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.
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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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    • "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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