Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: Potential insight into their anti-addictive properties

Lominac, Kevin D.; Kapasova, Zuzana; Hannun, Reem A.; Patterson, Cole; Middaugh, Lawrence D.; Szumlinski, Karen K.

doi:10.1016/j.drugalcdep.2006.04.003

Cited by 108 publications

(178 citation statements)

References 57 publications

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“…Another possibility is that glutamatergic transmission in some subregions of the NAc may be more responsive to ethanol challenge than others. For example, studies with probe placements largely, but not exclusively, within the NAc shell suggest this subregion responds to ethanol challenge in a dose-dependent manner (Lominac et al, 2006). Analysis of the present data did not reveal differences in GLU EX levels across NAc subregions following ethanol gavage.…”

Section: Discussioncontrasting

confidence: 50%

“…Although there appeared to be a trend to increase GLU EX at the higher dose (2 g/kg), the lack of a significant response to the ethanol challenge was observed even when differences between the groups in baseline GLU EX levels were taken into account. This was somewhat surprising given that other microdialysis studies in mice and rats have indicated systemic administration of low ethanol doses (0.5-1 g/kg) increase accumbal GLU EX levels (Lominac et al, 2006;Moghaddam and Bolinao, 1994;Selim and Bradberry, 1996;Smith et al, 2004;Szumlinski et al, 2008), whereas higher doses (2 to 3 g/kg) either decrease GLU EX or produce no change (Lominac et al, 2006;Piepponen et al, 2002;Smith et al, 2004;Yan et al, 1998). All of these earlier studies administered ethanol via the intraperitoneal route during dialysis, whereas ethanol was administered by gavage in this study.…”

Section: Discussionmentioning

confidence: 61%

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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: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 61%

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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“…Thus, while many drugs of abuse increase corticoaccumbens IEG Homer expression, this drug effect is transient and independent of a particular mechanism of drug action. In contrast to IEG Homers, the regulation of corticoaccumbens CC-Homer expression by drugs of abuse is more complex (Table 2) [39, 157,[166][167][168][169][170] and, as will be discussed below in greater detail, may reflect a compensatory response to either the immediate or longer-term effects of drug administration upon corticoaccumbens glutamate transmission.…”

Section: Homers Are Regulated Within Addiction-related Neural Circuitmentioning

confidence: 99%

“…The dose-response function for acute alcohol-induced changes in corticoaccumbens extracellular glutamate is biphasic; lower doses either do not change or increase glutamate levels, while moderate to higher doses reduce glutamate levels [39, 64,168,245]. Repeated alcohol administration alters basal glutamate content in the NAC [e.g., 38, [246][247][248] and sensitizes the capacity of alcohol to elevate extracellular glutamate levels, at least within the NAC [38,39,[249][250][251].…”

Section: Homers and Alcohol-induced Neuroplasticitymentioning

confidence: 99%

Homers regulate drug-induced neuroplasticity: Implications for addiction

Szumlinski

Ary

Lominac

2008

Biochemical Pharmacology

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118

160

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Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

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“…Immunoblotting B6 mice were permitted 24-h free access to water or alcohol (four bottle choice with 0, 3, 6, and 12% alcohol; Lominac et al, 2006) for a period of 3 months. At 2 days, 2 weeks, and 2 months withdrawal from end of the 3-month period of drinking, the entire NAC (shell and core) was dissected out over ice and homogenized in a medium consisting of radioimmunoprecipitation assay buffer (65 mM Tris, 150 mM NaCl, 1.8 mM Na-deoxycholic acid, 1.3 mM ethylenediaminetetraacetic acid (EDTA), 0.01% NP-40, 1% sodium dodecyl sulfate (SDS), Complete Mini-tab Protease Inhibitor Cocktail tablet (Roche Diagnostics GmbH, Mannheim, Germany)).…”

Section: Subjectsmentioning

confidence: 99%

Accumbens Homer2 Overexpression Facilitates Alcohol-Induced Neuroplasticity in C57BL/6J Mice

Szumlinski

Ary

Lominac

et al. 2007

Neuropsychopharmacol

178

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Homer proteins are integral components of the postsynaptic density that are necessary for alcohol-induced neuroplasticity within the nucleus accumbens (NAC). In this report, we describe the effects of chronic alcohol consumption upon NAC Homer expression and investigate the functional consequences of mimicking the alcohol-induced changes in Homer expression vis-à-vis alcohol-induced changes in NAC neurochemistry and behavior. Chronic alcohol consumption under continuous access (3 months; daily intake E11.271.5 g/kg/ day) produced a robust increase in NAC Homer2 protein levels that was apparent at 2 days, 2 weeks, and 2 months following withdrawal from alcohol drinking. The increased Homer2 expression was accompanied by a less enduring elevation in total mGluR1 and NR2b levels that were evident at 2 days and 2 weeks but not at the 2-month time point. Mimicking the alcohol-induced increase in Homer2 levels by viral transfection of NAC neurons in alcohol-preferring C57BL/6J inbred mice enhanced behavioral output for alcohol reinforcement and increased alcohol intake under both preprandial and postprandial conditions. Moreover, NAC Homer2 overexpression facilitated the expression of an alcohol-conditioned place preference, as well as the development of motor tolerance. Finally, NAC Homer2 overexpression facilitated NAC glutamate and dopamine release following an acute alcohol injection and augmented alcohol-induced dopamine and glutamate sensitization, but did not affect NAC g-aminobutyric acid levels. Thus, an upregulation in NAC mGluR-Homer2-N-methyl-D-aspartic acid receptor signaling appears to be an important molecular adaptation to alcohol that promotes neuroplasticity facilitating motivational drive for alcohol and the development of alcoholism-related behaviors.

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Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: Potential insight into their anti-addictive properties

Cited by 108 publications

References 57 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

Homers regulate drug-induced neuroplasticity: Implications for addiction

Accumbens Homer2 Overexpression Facilitates Alcohol-Induced Neuroplasticity in C57BL/6J Mice

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