Acute and chronic effects of pentobarbital in relation to postsynaptic GABA receptors: a study with muscimol

Muscimol, a GABA agonist, enhanced pentobarbital sleeping time in a dose-dependent manner. The GABA antagonists such as bicuculline and picrotoxin, and the CNS stimulant such as pentylenetetrazol, inhibited pentobarbital sleeping time; however, all except picrotoxin produced less than 35% maximum inhibition. Picrotoxin, and agent which blocks the chloride ionophore of GABA-receptor complex, exhibited a parallel dose-response curve with respect to muscimol. Chronic administration of pentobarbital by pellet implantation induced tolerance as evidenced by decreased sleeping time; the tolerance receded gradually upon abrupt withdrawal. Muscimol enhanced pentobarbital sleeping time both in tolerant and withdrawal mice. Na+-independent GABA-receptor binding, using [3H]muscimol as a ligand, was increased after acute and chronic pentobarbital administration; withdrawal of the pentobarbital reversed the increase in receptor population. None of the treatments altered the affinity of [3H]muscimol binding. These results support the contention that pentobarbital (a) directly acts on the postsynaptic chloride ionophore and (b) augments GABA-mediated postsynaptic effects. The functional significance of the increase in GABA receptor population after pentobarbital treatment is unclear.