Effects of topiramate and other anti-glutamatergic drugs on the acute intoxicating actions of ethanol in mice: modulation by genetic strain and stress

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.

Fig. 1

Effects of memantine and MK-801. (A) Both memantine and MK-801 potentiated 1.75 g/kg EtOH-induced ataxia (n=8/dose). (B) Neither memantine nor MK-801 affected 3.0 g/kg EtOH-induced hypothermia (n=8/dose). (D) MK-801 but not memantine potentiated 3.0 g/kg EtOH-induced sedation/hypnosis (n=7−8/dose). **p<.01, *p<.05 vs. vehicle (open bars) at the same memantine dose; ##p<.01 vs. vehicle/vehicle. Data in Figs 1-8 are Means ±SEM.

Fig. 2

Effects of dextromethorphan and MK-801. (A) MK-801 but not dextromethorphan potentiated 1.75 g/kg EtOH-induced ataxia (n=8/dose). (B) Neither dextromethorphan nor MK-801 affected 3.0 g/kg EtOH-induced hypothermia (n=8/dose). (C) MK-801 but not dextromethorphan potentiated EtOH-induced 3.0 g/kg sedation/hypnosis (n=8/dose).

Fig. 3

Effects of haloperidol and MK-801. (A) Both haloperidol and MK-801 potentiated 1.75 g/kg EtOH-induced ataxia (n=7−10/dose). (B) Neither MK-801 nor haloperidol affected 3.0 g/kg EtOH-induced hypothermia (n=7−10/dose). (C) Both haloperidol and MK-801 potentiated 3.0 g/kg EtOH-induced sedation/hypnosis (n=7−10/dose). **p<.01 vs. vehicle (open bars) at the same haloperidol dose; ##p<.01 vs. vehicle/vehicle.

Fig. 4

Effects of lamotrigine and MK-801. (A) MK-801 but not lamotrigine potentiated 1.75 g/kg EtOH-induced ataxia (n=9−11/dose). (B) Neither lamotrigine nor MK-801 affected 3.0 g/kg EtOH-induced hypothermia (n=8−12/dose). (C) Both lamotrigine and MK-801 potentiated 3.0 g/kg EtOH-induced sedation/hypnosis (n=7−10/dose). **p<.01 vs. vehicle (open bars) at the same lamotrigine dose; ##p<.01 vs. vehicle/vehicle.

Fig. 5

Effects of oxcarbazepine and MK-801. (A) MK-801 but not oxcarbazepine potentiated 1.75 g/kg EtOH-induced ataxia (n=8/dose). (B) Neither MK-801 nor oxcarbazepine affected 3.0 g/kg EtOH-induced hypothermia (n=7−8/dose). (C) MK-801 but not oxcarbazepine potentiated 3.0 g/kg EtOH-induced sedation/hypnosis (n=7−8/dose). **p<.01 vs. vehicle (open bars) at the same oxcarbazepine dose.

Fig. 6

Effects of topiramate and MK-801. (A) MK-801 but not topiramate potentiated 1.75 g/kg EtOH-induced ataxia (n=8/dose). (B) Neither MK-801 nor topiramate affected 3.0 g/kg EtOH-induced hypothermia (n=8−9/dose). (C) MK-801 but not topiramate potentiated 3.0 g/kg EtOH-induced sedation/hypnosis, while topiramate augmented MK-801's EtOH-potentiating effects (n=7−8/dose). **p<.01 vs. vehicle (open bars) at the same topiramate dose; ##p<.01, #p<.05 vs. vehicle/vehicle.

Fig. 7

Effects of topiramate across inbred strains. Topiramate potentiated 3.0 g/kg EtOH-induced sedation/hypnosis in BALB/cJ but not 129S1, C57BL/6J or DBA/2J. n=6-8/dose/strain. ‡ p<.01 vs. all other vehicle-treated strains; **p<.01 vs. vehicle-treated BALB/cJ; #p<.05 vs. C57BL/6J.

Fig. 8

Effects of topiramate following exposure to chronic stress. Topiramate potentiated 3.0 g/kg EtOH-induced sedation/hypnosis in C57BL/6J mice exposed to chronic swim stress, but not non-stressed controls. n=8/dose/stress condition. **p<.01 vs. vehicle-treated stressed.