Increased Extracellular Glutamate In the Nucleus Accumbens Promotes Excessive Ethanol Drinking in Ethanol Dependent Mice

Abstract

Using a well-established model of ethanol dependence and relapse, this study examined adaptations in glutamatergic transmission in the nucleus accumbens (NAc) and their role in regulating voluntary ethanol drinking. Mice were first trained to drink ethanol in a free-choice, limited access (2 h/day) paradigm. One group (EtOH mice) received repeated weekly cycles of chronic intermittent ethanol (CIE) exposure with intervening weeks of test drinking sessions, whereas the remaining mice (CTL mice) were similarly treated but did not receive CIE treatment. Over repeated cycles of CIE exposure, EtOH mice exhibited significant escalation in drinking (up to B3.5 g/kg), whereas drinking remained relatively stable at baseline levels (2-2.5 g/kg) in CTL mice. Using in vivo microdialysis procedures, extracellular glutamate (GLU EX ) levels in the NAc were increased approximately twofold in EtOH mice compared with CTL mice, and this difference was observed 7 days after final CIE exposure, indicating that this hyperglutamatergic state persisted beyond acute withdrawal. This finding prompted additional studies examining the effects of pharmacologically manipulating GLU EX in the NAc on ethanol drinking in the CIE model. The non-selective glutamate reuptake antagonist, threo-b-benzyloxyaspartate (TBOA), was bilaterally microinjected into the NAc and found to dose-dependently increase drinking in nondependent (CTL) mice to levels attained by dependent (EtOH) mice. TBOA also further increased drinking in EtOH mice. In contrast, reducing glutamatergic transmission in the NAc via bilateral injections of the metabotropic glutamate receptor-2/3 agonist LY379268 reduced drinking in dependent (EtOH) mice to nondependent (CTL) levels, whereas having a more modest effect in decreasing ethanol consumption in CTL mice. Taken together, these data support an important role of glutamatergic transmission in the NAc in regulating ethanol drinking. Additionally, these results indicate that ethanol dependence produces adaptations that favor elevated glutamate activity in the NAc which, in turn, promote excessive levels of ethanol consumption associated with dependence.

Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure

“…The increase that we observed in sEPSC frequency in D1+ MSNs of CIE treated mice may also be a compensatory change resulting from dampened excitatory signaling during ethanol vapor exposure. Similar increases in glutamate release have been observed after chronic ethanol exposure (Dahchour and De Witte, 1999; Dahchour et al, 2003; Griffin et al, 2014; Roberto et al, 2004; Rossetti and Carboni, 1995). The increase in sEPSC frequency was not accompanied by a change in PPR.…”

Habitual alcohol seeking: Modeling the transition from casual drinking to addiction

“…Chronic alcohol exposure has been shown to produce significant alterations in glutamatergic signaling. In particular, chronic ethanol is thought to induce a hyperglutamatergic state in select subregions including the nucleus accumbens(Griffin III, Haun, Hazelbaker, Ramachandra, & Becker, 2013; Kalivas, 2009). In addition to alterations in global glutamate levels, ethanol exposure also alters glutamate receptor and transporter expression and function in a timecourse dependent manner.…”

Effects of ceftriaxone on GLT1 isoforms, xCT and associated signaling pathways in P rats exposed to ethanol

“…The association between increased extracellular glutamate cocnentrations in the mesolimbic reward pathway and alcohol craving has been studied extensively (Bauer et al 2013; Griffin et al 2013; Kapasova and Szumlinski 2008). This increase in extracellular glutamate concentration was suggested to be a result of decreased glutamate clearance (Melendez et al 2005).…”