Regulation of Motivation to Self‐Administer Ethanol by mGluR5 in Alcohol‐Preferring (P) Rats

Besheer, Joyce; Faccidomo, Sara; Grondin, Julie J.M.; Hodge, Clyde W.

doi:10.1111/j.1530-0277.2007.00570.x

Cited by 95 publications

(101 citation statements)

References 43 publications

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“…Similarly, the mGluR5 antagonist MTEP also reduces the reinforcing effects of ethanol in rats and mice (Cowen et al, 2005;Cowen et al, 2007). Importantly, these dose-dependent effects of mGluR5 antagonists on ethanol self-administration are not associated with disruptions in motor performance (Besheer et al, 2007b;Cowen et al, 2007;Hodge et al, 2006). By contrast, other recent data indicate that blockade of post-synaptic mGluR1 (also group I) with the highly potent and brain penetrant antagonist JNJ 16259685 reduces alcohol self-administration and progressive ratio performance via nonspecific effects on motor activity in rats (Besheer et al, 2007a, b).…”

Section: Discussionmentioning

confidence: 90%

“…For example, the non-competitive mGluR5 antagonist MPEP has been shown suppress the reinforcing effects of ethanol in rats and mice (Backstrom et al, 2004;Hodge et al, 2006;Schroeder et al, 2005), attenuate the motivation to self-administer ethanol (Besheer et al, 2007b), block relapse-like behavior in multiple models (Backstrom et al, 2004;Schroeder et al, 2005), and inhibit the discriminative stimulus properties of investigator-and selfadministered ethanol (Besheer et al, 2003;Besheer et al, 2006). Similarly, the mGluR5 antagonist MTEP also reduces the reinforcing effects of ethanol in rats and mice (Cowen et al, 2005;Cowen et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082

Salling

Faccidomo

Hodge

2008

Pharmacology Biochemistry and Behavior

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Emerging evidence indicates that specific metabotropic glutamate receptors (mGluRs) modulate ethanol self-administration. In general, inhibition of glutamate transmission through blockade of postsynaptic mGluRs, or activation of presynaptic mGluRs, inhibits ethanol self-administration. The goal of this preclinical study was to further characterize mGluR regulation of ethanol selfadministration by examining effects of AMN082, an allosteric positive modulator of presynaptic mGluR7 activity. Separate groups of C57BL/6J male mice were trained to self-administer ethanol or sucrose on a fixed-ratio 4 schedule of reinforcement during 1 hour sessions. On test days, mice were pretreated with AMN082 (0, 1.0, 3.0, 5.6, or 10 mg/kg) 30 minutes prior to self-administration sessions. Functional specificity and activity was examined by testing the effects of AMN082 (0 -10 mg/kg) on open-field locomotor activity and HPA axis function as measured by plasma corticosterone levels. AMN082 (10 mg/kg) produced a significant reduction in ethanol and sucrose reinforced responding, and inhibited locomotor activity. Plasma corticosterone levels were significantly increased following AMN082 (5.6 and 10 mg/kg) suggesting a dose-dependent dissociation between the behavioral and hormonal effects of the compound. These data suggest that activation of mGluR7 by AMNO82 produces non-specific reductions in motivated behavior that are associated with negative effects on motor activity.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082

Salling

Faccidomo

Hodge

2008

Pharmacology Biochemistry and Behavior

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“…The overall phenotype of alcohol-avoiding therefore does not necessarily indicate a lack of ability to integrate the value of a reward. Indeed, recent pharmacological studies indicate a probable role for mGlu5 receptors in the motivation to self-administer alcohol in mice and rats (Besheer et al, 2007). Currently, there are no published studies of polymorphisms in the human mGlu5 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Ethanol has a broad range of effects in the mammalian nervous system, including inhibition of mGlu5 signalling via a PKC-dependent mechanism (Minami et al, 1998). A number of studies show that the mGlu5 antagonist, 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP), reduces the onset and maintenance of ethanol-seeking and attenuates relapse to ethanol-seeking after repeated deprivations in rats, and the motivation to self-administer ethanol (Backstrom et al, 2004 ;Besheer et al, 2007 ;Schroeder et al, 2005). Due to a number of shortcomings in MPEP, including off-target activity, further development resulted in the discovery of 3-[(2-methyl-1, 3-thiazol-4-yl)ethynyl]-pyridine (MTEP ; Cosford et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Metabotropic glutamate 5 receptors regulate sensitivity to ethanol in mice

Bird

Kirchhoff

Djouma

et al. 2008

Int. J. Neuropsychopharm.

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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.

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“…21 Moreover, selfadministration and reinstatement of cocaine, nicotine, alcohol, methamphetamine, and heroin was attenuated by mGluR5 antagonists. [22][23][24][25][26][27][28][29][30][31][32] Therefore, much effort is being undertaken to develop 4 pharmacological compounds with the ability to block mGluR5s, which is assumed to be one efficacious way to treat psychostimulant-addiction.…”

Section: Introductionmentioning

confidence: 99%

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

et al. 2013

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Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation. AbstractLong-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users exhibit altered mGluR5 availability compared to drug-naïve control subjects.Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with 11 C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology.Cocaine users and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared to non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen ...

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Regulation of Motivation to Self‐Administer Ethanol by mGluR5 in Alcohol‐Preferring (P) Rats

Cited by 95 publications

References 43 publications

Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082

Nonselective suppression of operant ethanol and sucrose self-administration by the mGluR7 positive allosteric modulator AMN082

Metabotropic glutamate 5 receptors regulate sensitivity to ethanol in mice

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

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