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

Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Biological psychiatry (Impact Factor: 10.26). 11/2009; 67(9):812-22. DOI: 10.1016/j.biopsych.2009.09.016
Source: PubMed


Systemic modulation of Group I and II metabotropic glutamate receptors (mGluRs) regulate ethanol self-administration in a variety of animal models. Although these receptors are expressed in reward-related brain regions, the anatomical specificity of their functional involvement in ethanol self-administration remains to be characterized. This study sought to evaluate the functional role of Group I (mGluR5) and Group II (mGluR2/3) in mesocorticolimbic brain regions in ethanol self-administration.
Alcohol-preferring (P) rats, a genetic model of high alcohol drinking, were trained to self-administer ethanol (15% v/v) versus water in operant conditioning chambers. Effects of brain site-specific infusion of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the mGluR2/3 agonist were then assessed on the maintenance of self-administration.
Microinjection of the mGluR5 antagonist MPEP in the nucleus accumbens reduced ethanol self-administration at a dose that did not alter locomotor activity. By contrast, infusion of the mGluR2/3 agonist LY379268 in the nucleus accumbens reduced self-administration and produced nonspecific reductions in locomotor activity. The mGluR5 involvement showed anatomical specificity as evidenced by lack of effect of MPEP infusion in the dorsomedial caudate or medial prefrontal cortex on ethanol self-administration. To determine reinforcer specificity, P-rats were trained to self-administer sucrose (.4% w/v) versus water, and effects of intra-accumbens MPEP were tested. The MPEP did not alter sucrose self-administration or motor behavior.
These results suggest that mGluR5 activity specifically in the nucleus accumbens is required for the maintenance of ethanol self-administration in individuals with genetic risk for high alcohol consumption.

