mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior

Abstract

Pharmacological blockade of the type 5 metabotropic glutamate receptor (mGluR5) attenuates cue-induced reinstatement of ethanol-seeking behavior, yet the brain regions involved in these effects are not yet known. The purpose of the present study was to determine if local blockade of mGluR5 receptors in the basolateral amygdala (BLA) and/or the nucleus accumbens (NAc), two brain regions known to be involved in stimulus-reward associations, attenuates the reinstatement of ethanol-seeking behavior induced by ethanol-paired cues. As a control for possible non-specific effects, the effects of mGluR5 blockade in these regions on cue-induced reinstatement of sucrose-seeking were also assessed. Male Wistar rats were implanted with bilateral microinjection cannulae aimed at the BLA or NAc. Following recovery, animals were trained to self-administer ethanol (10% w/v) or 45 mg sucrose pellets on an FR1 schedule of reinforcement in 30 min daily sessions using a sucrose fading procedure. Following stabilization of responding, animals underwent extinction training. Next, animals received infusions of vehicle or the selective mGluR5 antagonist MTEP (3 μg/μl) into the BLA or NAc prior to cue-induced reinstatement testing sessions. mGluR5 blockade eliminated cue-induced reinstatement of alcohol-but not sucrose-seeking behavior. Results from this study indicate that mGluR5 receptors in the BLA and NAc mediate cue-induced reinstatement of ethanol-seeking behavior, and provide two potential neuroanatomical sites of action where systemically administered mGluR5 antagonists attenuate cue-induced reinstatement. These data are consistent with previous findings that cue-induced reinstatement of ethanol-seeking increases neuronal activity and glutamatergic transmission in these two regions.

Adolescent Mice Are Resilient to Alcohol Withdrawal-Induced Anxiety and Changes in Indices of Glutamate Function within the Nucleus Accumbens

“…Indeed, our laboratory has detected alcohol-induced changes in Acb levels of mGlu5 in some (Figure 5B; Goulding et al, 2011; Cozzoli et al, 2012), but not all studies (Szumlinski et al, 2007), which may reflect differences in the subregions examined, route of administration/drinking paradigm employed. Nevertheless, intact mGlu5 function within Acb subregions, notably the AcbSh, is important for binge-drinking behavior (Cozzoli et al, 2009; Besheer et al, 2010; Sinclair et al, 2012). Therefore, behavioral differences could be driven by changes in receptor function that are not reflected in changes in total protein expression.…”

Effects of Ceftriaxone on Chronic Ethanol Consumption: a Potential Role for xCT and GLT1 Modulation of Glutamate Levels in Male P Rats

“…Drug reinforcement is attributed to various brain reward regions, in particular the PFC (Goldstein and Volkow, 2002), NAc (Childress et al, 1999, Obara et al, 2009), and AMG (Zarrindast et al, 2010, Sinclair et al, 2012, Christian et al, 2013). While it is well known that dopamine is one of the major neurotransmitters responsible for the development of drug dependence (Anderson and Swanson, 2000, Ito et al, 2004), studies focusing on these brain reward centers have clearly demonstrated an underlying relationship between glutamatergic transmission and ethanol abuse (Carrara-Nascimento et al, 2011, Gass et al, 2011, Mishra et al, 2012).…”

Genetic studies of alcohol dependence in the context of the addiction cycle

“…mGlu5 signaling on striatal Dopamine-D1 receptor expressing neurons is necessary for both novelty-seeking behavior and the abstinence-induced escalation of alcohol drinking in mice (Parkitna et al, 2013). mGlu5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior (Sinclair et al, 2012). Thus, although SNPs in GRM5 did not meet the stringent genome-wide significant threshold in the study by Bierut et al, 2010, results from human alcoholic brain and animal models of alcohol dependence support a key role of GRM5 in alcohol dependence phenotypes and the negative affective state during protracted abstinence.…”