Glutamate hyperexcitability and aggression during withdrawal from escalated ethanol consumption in outbred male mice.
Nathanson, Anna J.
- Ethanol withdrawal syndrome, characterized by glutamatergic hyperexcitability in the brain, is a defining characteristic of alcohol dependence. Glutamate hyperexcitability and an upregulation of NMDA receptors have been observed in the brains of mice in withdrawal from ethanol consumption. The present study examined the effects of the uncompetitive NMDA receptor antagonist memantine on aggression ... read moreduring withdrawal from ethanol. Outbred Carworth Farm Webster (CFW) male mice were given intermittent, 2-bottle choice access to 20% w/v ethanol and water for ten weeks. CFW males voluntarily consumed ethanol, ranging from 5-20 grams/kilogram (g/kg) bodyweight in 24 hours over the 10 weeks of intermittent access. To measure alcohol withdrawal severity, handling-induced convulsion (HIC) scores were assessed every two hours during the ethanol withdrawal period. Outbred mice exhibited significantly greater HIC severity than water controls. In the same individuals, aggression during withdrawal was probed with a memantine or ketamine challenge to assess glutamate excitability. Resident CFW mice were injected with memantine (0, 3, 5, 10, or 30 mg/kg, i.p.) or ketamine (0, 3, 5, or 10 mg/kg, i.p.) and tested for aggression against an intruder at eight hours into withdrawal. Memantine significantly increased aggression in CFW mice during the withdrawal period, specifically at the 5 mg/kg dose, while ketamine did not significantly affect measures of aggression during ethanol withdrawal. These findings suggest that the uncompetitive NMDA receptor antagonist memantine, but not ketamine, biphasically increased withdrawal-related aggression in outbred CFW mice. Future studies will use microdialysis to examine glutamate levels in the mouse brain throughout the ethanol withdrawal period and will measure NMDA receptor regulation in the ethanol-withdrawn brain using immunohistological techniques.read less