Effects of Topiramate and Other Anti-Glutamatergic Drugs on the Acute Intoxicating Actions of Ethanol in Mice: Modulation by Genetic Strain and Stress

Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 11/2008; 34(6):1454-66. DOI: 10.1038/npp.2008.182
Source: PubMed


Compounds with anti-glutamatergic properties currently in clinical use for various indications (eg Alzheimer's disease, epilepsy, psychosis, mood disorders) have potential utility as novel treatments for alcoholism. Enhanced sensitivity to certain acute intoxicating effects (ataxia, sedative) of alcohol may be one mechanism by which anti-glutamatergic drugs modulate alcohol use. We examined the effects of six compounds (memantine, dextromethorphan, haloperidol, lamotrigine, oxcarbazepine, and topiramate) on sensitivity to acute intoxicating effects of ethanol (ataxia, hypothermia, sedation/hypnosis) in C57BL/6J mice. Analysis of topiramate was extended to determine the influence of genetic background (by comparison of the 129S1, BALB/cJ, C57BL/6J, DBA/2J inbred strains) and prior stress history (by chronic exposure of C57BL/6J to swim stress) on topiramate's effects on ethanol-induced sedation/hypnosis. Results showed that one N-methyl-D-aspartate receptor (NMDAR) antagonist, memantine, but not another, dextromethorphan, potentiated the ataxic but not hypothermic or sedative/hypnotic effects of ethanol. Haloperidol increased ethanol-induced ataxia and sedation/hypnosis to a similar extent as the prototypical NMDAR antagonist MK-801. Of the anticonvulsants tested, lamotrigine accentuated ethanol-induced sedation/hypnosis, whereas oxcarbazepine was without effect. Topiramate was without effect per se under baseline conditions in C57BL/6J, but had a synergistic effect with MK-801 on ethanol-induced sedation/hypnosis. Comparing inbred strains, topiramate was found to significantly potentiate ethanol's sedative/hypnotic effects in BALB/cJ, but not 129S1, C57BL/6J, or DBA/2J strains. Topiramate also increased ethanol-induced sedation/hypnosis in C57BL/6J after exposure to chronic stress exposure. Current data demonstrate that with the exception of MK-801 and haloperidol, the compounds tested had either no significant or assay-selective effects on sensitivity to acute ethanol under baseline conditions in C57BL/6J. However, significant effects of topiramate were revealed as a function of co-treatment with an NMDAR blocker, genetic background, or prior stress history. These findings raise the possibility that topiramate and possibly other anti-glutamatergic drugs could promote the acute intoxicating effects of ethanol in specific subpopulations defined by genetics or life history.

