Effects of Picrotoxin Treatment on GABA_A Receptor Supramolecular Complexes in Rat Brain

Abstract The effects of acute and chronic administration of a subconvulsive dose of picrotoxin on t‐[³⁵S]butylbieyclophosphorothionate ([³⁵S]TBPS), [³H]muscimol, and [³H]flunitrazepam binding characteristics in various regions and on the convulsant potency of picrotoxin in Sprague‐Dawley rats were examined. Acute administration of a sub‐convulsive dose of picrotoxin (3 mg/kg, i. p.) significantly increased [³⁵S]TBPS and [³H]muscimol binding in cerebellum (CB) with no change in frontal cortex (FC). In rats treated chronically with picrotoxin (3 mg/kg, i.p., daily for 10 days), the B_max of [³⁵S]TBPS binding site was significantly decreased in the FC., striatum (ST), and CB with no change in K_D values. Neither [³H]muscimol binding in the FC and CB nor [³H]fiunitrazepam binding in the FC was affected in these rats. In addition, the potency of pentobarbital to inhibit [³⁵S]TBPS binding in vitro was not altered following acute or chronic treatment of picrotoxin. Chronic administration of picrotoxin did not affect convulsive ED₅₀ or LD₅₀ of picrotoxin; however, it delayed the onset of convulsions and increased the time to death. These results suggest that treatment with picrotoxin at a subconvulsive dose for 10 days causes down‐regulation of [³⁵S]TBPS binding sites and that this down‐regulation might be related, at least in part, to the decreased extent of convulsant potency of picrotoxin. In addition, the results indicate possible interaction between convulsant binding sites and GABA_A receptor sites in the CB following picrotoxin treatment.