"Central" and "peripheral" benzodiazepines and kinetics of lindane-induced toxicity

Because hypothermia and anorexia were previously found to be more sensitive indices of the effects of lindane than were convulsions, these endpoints were used to quantify the ability of benzodiazepines (BDs) and phenytoin either to ameliorate or exacerbate the toxicity of lindane in the rat. After administration of lindane (40 or 50 mg/kg) in oil per os, toxicity was counteracted by phenytoin and the "central" BD agonists diazepam and clonazepam, but was worsened by Ro 5-4864 a "peripheral" BD agonist. Clonazepam and diazepam were each more effective in counteracting lindane-induced anorexia than in stimulating food intake, presumably because the animals had been fasted and probably even controls ate maximally when food was presented. Diazepam alone (3 injections in 1 day) produced withdrawal-induced decreased food intake the following day. Clonazepam and diazepam alone each transiently decreased colonic temperature, yet effectively blocked the more severe hypothermia produced by lindane. Ro 5-4864 by itself did not produce any measurable effects, yet exacerbated all of the effects, including lethal effects, of lindane. The present findings are compatible with other evidence that lindane and Ro 5-4864 act at the picrotoxinin receptor of the GABAA-activated chloride channel and that systemic administration of agents acting at this site may produce a constellation of effects, including seizures, hypothermia and anorexia.