Metabotropic Glutamate Receptor 5 Activity in the Nucleus Accumbens Is Required for the Maintenance of Ethanol Self-Administration in a Rat Genetic Model of High Alcohol Intake

Besheer, Joyce; Grondin, Julie J.M.; Cannady, Reginald; Sharko, Amanda C.; Faccidomo, Sara; Hodge, Clyde W.

doi:10.1016/j.biopsych.2009.09.016

Cited by 107 publications

(106 citation statements)

References 109 publications

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“…The lack of substitution for alcohol following mGlu2/3 receptor activation in our study suggests that reported reductions in self-administration are likely not due to the agonist producing alcohol-like effects, and the possibility exists that mGlu2/3 receptor activation may blunt the interoceptive effects of the consumed alcohol. Interestingly, previous work has shown no specific changes in alcohol self-administration behavior following mGlu2/3 receptor activation in the nucleus accumbens (Besheer et al, 2010). This is consistent with findings in this work showing lack of intra-accumbens involvement of mGlu2/3 receptors in modulating the interoceptive effects of alcohol.…”

Section: Discussionsupporting

confidence: 92%

“…That is, a lower LY379268 dose (3 mg) caused profound reductions in response rate when injected into the nucleus accumbens, whereas the amygdala was relatively insensitive to motor impairing effects as a twofold higher dose (6 mg) did not alter response rate. Previous work has shown motor-impairing effects after systemic mGlu2/3 receptor agonist administration (Cartmell et al, 2000;Winter et al, 2004;Backstrom and Hyytia, 2005) and intra-accumbens administration (Besheer et al, 2010). Taken together, these data suggest that the nucleus accumbens may have a contributing role in the reported motor impairing effects induced by mGlu2/3 receptor agonists.…”

Section: Discussionsupporting

confidence: 60%

“…It is interesting that the highest dose of LY379268 (6 mg) was necessary to reduce alcohol-appropriate responding. This dose is indeed higher than that previously reported in microinjection studies using LY379268 (Besheer et al, 2010;Uejima et al, 2007). It may be that repeated alcohol exposure, as used in the present study, induces changes in mGlu2/3 receptor density particularly within the amygdala, thus requiring a higher dose of the agonist to alter behavior.…”

Section: Discussioncontrasting

confidence: 50%

“…Alcohol-appropriate responding was significantly increased in a dose-dependent manner after cumulative alcohol administration ( Figure 1a; F(3,60) ¼ 38.221, po0.001), with 1.7 g/kg fully substituting (480%) for the alcohol training dose (ie, producing stimulus properties similar to the training dose). The 1.0 g/kg alcohol dose (training dose) generally produces 490% alcohol-appropriate responding during regular training sessions, but tends to produce roughly 60% alcohol-appropriate responding during the cumulative dosing procedure Besheer et al, 2010). There were no significant changes in response rate throughout cumulative alcohol testing (Figure 1b; p ¼ 0.076).…”

Section: Confirmation Of Discriminative Stimulus Control By Alcoholmentioning

confidence: 97%

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Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Cannady

Grondin

Fisher

et al. 2011

Neuropsychopharmacol

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Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3-10 mg/kg) did not produce alcohollike stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 mg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 mg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 mg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 60%

Section: Discussioncontrasting

confidence: 50%

Section: Confirmation Of Discriminative Stimulus Control By Alcoholmentioning

confidence: 97%

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Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Cannady

Grondin

Fisher

et al. 2011

Neuropsychopharmacol

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“…The deletion of mGluR5 results in marked deficits in responding to the reinforcing and locomotor stimulating effects of cocaine [7] . Furthermore, the administration of the noncompetitive selective mGluR5 antagonist 2-methyl-6 (phenyethynyl) pyridine (MPEP) decreased the self-administration and/or relapse of nicotine [8,9] , cocaine [10,11] , ethanol [12][13][14] , and heroin [15,16] . MTEP, another antagonist of mGluR5, also can attenuate opiate selfadministration and opiate-seeking behavior in mice [17] .…”

