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Interactions between loreclezole, chlormethiazole and pentobarbitone at GABA A receptors: functional and binding studies
Author(s) -
Zhong Yu,
Simmonds Michael A
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701269
Subject(s) - muscimol , chemistry , long term potentiation , cuneate nucleus , receptor , gabaa receptor , depolarization , pharmacology , biophysics , biochemistry , endocrinology , central nervous system , biology
Interations were investigated between loreclezole, chlormethiazole and pentobarbitone as potentiators of depolarization responses mediated by γ‐aminobutyric acid A (GABA A ) receptors on afferent nerve terminals in the rat cuneate nucleus in vitro . These drugs were also compared as modulators of [ 3 H]‐flunitrazepam (FNZ) binding to synaptic membranes prepared from rat whole brain homogenate. In rat cuneate nucleus slices, the drugs shifted muscimol log dose–response lines to the left in an approximately parallel fashion with the result that 200 μ M chlormethiazole potentiated muscimol responses by 0.567±0.037 log unit (mean±s.e.mean, n =4) while loreclezole gave a maximal potentiation at 10 μ M of only 0.121±0.037 ( n =6) log unit and 0.071±0.039 ( n =22) at 50 μ M . While 50 μ M chlormethiazole and 30 μ M pentobarbitone showed no significant interactions between each other when potentiating muscimol responses in combination, 50 μ M loreclezole in combination with either chlormethiazole or pentobarbitone attenuated their potentiating effects, possibly by inducing desensitization of GABA A receptors. In the [ 3 H]‐FNZ binding studies on well‐washed membranes, loreclezole enhanced binding to a maximum of 47.3±2.83% of control (mean±s.e.mean, n =3) at 300 μ M . Scatchard analysis revealed no change in B max but a decrease in K D for [ 3 H]‐FNZ from 3.9±0.29 n M to 2.7±0.10 n M (mean±s.e.mean, n =4) in the presence of 100 μ M loreclezole. In contrast, 100 μ M chlormethiazole caused no potentiation. A small component of the enhancement by loreclezole could be blocked by 100 μ M bicuculline and could also be blocked by 100 μ M chlormethiazole. It seems likely that the effects on [ 3 H]‐FNZ binding are due predominantly to direct actions of the drugs on the GABA A receptor and are separate from the GABA‐potentiating effects. The results indicate distinctly different profiles of action for loreclezole, chlormethiazole and pentobarbitone on GABA A receptors.