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.