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.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004361:Drug Tolerance; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009118:Muscimol / Q000378:metabolism* / Q000494:pharmacology; D010080:Oxazoles / Q000378:metabolism*; D010424:Pentobarbital / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A; D012890:Sleep / Q000187:drug effects; D013375:Substance Withdrawal Syndrome; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D010080:Oxazoles; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital