The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice

Hodge, Clyde W.; Miles, Michael F.; Sharko, Amanda C.; Stevenson, Rebekah A.; Hillmann, Jennie R.; Lepoutre, Veronique; Besheer, Joyce; Schroeder, Jeanne L.

doi:10.1007/s00213-005-0217-y

Cited by 134 publications

(130 citation statements)

References 73 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: 97%

“…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: 97%

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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“…Although the reinforcing effects of ethanol have been successfully demonstrated when the drug is continuously available (Besheer et al, 2004;Hodge et al, 2006;Olive et al, 2000;Risinger et al, 1998Risinger et al, ,1999, data evaluating ethanol reinforcement in mice under a limited access condition is less well studied. Studies with mice responding on a fixed ratio 1 (FR1) (Middaugh et al 2000;Roberts et al 2000) or FR3 (Tsiang and Janak, 2006) reinforcement schedule reported ethanol intake approximating 0.5 g/kg, which correspond to values in rats responding on a FR schedule (e.g., Samson, 2000).…”

Section: Introductionmentioning

confidence: 99%

Influence of reinforcement schedule on ethanol consumption patterns in non-food restricted male C57BL/6J mice

Ford

Fretwell²,

Mark

et al. 2007

Alcohol

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Ethanol reinforcement should ideally be evaluated in animals that are not food deprived to ensure that the motivation behind its consumption is pharmacological, and not caloric, in nature. The objective of this work was to assess the influence of reinforcement schedule on ethanol intake in non-deprived mice. Male C57BL/6J mice were trained to respond on an ethanol-reinforced lever on a fixed ratio (FR) 4 reinforcement schedule for 10% ethanol (10E). The appetitive and consummatory phases were then procedurally separated by changing the response requirement (RR), so that mice were permitted 30-min continuous 10E access after completion of either four (RR4) or eight (RR8) responses. Phase separation yielded a heightened appetitive drive to acquire 10E access (as indexed by a significant decrease in the latency to first active lever and a trend towards a decrease in the latency to 1st sipper contact) and an augmented level of drinking (2-fold elevation in the ethanol dose consumed). Robust extinction responding on the ethanol-appropriate lever indicated that ethanol was effective as a behavioral reinforcer. These results suggest that the separation of appetitive and consummatory phases of ethanol self-administration may prove useful in future evaluations of the pharmacological and genetic bases of ethanol reinforcement in mice.

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“…However, little data exist to support the regulation of alcohol-induced changes in NAC neurotransmitter levels by NMDA receptors (Ericson et al, 2003;Gonzales and Roper, 1993) and both mGluR1 and mGluR5 are necessary for the rise in NAC dopamine and glutamate produced by an acute alcohol injection (Lominac et al, 2006). As Group1 mGluR antagonists are effective at blocking various aspects of alcohol reward in rodents (eg Backstrom et al, 2004;Backstrom and Hyytia, 2007;Hodge et al, 2006;Lominac et al, 2006;McMillen et al, 2005;Olive et al, 2005;Schroeder et al, 2005) and can alter sensitivity to the motor effects of alcohol (Lominac et al, 2006), we propose alcohol-induced increases in Group1 mGluR signaling through Homer2 as a key substrate mediating alcohol-induced neurochemical sensitization within the NAC that underlies the development of alcohol-induced behavioral plasticity relevant to alcoholism.…”

Section: Accumbens Homer2b Upregulation Promotes Alcohol Rewardmentioning

confidence: 99%

“…Deletion of Homer2 (Szumlinski et al, 2005b) or pharmacological blockade of either Group1 mGluRs (eg Backstrom et al, 2004;Backstrom and Hyytia, 2007;Hodge et al, 2006;Lominac et al, 2006;Schroeder et al, 2005) or NMDA receptors (eg Boyce-Rustay et al, 2004; for reviews, see Chandler, 2003;Chandler et al, 1998;Hoffman, 2003;Krystal et al, 2003) reduces various aspects of alcohol reward in laboratory animals. Furthering an active and important role for Homer2 proteins in the behavioral effects of alcohol, an intra-NAC infusion of AAV-Homer2b, reverses the alcoholavoiding phenotype of Homer2 KO mice (Szumlinski et al, 2005b).…”

Section: Accumbens Homer2b Upregulation Promotes Alcohol Rewardmentioning

confidence: 99%

Accumbens Homer2 Overexpression Facilitates Alcohol-Induced Neuroplasticity in C57BL/6J Mice

Szumlinski

Ary

Lominac

et al. 2007

Neuropsychopharmacol

178

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Homer proteins are integral components of the postsynaptic density that are necessary for alcohol-induced neuroplasticity within the nucleus accumbens (NAC). In this report, we describe the effects of chronic alcohol consumption upon NAC Homer expression and investigate the functional consequences of mimicking the alcohol-induced changes in Homer expression vis-à-vis alcohol-induced changes in NAC neurochemistry and behavior. Chronic alcohol consumption under continuous access (3 months; daily intake E11.271.5 g/kg/ day) produced a robust increase in NAC Homer2 protein levels that was apparent at 2 days, 2 weeks, and 2 months following withdrawal from alcohol drinking. The increased Homer2 expression was accompanied by a less enduring elevation in total mGluR1 and NR2b levels that were evident at 2 days and 2 weeks but not at the 2-month time point. Mimicking the alcohol-induced increase in Homer2 levels by viral transfection of NAC neurons in alcohol-preferring C57BL/6J inbred mice enhanced behavioral output for alcohol reinforcement and increased alcohol intake under both preprandial and postprandial conditions. Moreover, NAC Homer2 overexpression facilitated the expression of an alcohol-conditioned place preference, as well as the development of motor tolerance. Finally, NAC Homer2 overexpression facilitated NAC glutamate and dopamine release following an acute alcohol injection and augmented alcohol-induced dopamine and glutamate sensitization, but did not affect NAC g-aminobutyric acid levels. Thus, an upregulation in NAC mGluR-Homer2-N-methyl-D-aspartic acid receptor signaling appears to be an important molecular adaptation to alcohol that promotes neuroplasticity facilitating motivational drive for alcohol and the development of alcoholism-related behaviors.

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The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice

Abstract: These data indicate that mGlu5 receptors selectively regulate the onset and maintenance of ethanol self-administration in a manner that is consistent with reduction in ethanol's reinforcement function.

Cited by 134 publications

References 73 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

Influence of reinforcement schedule on ethanol consumption patterns in non-food restricted male C57BL/6J mice

Accumbens Homer2 Overexpression Facilitates Alcohol-Induced Neuroplasticity in C57BL/6J Mice

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