Bicuculline Up‐Regulation of GABAA Receptors in Rat Brain

Abstract

Effects of acute and subacute administration of Dicuculline on [³H]muscimol, [³H]flunitrazepam, and t-[³⁵S]butylbicyclophosphorothionate ([³⁵S]TBPS) binding to various brain regions were studied in Sprague-Dawley rats. Acute administration of bicuculline affected neither the K_D nor the B_max of the three receptor sites. In rats treated sub-acutely with bicuculline (2 mg/kg, i.p., daily for 10 days), [³H]muscimol binding was increased in the frontal cortex, cerebellum, striatum, and substantia nigra. Scatchard analysis revealed that subacute treatment of rats with bicuculline resulted in a significantly lower K_D of high-affinity sites in the striatum and in a significantly lower K_D of high- and low-affinity sites in the frontal cortex. In the cerebellum, two binding sites were apparent in controls and acutely treated animals; however, only the high-affinity site was defined in subacutely treated animals, with an increase in the B_max value. Triton X-100 treatment of frontal cortical membranes eliminated the difference in [³H]muscimol binding between control and subacute bicuculline treatments. On the other hand, [³H]muscimol binding was significantly increased in the cerebellum from bicuculline-treated animals even after Triton X-100 treatment. The apparent K_i of bicuculline for the GABA_A receptor was also decreased in the frontal cortex and the striatum following the treatment. However, subacute administration of bicuculline affected neither the K_D nor the B_max of [³H]-flunitrazepam and [³⁵S]TBPS binding in the frontal cortex and the cerebellum. These results suggest that GABA_A receptors are up-regulated after subacute administration of bicuculline, with no change in benzodiazepine and picro-toxin binding sites.