Zonisamide decreases ethanol intake in rats and mice

Division of Psychiatry, Boston University School of Medicine, Boson, MA 02118, USA.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 06/2007; 87(1):65-72. DOI: 10.1016/j.pbb.2007.04.001
Source: PubMed


Several anticonvulsant agents, including topiramate and valproate, have been found to reduce alcohol consumption in rodent models of drinking. The question of whether the novel anticonvulsant agent, zonisamide, shares similar actions in either mice or rats was investigated in the present experiments. In an initial experiment, the consumption of a 10% ethanol-5% sucrose solution, available for one hour, by Wistar rats treated with lactose, topiramate, or zonisamide was determined. In a second experiment, the intake of a 10% ethanol/water solution, accessible for two hours, by C57BL/B6N mice treated with either zonisamide or vehicle was assessed. In the rat, 50 mg/kg (PO) doses of either topiramate or zonisamide produced significant, but moderate decreases in ethanol/sucrose intake. The administration of a 50 mg/kg (IP) dose of zonisamide to mice resulted in a marked lowering in ethanol consumption. These results provide evidence that zonisamide administration will decrease ethanol consumption by both mice and rats in limited access models of drinking, and might, like topiramate, be useful as a medication for alcoholism.

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Available from: Domenic A Ciraulo
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    • "US NIH, 2009). Topiramate has been shown to reduce ethanol consumption in Wistar rats using two-bottle choice tests (Knapp et al., 2007); it reduced the motivation to lick for beer (Hargreaves and McGregor, 2007) and attenuated the withdrawal signs after chronic intermittent ethanol treatment (Cagetti et al., 2004). Effects of topiramate on ethanol intake have also been demonstrated in rats that were selectively bred for high ethanol preference and in mice (Nguyen et al., 2007; Breslin et al., 2010; Zalewska-Kaszubska et al., 2013). "
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    Preview · Article · Feb 2014 · British Journal of Pharmacology
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    • "Ethanol selfadministration is reduced by competitive and non-competitive NDMA receptor antagonists (Rassnick et al., 1992; Bienkowski et al., 1999; Holter et al., 2000; Malpass et al., 2010) and competitive AMPA/kainate receptor antagonists (Stephens and Brown, 1999). Cue-induced reinstatement of ethanol maintained responding is reduced by lamotrigine, a glutamate release inhibitor (Vengeliene et al., 2007), competitive NMDA receptor antagonists (Backstrom and Hyytia, 2004; Bachteler et al., 2005), the NMDA receptor modulator acamprosate (Bachteler et al., 2005) as well as competitive AMPA/kainate antagonists (Backstrom and Hyytia, 2004; Sanchis-Segura et al., 2006), including topiramate (Knapp et al., 2007; Lynch et al., 2011). Previous studies in humans demonstrate clearly the potential role of iGluR modulators in the regulation of alcohol "
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    ABSTRACT: Functional impairment of the orbital and medial prefrontal cortex underlies deficits in executive control that characterize addictive disorders, including alcohol addiction. Previous studies indicate that alcohol alters glutamate neurotransmission and one substrate of these effects may be through the reconfiguration of the subunits constituting ionotropic glutamate receptor (iGluR) complexes. Glutamatergic transmission is integral to cortico-cortical and cortico-subcortical communication and alcohol-induced changes in the abundance of the receptor subunits and/or their splice variants may result in critical functional impairments of prefrontal cortex in alcohol dependence. To this end, the effects of chronic ethanol self-administration on glutamate receptor ionotropic AMPA (GRIA) subunit variant and kainate (GRIK) subunit mRNA expression were studied in the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) of male cynomolgus monkeys. In DLPFC, total AMPA splice variant expression and total kainate receptor subunit expression were significantly decreased in alcohol drinking monkeys. Expression levels of GRIA3 flip and flop and GRIA4 flop mRNAs in this region were positively correlated with daily ethanol intake and blood ethanol concentrations (BEC) averaged over the 6 months prior to necropsy. In OFC, AMPA subunit splice variant expression was reduced in the alcohol treated group. GRIA2 flop mRNA levels in this region were positively correlated with daily ethanol intake and BEC averaged over the 6 months prior to necropsy. Results from these studies provide further evidence of transcriptional regulation of iGluR subunits in the primate brain following chronic alcohol self-administration. Additional studies examining the cellular localization of such effects in the framework of primate prefrontal cortical circuitry are warranted.
    Full-text · Article · Jan 2011 · Frontiers in Psychiatry
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    • "In this context, lamotrigine has been found to attenuate cue-induced alcoholseeking in rats (Vengeliene et al., 2007) but has no effect on EtOH-withdrawal anxiety-like behavior (Knapp et al., 2007b). Moreover, while there are to our knowledge no published reports of oxcarbazepine effects on rodent EtOH-related behaviors, topiramate has no effect on EtOH conditioned place preference but does attenuate EtOH withdrawal and drinking, perhaps most robustly after EtOH deprivation (Cagetti et al., 2004; Farook et al., 2007; Gabriel and Cunningham, 2005; Gremel et al., 2006; Hargreaves and McGregor, 2007; Knapp et al., 2007a; Nguyen et al., 2007). "
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    ABSTRACT: 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.
    Preview · Article · Nov 2008 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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