脳内GABA受容体の神経化学的・薬理学的研究

抄録

GABA_A receptors of the mammalian central nervous system are ligand-gated Cl^- ion channels and the sites of action of many pharmacologically important drugs. GABA_A 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 GABA_A-receptor molecule, thus resulting in access increase of the GABA agonist and access decrease of the antagonist to GABA_A receptors. In the cerebellum, the B_max values of [³H] muscimol and [³H] SR 95531 binding and V_max 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 GABA_A receptors.