Acute Effects of Acamprosate and MPEP on Ethanol Drinking‐in‐the‐Dark in Male C57BL/6J Mice

Gupta, T. K. Das; Syed, Y. M.; Revis, Andrew A.; Miller, Samantha A.; Martínez, Melissa A.; Cohn, Kellen A.; Demeyer, Michael R.; Patel, Kevin; Brzezinska, Weronika J.; Rhodes, Justin S.

doi:10.1111/j.1530-0277.2008.00787.x

Cited by 66 publications

(68 citation statements)

References 44 publications

(78 reference statements)

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“…Limitations include that while showing similar treatment effects as the selective mGluR5 antagonist MPEP (20 mg/ kg) in the drinking-in-the-dark mouse model, acamprosate (300 mg/kg) was significantly less potent (Gupta et al 2008). Acamprosate has poor oral bioavailability (about 11%) and low intestinal permeability requiring high and frequent dosing (Forest Pharmaceuticals Inc 2005), a requirement which may limit the tolerability of the drug as we found given gastrointestinal distress in 2 of 3 patients.…”

Section: Discussionmentioning

confidence: 97%

“…Acamprosate and MPEP have both been associated with increased sedative effects of alcohol and reduced alcohol withdrawal in mice; no effects of acamprosate or MPEP were noted in mGluR5 knockout mice (Blednov and Adron Harris 2008). Gupta and colleagues (2008) demonstrated that acamprosate and MPEP both dose dependently reduced ethanol drinking in the drinking-inthe-dark mouse model (Gupta et al 2008). In a conflicting report, at concentrations typically achieved in humans, acamprosate did not modulate the function of many neuroreceptors, including mGluR receptors, in an electrophysiological study in Xenopus oocytes (Reilly et al 2008).…”

Section: Introductionmentioning

confidence: 96%

“…Research into the mechanism of action of acamprosate (calcium acetylhomotaurine), a drug approved for maintenance of abstinence from alcohol, has recently focused on mGluR5 antagonism (Blednov and Adron Harris 2008;Gupta et al 2008;Harris et al 2002). In rat brain specimens, Harris et al (2002) initially demonstrated that acamprosate had binding and functional characteristics consistent with an mGluR antagonist combined with functional similarity to the non-competitive mGluR5 antagonist SIB-1893 (Harris et al 2002).…”

Section: Introductionmentioning

confidence: 98%

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Brief Report: Acamprosate in Fragile X Syndrome

Erickson

Mullett

McDougle

2010

J Autism Dev Disord

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Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). We report on the first trial of acamprosate, a drug with putative mGluR5 antagonism, in three adults with FXS and autism. Medical records describing open-label treatment with acamprosate in 3 patients with FXS and a comorbid diagnosis of autistic disorder were reviewed. In all three patients, acamprosate was associated with improved linguistic communication. Three patients received acamprosate over a mean 21.3 weeks of treatment. All patients showed global clinical benefit as rated with the Clinical Global Impressions-Improvement scale. Marked communication improvement was unexpected and has potential implications for the treatment of FXS, as well as idiopathic autism.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

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Brief Report: Acamprosate in Fragile X Syndrome

Erickson

Mullett

McDougle

2010

J Autism Dev Disord

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“…Taken together, these results suggest that the increased sensitivity to the sedative/hypnotic effects of ethanol seen in ClockD19 mice may be because of a hyperglutamatergic system and are likely not due to differences in GABAergic transmission. Gupta et al (2008) reported that glutamatergic signaling has a role in binge-like ethanol drinking in the drinking in the dark (DID) paradigm, where they reported that mice pretreated with acamprosate or MPEP (an mGluR5 antagonist) exhibited decreased DID. Perhaps, the altered glutamatergic tone indirectly measured by ketamine LORR and directly measured and described by Beaulé et al (2009) in ClockD19 mice would lead to increased binge-like ethanol drinking in the DID paradigm.…”

Section: Clockd19 Mice Exhibit Augmented Responses To the Sedative Efmentioning

confidence: 99%

The Role of Clock in Ethanol-Related Behaviors

Ozburn

Falcón

Mukherjee

et al. 2013

Neuropsychopharmacol

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Mice with a mutation in the Clock gene (ClockD19) exhibit increased preference for stimulant rewards and sucrose. They also have an increase in dopaminergic activity in the ventral tegmental area (VTA) and a general increase in glutamatergic tone that might underlie these behaviors. However, it is unclear if their phenotype would extend to a very different class of drug (ethanol), and if so, whether these systems might be involved in their response. Continuous access voluntary ethanol intake was evaluated in ClockD19 mutants and wild-type (WT) mice. We found that ClockD19 mice exhibited significantly increased ethanol intake in a two-bottle choice paradigm. Interestingly, this effect was more robust in female mice. Moreover, chronic ethanol experience resulted in a long-lasting decrease in VTA Clock expression. To determine the importance of VTA Clock expression in ethanol intake, we knocked down Clock expression in the VTA of WT mice via RNA interference. We found that reducing Clock expression in the VTA resulted in significantly increased ethanol intake similar to the ClockD19 mice. Interestingly, we also discovered that ClockD19 mice exhibit significantly augmented responses to the sedative effects of ethanol and ketamine, but not pentobarbital. However, their drinking behavior was not affected by acamprosate, an FDA-approved drug for the treatment of alcoholism, suggesting that their increased glutamatergic tone might underlie the increased sensitivity to the sedative/hypnotic properties of ethanol but not the rewarding properties of ethanol. Taken together, we have identified a significant role for Clock in the VTA as a negative regulator of ethanol intake and implicate the VTA dopamine system in this response.

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“…Acamprosate has pleiotropic effects impacting glutamate and GABA neurotransmission (34). Its mGluR5 antagonist effect has been demonstrated in animal models of alcoholism (30,35,36) followed by two pilot clinical trials conducted by Erickson et al 2011 and 2013 in patients with FXS + ASD finding that 75% of the sample responded to treatment exhibiting improvement in social behavior, hyperactivity and communication skills (33). This medication should be studied further not only in those with FXS but also to treat the alcoholism that can occur in this disorder.…”

Section: Casementioning

confidence: 99%