Acamprosate Inhibits the Binding and Neurotoxic Effects of Trans‐ACPD, Suggesting a Novel Site of Action at Metabotropic Glutamate Receptors

Harris, Barton R.; Prendergast, Mark A.; Gibson, D. Alex; Rogers, Dennis T.; Blanchard, John; Holley, Robert C.; Fu, May C.; Hart, Stewart R.; Pedigo, Norman W.; Littleton, John M.

doi:10.1111/j.1530-0277.2002.tb02484.x

Cited by 107 publications

(25 citation statements)

References 67 publications

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“…Alcohol inhibits mGluR5 function (Minami et al, 1998) and the therapeutic efficacy of acamprosate for treating alcoholism is hypothesized to relate to a reduction in alcohol-induced glutamate hyperexcitability via mGluR5 blockade (Harris et al, 2002; Littleton and Zieglgansberger, 2003; Lominac et al, 2006). The present data provide the first evidence that glutamate activation of mGluR5 receptors located specifically within the NAC shell is necessary for high levels of binge alcohol drinking behavior under limited-access conditions and thereby point to NAC shell mGluR5 receptors as important for the “anti-alcohol” effects of systemic mGluR5 antagonist treatment – a finding consistent with the results of a recent intravenous alcohol self-administration study by Gass and Olive (2009).…”

Section: Discussionmentioning

confidence: 99%

Binge Drinking Upregulates Accumbens mGluR5-Homer2-PI3K Signaling: Functional Implications for Alcoholism

Cozzoli¹,

Goulding²,

Zhang

et al. 2009

Journal of Neuroscience

139

337

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The glutamate receptor-associated protein Homer2 regulates alcohol-induced neuroplasticity within the nucleus accumbens (NAC), but the precise intracellular signaling cascades involved are not known. This study examined the role for NAC metabotropic glutamate receptor (mGluR)-Homer2-phosphatidylinositol 3-kinase (PI3K) signaling in regulating excessive alcohol consumption within the context of the scheduled high alcohol consumption (SHAC) model of binge alcohol drinking. Repeated bouts of binge drinking (ϳ1.5 g/kg per 30 min) elevated NAC Homer2a/b expression and increased PI3K activity in this region. Virus-mediated knockdown of NAC Homer2b expression attenuated alcohol intake, as did an intra-NAC infusion of the mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride] (0.1-1 g/side) and the PI3K antagonist wortmannin (50 ng/side), supporting necessary roles for mGluR5/Homer2/PI3K in binge alcohol drinking. Moreover, when compared with wild-type littermates, transgenic mice with an F1128R point mutation in mGluR5 that markedly reduces Homer binding exhibited a 50% reduction in binge alcohol drinking, which was related to reduced NAC basal PI3K activity. Consistent with the hypothesis that mGluR5-Homer-PI3K signaling may be a mechanism governing excessive alcohol intake, the "anti-binge" effects of MPEP and wortmannin were not additive, nor were they observed in the mGluR5 F1128R transgenic mice. Finally, mice genetically selected for a high versus low SHAC phenotype differed in NAC mGluR, Homer2, and PI3K activity, consistent with the hypothesis that augmented NAC mGluR5-Homer2-PI3K signaling predisposes a high binge alcohol-drinking phenotype. Together, these data point to an important role for NAC mGluR5-Homer2-PI3K signaling in regulating binge-like alcohol consumption that has relevance for our understanding of the neurobiology of alcoholism and its pharmacotherapy.

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Section: Discussionmentioning

confidence: 99%

Binge Drinking Upregulates Accumbens mGluR5-Homer2-PI3K Signaling: Functional Implications for Alcoholism

Cozzoli¹,

Goulding²,

Zhang

et al. 2009

Journal of Neuroscience

139

337

View full text Add to dashboard Cite

show abstract

“…Acamprosate is hypothesized to have combined effects on excitatory:inhibitory balance in brain, including potential potentiation of GABA(A) activity [95] and antagonism at mGluR5 [96] and NMDA glutamate receptors [97]. Acamprosate has been the subject of several open-label reports in FXS including an initial report on 3 adults with FXS who received a mean 21.3 weeks of acamprosate treatment [98].…”

Section: Modulation Of Glutamate and Gaba Neurotransmissionmentioning

confidence: 99%

Fragile X targeted pharmacotherapy: lessons learned and future directions

Erickson

Davenport

Schaefer

et al. 2017

J Neurodevelop Disord

102

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Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

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“…Of note, it has been proposed that acamprosate also acts as an antagonist for mGluR5 (Harris et al 2002). Erickson and colleagues have conducted several small trials of acamprosate in both FXS and autism (Erickson et al 2010; Erickson et al 2011; Erickson et al 2013b).…”

Section: Drug Treatments In Autism Involving Glutamatergic Neurotransmentioning

confidence: 99%

The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment

Rojas

2014

J Neural Transm

160

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Glutamate is the major excitatory neurotransmitter in the brain and may be a key neurotransmitter involved in autism. Literature pertaining to glutamate and autism or related disorders (e.g., Fragile X syndrome) is reviewed in this article. Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models. Currently, there are no pharmaceutical interventions approved for autism that address glutamate deficits in the disorder. New treatments related to glutamatergic neurotransmission, however, are emerging. In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder.

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Acamprosate Inhibits the Binding and Neurotoxic Effects of Trans‐ACPD, Suggesting a Novel Site of Action at Metabotropic Glutamate Receptors

Cited by 107 publications

References 67 publications

Binge Drinking Upregulates Accumbens mGluR5-Homer2-PI3K Signaling: Functional Implications for Alcoholism

Binge Drinking Upregulates Accumbens mGluR5-Homer2-PI3K Signaling: Functional Implications for Alcoholism

Fragile X targeted pharmacotherapy: lessons learned and future directions

The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment

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