.…”

“…The endogenous activity of hepatic ALDH was determined for each animal by the nicotinamide adenine dinucleotide-induced increase in absorbance at 340 nm on a microplate spectrophotometer (BioeRad Benchmark Plus; BioeRad Laboratories, CA, USA) (Bird et al, 2008;Lodge & Lawrence, 2003 …”