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confidence: 99%

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

et al. 2014

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Aim: Glutamatergic neurotransmission in the nucleus accumbens (NAc) is crucial for the relapse to heroin seeking. The aim of this study was to determine whether mGluR5 in the NAc core or shell involved in heroin seeking behavior in rats. Methods: Male SD rats were self-administered heroin under a fixed-ratio 1 (FR1) reinforcement schedule for 14 d, and subsequently withdrawn for 2 weeks. The selective mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 5, 15 and 50 nmol per side) was then microinjected into the NAc core or shell 10 min before a heroin-seeking test induced by context, cues or heroin priming. Results: Microinjection of MPEP into the NAc shell dose-dependently decreased the heroin seeking induced by context, cues or heroin priming. In contrast, microinjection of MPEP into the NAc core did not alter the heroin seeking induced by cues or heroin priming. In addition, microinjection with MPEP (15 nmol per side) in the NAc shell reversed both the percentage of open arms entries (OE%) and the percentage of time spent in open arms (OT%) after heroin withdrawal. Microinjection of MPEP (50 nmol per side) in the striatum as a control location did not affect the heroin seeking behavior. Microinjection of MPEP in the 3 locations did not change the locomotion activities. Conclusion: Blockade of mGluR5 in NAc shell in rats specifically suppresses the relapse to heroin-seeking and anxiety-like behavior, suggesting that mGluR5 antagonists may be a potential candidate for the therapy of heroin addiction.Keywords: heroin; addiction; relapse; mGluR5; MPEP; the nucleus accumbens; striatum Acta Pharmacologica Sinica (2014Sinica ( ) 35: 1485Sinica ( -1492 doi: 10.1038/aps.2014 published online Nov 17 2014 Original Article IntroductionRelapse is the most important manifestation of heroin addiction following prolonged periods of abstinence [1] . Relapse arises from intense craving that can be triggered by a single drug-taking experience or exposure to an environmental stimulus [2] . The pre-clinical literature indicates that longterm drug-induced alterations in glutamatergic transmission within the NAc may underlie relapse to drug-seeking behavior following the re-exposure to drugs and drugassociated stimuli during abstinence of the drug [3,4] . Type 5 metabotropic glutamate receptor (mGluR5) as a postsynaptic element is abundantly present throughout in the NAc, where it is positively coupled to NMDA receptor function and mediates various forms of synaptic plasticity [5,6] . The deletion of mGluR5 results in marked deficits in responding to the reinforcing and locomotor stimulating effects of cocaine [7] . Furthermore, the administration of the noncompetitive selective mGluR5 antagonist 2-methyl-6 (phenyethynyl) pyridine (MPEP) decreased the self-administration and/or relapse of nicotine [8,9] , cocaine [10,11] , ethanol [12][13][14] , and heroin [15,16] . MTEP, another antagonist of mGluR5, also can attenuate opiate selfadministration and opiate-seeking behavior in mice [17] . These data indicate mGluR5 plays a...

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GET73 increases rat extracellular hippocampal CA1 GABA levels through a possible involvement of local mGlu5 receptor

Beggiato

O’Connor

Tomasini

et al. 2013

Synapse

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N-[(4-trifluoromethyl) benzyl] 4-methoxybutyramide (GET73) is a newly synthesized compound displaying anti-alcohol and anxiolytic properties. In light of the importance of the hippocampal CA1 subregion in alcohol addiction and anxiety-like behaviors-this in vivo microdialysis study characterized the effect of GET73 on extracellular GABA levels in the hippocampal CA1 region of the freely moving rat-including a possible role for mGlu5 receptor in mediating this effect. Both intraperitoneal administration (2-10 mg/kg) and local intra-hippocampal CA1 perfusion with GET73 (50-1000 nM) were associated with a transient, step-wise increase in dialysate hippocampal CA1 GABA levels. The GET73 (10 mg/kg)-induced increase in GABA levels was not affected by intra-CA1 perfusion with either the GABA reuptake inhibitor SKF89976A (0.5 mM) or by local GABAA (bicuculline; 1μM) and GABAB (CGP35348; 500 μM) receptor antagonists. On the contrary, the GET73-induced increase in GABA levels was partially counteracted by the intra-CA1 perfusion with the mGlu5 receptor negative allosteric modulator MPEP (300 µM). Interestingly, GET73 at the lowest (2 mg/kg) dose tested, by itself ineffective, fully counteracted the increase in GABA levels induced by the mGlu5 receptor agonist CHPG (1000 µM). Taken together, these findings suggest that the GET73-induced increase in hippocampal CA1 GABA levels operates independently of local GABA reuptake and/or GABAA or GABAB receptors. Furthermore, the present data lead to hypothesize a possible interaction between GET73 and mGluR5-mediated regulation of hippocampal CA1 GABA transmission, an effect which may be relevant to the ability of GET73 to reduce alcohol intake in an alcohol-preferring rat strain.

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Metabotropic Glutamate Receptor 5 Activity in the Nucleus Accumbens Is Required for the Maintenance of Ethanol Self-Administration in a Rat Genetic Model of High Alcohol Intake

Cited by 107 publications

References 109 publications

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

GET73 increases rat extracellular hippocampal CA1 GABA levels through a possible involvement of local mGlu5 receptor

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