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    • "However, few molecules are characterized by efficient antiglutamatergic activity;25 for example, memantine,26,27 Dextrometrophan,28 and budipine are considered antiglutamatergic drugs, yet only anecdotal reports showed LIDs or ICDs reduction. Lamotrigine, oxcarbazepine, and topiramate represent a class of anticonvulsant compounds with glutamate-release-inhibiting properties that shows encouraging evidence as novel medications for alcoholism.29,30 However, their potential in ICDs still needs to be demonstrated. "
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    ABSTRACT: Introduction Dopamine replacement therapy for Parkinson’s disease (PD) was recently linked to the development of impulse control disorders such as pathological gambling (PG), hypersexuality, compulsive shopping, and binge or compulsive eating. Antiglutamatergic agents including amantadine (Ama) reduce these behaviors in PD and non-PD patients. The aim of our study is to evaluate the changes in executive functions, emotions, and reward/loss processing during Ama treatment in PD patients. Methods Thirty-three patients affected by idiopathic PD were selected from a cohort of 1,096 PD patients and categorized in three different groups: ten affected by PG (PD-PG); nine PD patients with other impulse control disorder (PD-ICD); and 14 PD patient without any psychiatric disorder (PD-CTR-controls). For the neuropsychological evaluation, the following behavioral tasks where administered: the Stroop, the emotional Stroop, and the monetary reward/loss risk-taking tasks. Results During Ama treatment, PD-PGs showed a decrease in risky choices and an increase in non-risky choices (t(9)=−2.40, P<0.05 and t(9)=2,67, P<0.05 uncorrected, respectively). Between-group comparison showed a significant decrease in risky choices for PD-PG with respect to PD-CTR (t(22)=−4.16, P<0.01), and a decreased accuracy for positive words in comparison between PD-PG and PD-ICD (t(17)=−7,49, P<0.01) and PD-PG and PD-CTR (t(22)=−4.29, P<0.01). No within- and between-group differences were observed for Stroop task. Discussion Our data showed that Ama add-on therapy reduces hypersensitivity to reward and sustains activation toward uncertainty in PD-PG patients. These finding might explain the behavioral mechanism underlying the effect of antiglutamatergic drugs.
    Neuropsychiatric Disease and Treatment 06/2014; 10:1093-101. DOI:10.2147/NDT.S54423 · 1.74 Impact Factor
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    • "As noted in the Introduction, we previously reported that B6 and S1 differ in the LORR response to 3 mg/kg EtOH, but not in either the hypothermia response to 3 mg/kg EtOH or the ataxic response to 1.75 g/kg EtOH (Chen and Holmes 2009; Palachick et al. 2008). To confirm these differences and extend the strain comparison to higher doses, we compared male B6 and S1, obtained from The Jackson Laboratory (Bar Harbor, ME), for responses in each assay to two different EtOH doses: ataxia (1.75 or 2.0 mg/kg), hypothermia (3.0 or 3.5 mg/kg), and LORR (3.0 or 3.5 mg/kg) (n = 8 per strain, per dose). "
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    ABSTRACT: Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6 × S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans. Electronic supplementary material The online version of this article (doi:10.1007/s00335-012-9394-2) contains supplementary material, which is available to authorized users.
    Mammalian Genome 02/2012; 23(5-6):305-21. DOI:10.1007/s00335-012-9394-2 · 3.07 Impact Factor
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    • "The precise mechanisms underlying the EtOH hypersensitivity in the PSD-95 KO mice also remains to be determined. The effects of deleting PSD-95 on EtOH intoxication and drinking phenocopies the effects produced by treatment with an NMDAR antagonist in nonmutant mice (Gass & Olive 2008; Palachick et al. 2008; Chen & Holmes 2009), and as just mentioned, PSD-95 has a critical function in the trafficking, stabilization and signal transduction of NMDARs. On this basis, we reasoned that the PSD-95 KO phenotype might reflect functional impairment of the NMDAR, at least in the receptor's response to EtOH, and that such an alteration could be interrogated by measuring sensitivity to NMDAR antagonist effects on EtOH intoxication. "
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    ABSTRACT: The synaptic signaling mechanisms mediating the behavioral effects of ethanol (EtOH) remain poorly understood. Post-synaptic density 95 (PSD-95, SAP-90, Dlg4) is a key orchestrator of N-methyl-D-aspartate receptors (NMDAR) and glutamatergic synapses, which are known to be major sites of EtOH's behavioral actions. However, the potential contribution of PSD-95 to EtOH-related behaviors has not been established. Here, we evaluated knockout (KO) mice lacking PSD-95 for multiple measures of sensitivity to the acute intoxicating effects of EtOH (ataxia, hypothermia, sedation/hypnosis), EtOH drinking under conditions of free access and following deprivation, acquisition and long-term retention of EtOH conditioned place preference (CPP) (and lithium chloride-induced conditioned taste aversion), and intoxication-potentiating responses to NMDAR antagonism. PSD-95 KO exhibited increased sensitivity to the sedative/hypnotic, but not ataxic or hypothermic, effects of acute EtOH relative to wild-type controls (WT). PSD-95 KO consumed less EtOH than WT, particularly at higher EtOH concentrations, although increases in KO drinking could be induced by concentration-fading and deprivation. PSD-95 KO showed normal EtOH CPP 1 day after conditioning, but showed significant aversion 2 weeks later. Lithium chloride-induced taste aversion was impaired in PSD-95 KO at both time points. Finally, the EtOH-potentiating effects of the NMDAR antagonist MK-801 were intact in PSD-95 KO at the dose tested. These data reveal a major, novel role for PSD-95 in mediating EtOH behaviors, and add to growing evidence that PSD-95 is a key mediator of the effects of multiple abused drugs.
    Addiction Biology 02/2011; 16(3):428-39. DOI:10.1111/j.1369-1600.2010.00282.x · 5.36 Impact Factor
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