Modulation of GABA binding sites by CNS depressants and CNS convulsants

Neurochem Int. 1982;4(4):259-68. doi: 10.1016/0197-0186(82)90062-6.


[(3)H]Muscimol binding at 23 degrees C and muscimol stimulated [(3)H]flunitrazepam binding at 37 degrees C to membranes of rat cerebral cortex have been investigated. In washed membrane preparations, 2 apparent populations of [(3)H]muscimol binding sites can be observed. At 23 degrees C [(3)H]muscimol binding is more sensitive to inhibition by NaCl and by other salts than at 0 degrees C. The CNS depressants etazolate and pentobarbital reversibly enhance [(3)H]muscimol binding and they increase the affinity of muscimol as a stimulator of [(3)H]flunitrazepam binding. Conversely the CNS convulsants picrotoxin, picrotoxinin and isopropylbicyclophosphate (IPTBO) reversibly interfere with [(3)H]muscimol binding when NaCl is present and these drugs antagonize the effects of etazolate. In the presence of NaCl, picrotoxin, picrotoxinin and IPTBO also decrease the apparent affinity of muscimol or GABA as stimulator of [(3)H]flunitrazepam binding. Binding of [(3)H]muscimol to GABA recognition sites of rat cerebral cortex is enhanced by Ag(+), Hg(+) and Cu(2+) in ?M concentrations, Ag(+) being most potent. The effects of 100 ?M AgNO(3) persist after repeated washing of the membranes. When membranes are pretreated with AgNO(3) only one apparent population of [(3)H]muscimol binding sites with high affinity (K(d): 6-8 nM) is found. In AgNO(3) pretreated membranes, the affinity of muscimol as stimulator of [(3)H]flunitrazepam binding is increased 18 times (EC(50) 14 nM) when compared to control membranes, (EC(50) 253 nM). In AgNO(3) pretreated membranes, etazolate, pentobarbital and IPTBO fail to perturb either [(3)H]muscimol binding or baseline and muscimol stimulated [(3)H]flunitrazepam binding. The results demonstrate that the apparent sensitivity of GABA binding sites of the GABA-benzodiazepine-picrotoxin receptor complex can be increased by etazolate and pentobarbital and decreased by picrotoxin and IPTBO. These drugs have in common that they interfere with [(3)H]dihydropicrotoxinin binding.