6-methyl-2-(phenylethynyl)pyridine and Alcohol-Withdrawal-Seizures

In alcoholic patients, ethanol is often consumed in a repeated cyclic pattern of intoxication followed by abstinence and the emergence of withdrawal symptoms. Repeated cycles of ethanol intoxication and withdrawal lead to a sensitization of central nervous system hyperexcitability as a result of an imbalance between inhibitory GABAergic transmission and excitatory glutamatergic transmission. Symptoms of alcohol withdrawal are usually treated pharmacologically with either benzodiazepines or anticonvulsant medications. However, recent evidence suggests that inhibition of glutamate transmission by stimulation of presynaptic inhibitory metabotropic glutamate receptors (i.e., mGluR2/3 receptors) or inhibition of mGluR5 receptors produces anticonvulsant effects. Therefore, the present study was designed to determine the effects the mGluR2/3 agonist LY379268 and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on ethanol withdrawal-induced seizure activity. Adult male C3H/He mice received chronic 16 h of ethanol vapor exposure in inhalation chambers followed by 8 h of withdrawal daily for 4 consecutive days. During the final (fourth) withdrawal cycle, mice were evaluated hourly for handling-induced convulsions (HIC), and were treated with vehicle, LY379268 (0.3, 1, and 3mg/kg) or MPEP (1, 3, and 10mg/kg) treatment at 4 and 8h into withdrawal. Significant reductions in overall HIC activity were not observed following administration of either compound. These results suggest that inhibition of glutamate transmission by mGluR2/3 agonists or mGluR5 antagonists does not alter HIC activity during withdrawal from repeated ethanol exposure, and as such these compounds may have limited usefulness in the treatment of central nervous system hyperexcitability during alcohol withdrawal.

Topics: Alcohol Withdrawal Seizures; Amino Acids; Animals; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System Depressants; Dose-Response Relationship, Drug; Ethanol; Excitatory Amino Acid Antagonists; Handling, Psychological; Male; Mice; Mice, Inbred C3H; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Structure-Activity Relationship