Alcohol drinking and deprivation alter basal extracellular glutamate concentrations and clearance in the mesolimbic system of alcohol‐preferring (<scp>P</scp>) rats

Ding, Zheng Ming; Rodd, Zachary A.; Engleman, Eric A.; Bailey, Jason A.; Lahiri, Debomoy K.; McBride, William J.

doi:10.1111/adb.12018

Cited by 78 publications

(99 citation statements)

References 47 publications

(82 reference statements)

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“…In general, this finding is consistent with other studies showing increased basal GLU EX in the NAc (Ding et al, 2013;Kapasova and Szumlinski, 2008;Melendez et al, 2005) as well as other brain regions such as hippocampus (Chefer et al, 2011;Dahchour and De Witte, 1999;Moghaddam and Bolinao, 1994) and the amygdala (Roberto et al, 2004). However, results from the present study are unique in two ways.…”

Section: Discussionsupporting

confidence: 93%

“…Similarly, reduced glutamate clearance was reported to accompany increased accumbal GLU EX concentrations in C57BL/6J mice after repeated ethanol injection treatment (Kapasova and Szumlinski, 2008). In a recent study in alcohol-preferring (P) rats, several weeks of free-choice ethanol consumption produced elevated GLU EX levels in NAc that was associated with reduced glutamate clearance and decreased expression of EAAT1 but not EAAT2 (Ding et al, 2013). Thus, altered expression and/or function of EAATs expressed in glia (EAAT1 and EAAT2) and possibly in neurons (EAAT3/EAAC1) following chronic ethanol exposure may contribute to the resultant elevated glutamate activity in NAc.…”

Section: Discussionmentioning

confidence: 89%

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

Griffin

Haun

Hazelbaker

et al. 2013

Neuropsychopharmacol

127

112

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 89%

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

Griffin

Haun

Hazelbaker

et al. 2013

Neuropsychopharmacol

127

112

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“…Molecular work also demonstrates an upregulation of NMDAR following chronic EtOH and withdrawal (Clapp et al 2010; Kalluri et al 1998; Rani and Ticku 2006). Our results extend these findings by measuring intra-mPFC glutamate in mice withdrawn from two-bottle choice drinking (Ding et al 2013). Prefrontal cortical pyramidal neurons are rich in glutamate projections that release excitatory amino acids in the nucleus accumbens and ventral tegmental area (Sesack and Pickel 1992; Taber and Fibiger 1995).…”

Section: Discussionsupporting

confidence: 79%

“…We also found increased glutamine concentrations in the mPFC, so astrocytes may be a candidate for the source of glutamate. In support of this hypothesis, others have found altered glial plasticity in the mPFC (Kim et al 2014) and decreased glutamate clearance caused by the excitatory amino acid transporter, which normalizes after 2 wks of abstinence (Ding et al 2013; Kalinine et al 2014). An unexpected finding was that glutamate activity was different after memantine injection in the 1 wk versus 8 wk H2O mice.…”

Section: Discussionmentioning

confidence: 84%

Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice

et al. 2015

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Rationale Disrupted social behavior, including occasional aggressive outbursts, is characteristic of withdrawal from long-term alcohol (EtOH) use. Heavy EtOH use and exaggerated responses during withdrawal may be treated using glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonists. Objectives The current experiments explore aggression and medial prefrontal cortex (mPFC) glutamate as consequences of withdrawal from intermittent access to EtOH, and changes in aggression and mPFC glutamate caused by NMDAR antagonists memantine and ketamine. Methods Swiss male mice underwent withdrawal following 1-8 weeks of intermittent access to 20% EtOH. Aggressive and non-aggressive behaviors with a conspecific were measured 6-8 h into EtOH withdrawal after memantine or ketamine (0-30 mg/kg, i.p.) administration. In separate mice, extracellular mPFC glutamate after memantine was measured during withdrawal using in vivo microdialysis. Results At 6-8 h withdrawal from EtOH, mice exhibited more convulsions and aggression, and decreased social contact compared to age-matched water controls. Memantine, but not ketamine, increased withdrawal aggression at the 5 mg/kg dose in mice with a history of 8 weeks EtOH but not 1 or 4 weeks of EtOH or in water drinkers. Tonic mPFC glutamate was higher during withdrawal after 8 weeks EtOH compared to 1 week EtOH or 8 weeks water. Five mg/kg memantine increased glutamate in 8 week EtOH mice, but also in 1 week EtOH and water drinkers. Conclusions These studies reveal aggressive behavior as a novel symptom of EtOH withdrawal in outbred mice and confirm a role of NMDARs during withdrawal aggression and for disrupted social behavior.

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“…For instance, ERK1/2 phosphorylation requires the coordinated activation of dopamine D1-like and NMDA receptors (Shiflett and Balleine 2011). Ethanol increases dopamine levels in the NAC (Di Chiara and Imperato 1986; Olive et al 2000) and PFC (Schier et al 2013), and elevates glutamate levels in the NAC (Ding et al 2013; Griffin et al 2014; Szumlinski et al 2007) and AMY (Roberto et al 2004). Moreover, ethanol activates ERK1/2 via a D1-dependent mechanism in NAC and AMY (Ibba et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

et al. 2015

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Rationale Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown. Objective To pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC) and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2). Methods Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9% ethanol+2% sucrose (ethanol) or 2% sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0–1.7 μg/side) in PFC, NAC or AMY prior to self-administration. Results pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg=1.21 g/kg; BAC=54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions. Conclusions Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.

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Alcohol drinking and deprivation alter basal extracellular glutamate concentrations and clearance in the mesolimbic system of alcohol‐preferring (P) rats

Cited by 78 publications

References 47 publications

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

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

Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice

Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

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