[Neurochemical and pharmacological studies on brain GABA receptors]

GABAA receptors of the mammalian central nervous system are ligand-gated Cl- ion channels and the sites of action of many pharmacologically important drugs. GABAA receptors were characterized using a potent antagonist, [3H]SR 95531, and agonists such as [3H]GABA and [3H]muscimol. Pretreatment of brain membranes with Triton X-100 or phospholipase A2 increased [3H]GABA and [3H]muscimol binding in the frontal cortex and cerebellum, whereas these treatments significantly decreased [3H]SR 95531 binding. The treatment of rats subacutely with a subconvulsive dose of bicuculline (2 mg/kg, i.p., daily for 10 days) significantly increased the apparent affinity for [3H]muscimol in the frontal cortex, cerebellum, striatum and substantia nigra. On the other hand, the apparent affinity for [3H]SR 95531 binding was significantly decreased in these regions. These results suggest that subacute bicuculline treatment in vivo and treatment in vitro of brain membranes with Triton X-100 or phospholipase A2 bring about a conformational change in the GABAA-receptor molecule, thus resulting in access increase of the GABA agonist and access decrease of the antagonist to GABAA receptors. In the cerebellum, the Bmax values of [3H]muscimol and [3H]SR 95531 binding and Vmax value of muscimol-stimulated 36Cl- uptake were significantly increased following subacute bicuculline treatment with no change in the frontal cortex, with this process involving increased de novo synthesis of GABAA receptors.