Download full-text


Available from: Reginald Cannady, Oct 11, 2015
36 Reads
  • Source
    • "One potential pharmacotherapeutic target is the metabotropic glutamate receptor 5 (mGluR5). Inhibition of mGluR5 signaling using the antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) reduced the rewarding effects of EtOH in animal models of EtOH drinking as well as during self-administration and reinstatement (B€ ackstr€ om et al., 2004; Besheer et al., 2010; Hodge et al., 2006; Lominac et al., 2006; McMillen et al., 2005; Olive et al., 2005; Schroeder et al., 2005). When locally infused into the nucleus accumbens (NAc), MPEP significantly decreased binge EtOH consumption (Cozzoli et al., 2009, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Binge ethanol (EtOH) intake during adolescence leads to an array of behavioral and cognitive consequences including elevated intake of EtOH during adulthood, with female mice showing greater susceptibility than males. Administration of the metabotropic glutamate receptor 5 (mGluR5) antagonist 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) has been shown to reduce EtOH self-administration in adult male mice, but little is known about its effect on female and adolescent mice.MethodsMTEP (0, 10, 20 mg/kg, i.p.) was repeatedly administered to female and male, adult and adolescent C57BL/6J mice during binge sessions using the scheduled high alcohol consumption paradigm. Next, we assessed whether MTEP administration during binge altered the subsequent 24-hour EtOH intake following a period of abstinence. Finally, we investigated whether MTEP administration during binge followed by an abstinence period altered mRNA of glutamatergic genes within the nucleus accumbens of female mice.ResultsMTEP significantly decreased binge EtOH intake in all mice, but only female mice exhibited altered subsequent 24-hour EtOH intake. Interestingly, the alteration in subsequent EtOH intake in female animals was age dependent, with adolescent exposure to MTEP during binge decreasing 24-hour intake and adult exposure to MTEP during binge increasing 24-hour intake. Finally, while there were no effects of MTEP pretreatment on the genes examined, there was a robust age effect found during analysis of mGluR1 (Grm1), mGluR5 (Grm5), the NR2A subunit of the NMDA receptor (Grin2a), phosphatidylinositol 3-kinase (Pik3r1), mammalian target of rapamycin (Mtor), and extracellular signal-regulated kinase (Mapk1) mRNA, with adolescent female animals having lower expression than their adult counterparts.Conclusions Collectively, the present findings add to existing evidence implicating the contribution of long-term effects of adolescent binge drinking to enhance alcohol abuse in adulthood, while suggesting that mGluR5 antagonism may not be the best pharmacotherapy to treat binge alcohol consumption in female and adolescent animals.
    Alcoholism Clinical and Experimental Research 03/2014; 38(3). DOI:10.1111/acer.12292 · 3.21 Impact Factor
  • Source
    • "Microdialysis studies focused on alcohol-consuming rats have demonstrated that there are significant Glu increases in the ventral striatum associated with seizure activity and hyperexcitability during abstinence (Rossetti et al, 1999; Dahchour and De Witte, 2000). Chronic alcohol consumption was found to be associated with morphological changes in the dendritic spines of the medium spiny neurons in the NAcc (Zhou et al, 2007), and metabotropic Glu receptor activity in the NAcc was shown to be required for the maintenance of ethanol self-administration in alcohol-preferring rats (Besheer et al, 2010). Interestingly, in a very recent human off-label investigation in a patient with chronic alcoholism, craving and relapses were reduced by deep brain stimulation in the NAcc (Heldmann et al, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The upregulation of glutamatergic excitatory neurotransmission is thought to be partly responsible for the acute withdrawal symptoms and craving experienced by alcohol-dependent patients. Most physiological evidence supporting this hypothesis is based on data from animal studies. Additionally, clinical data show that GABAergic and anti-glutamatergic drugs ameliorate withdrawal symptoms, offering indirect evidence indicative of glutamatergic hyperexcitability in alcohol-dependent subjects. We used proton magnetic resonance spectroscopy to quantify the glutamate levels in healthy control subjects and in alcohol-dependent patients immediately after detoxification. The volumes of interest were located in the nucleus accumbens and the anterior cingulate cortex, which are two brain areas that have important functions in reward circuitry. In addition to glutamate, we quantified the levels of combined glutamate and glutamine, N-acetylaspartate, choline-containing compounds, and creatine. The glutamate levels in the nucleus accumbens were significantly higher in patients than in controls. Craving, which was measured using the Obsessive Compulsive Drinking Scale, correlated positively with levels of combined glutamate and glutamine in the nucleus accumbens and in the anterior cingulate cortex. The levels of all other metabolites were not significantly different between patients and controls. The increased glutamate levels in the nucleus accumbens in alcohol-dependent patients shortly after detoxification confirm the animal data and suggest that striatal glutamatergic dysfunction is related to ethanol withdrawal. The positive correlation between craving and glutamatergic metabolism in both key reward circuitry areas support the hypothesis that the glutamatergic system plays an important role in the later course of alcohol dependence with respect to abstinence and relapse.Neuropsychopharmacology accepted article preview online, 12 February 2013; doi:10.1038/npp.2013.45.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2013; 38(8). DOI:10.1038/npp.2013.45 · 7.05 Impact Factor
  • Source
    • "Dendritic spines on MSNs are the primary loci of glutamatergic (Kemp & Powell, 1971) and dopaminergic (Freund, Powell, & Smith, 1984) synapses in the striatum, with cholinergic synapses from local interneurons primarily occupying sites on the soma and dendritic shafts (Izzo & Bolam, 1988). In other brain regions, each receptor system has been shown to be altered in ethanol-exposed animals (Allan et al., 1997; Allan, Wu, Paxton, & Savage, 1998; Kelly & Dillingham, 1994; Savage, Cruz, Duran, & Paxton, 1998; Zhou, Bledsoe, Lumeng, & Li, 1991), and in relation to selfadministration of ethanol and other drugs (Besheer et al., 2010; Oleson, Richardson, & Roberts, 2011; Tuesta, Fowler, & Kenny, 2011). At present, it is not clear how alterations in these receptor systems might be related to changes in dendritic morphology in the Acb. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Reductions in measures of dendritic morphology in the agranular insular cortex have been identified as consequences of prenatal exposure to moderate levels of ethanol in the rat. Motivated by the strong connectivity between this region of frontal cortex and the striatum and a growing body of data linking specific components of the mesocortical/limbic system to effects of ethanol and ethanol self-administration, the current study investigated the effects of moderate fetal ethanol exposure on the dendritic morphology of medium spiny neurons (MSNs) in several regions of the striatum. Throughout gestation, pregnant rat dams either consumed a saccharin solution (control) or achieved average daily blood ethanol concentrations of 84 mg% via voluntary consumption of a 5% ethanol solution. The brains of adult male offspring were extracted and processed for Golgi-Cox staining. MSNs from the dorsomedial striatum, dorsolateral striatum and the nucleus accumbens core and shell were sampled for analysis. Relative to saccharin controls, robust reductions in dendritic length and branching, but not spine density, were observed in the shell of the nucleus accumbens in fetal-ethanol-exposed rats. No significant prenatal ethanol effects were found in the other regions of the striatum. These findings suggest that exposure to moderate levels of ethanol in utero can have profound effects on brain regions related to reward processing and provide possible clues relevant to understanding increased self-administration of drugs of abuse in animals exposed to ethanol during brain development.
    Alcohol (Fayetteville, N.Y.) 06/2012; 46(6):577-84. DOI:10.1016/j.alcohol.2011.11.008 · 2.01 Impact Factor
Show more