Drug withdrawal convulsions and susceptibility to convulsants after short-term selective breeding for acute ethanol withdrawal

Abstract

High Alcohol Withdrawal (HAW) and Low Alcohol Withdrawal (LAW) mice were selectively bred from a foundation population of C57BL6/J (B6)×DBA/2J (D2) F2 intercross progeny for display of intense or mild handling-induced withdrawal convulsions, respectively, following a single injection of a hypnotic dose of ethanol (alcohol; 4 g/kg). The HAW line had significantly greater alcohol withdrawal severity scores compared to the LAW line after only a single generation of selection; the magnitude of the line difference was 8-fold by the fourth selected generation. We tested these lines for severity of withdrawal convulsions following the benzodiazepine, diazepam; the gaseous anesthetic, nitrous oxide; the imidazopyridine, zolpidem and the barbiturate, pentobarbital. In all cases, HAW mice had significantly greater withdrawal severity than mice of the LAW line. These results indicate that some genes influencing withdrawal convulsion severity following ethanol also affect withdrawal from other CNS depressants. D2 mice are more sensitive to a variety of convulsants than B6 mice (and have more severe withdrawal convulsions). We, therefore, tested separate groups of mice of both selectively bred lines for threshold sensitivity to pentylenetetrazol (PTZ), N-methyl- d-aspartate (NMDA) and kainic acid (KA). No line differences were detected. These results indicate that genes influencing severity of withdrawal from several depressant drugs are largely different from those affecting susceptibility to GABAergic or glutamatergic convulsants.