Korpi E R, Wong G, Lüddens H
Biomedical Research Center, Alko Group Ltd, Helsinki, Finland.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Oct;352(4):365-73. doi: 10.1007/BF00172773.
Clozapine, an atypical neuroleptic, functionally antagonizes the gamma-aminobutyric acid-induced chloride uptake via the main central inhibitory receptor, gamma-aminobutyric acid type A (GABAA) receptor, in brain vesicles. GABAA antagonism by micromolar concentrations of clozapine is more efficient in rat cerebrocortical and hippocampal membranes than in cerebellar membranes, as evidenced by clozapine reversal GABA-inhibition of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding. A typical neuroleptic, haloperidol, failed to antagonize GABA in any of these brain regions, while the specific GABAA antagonist 2'-(3'-carboxy-2',3'-propyl)-3-amino-6-p -methoxyphenylpyrazinium bromide (SR 95531) was efficient in all three brain regions. Clozapine action on [35S]TBPS binding was unaffected by the benzodiazepine receptor antagonist flumazenil. Clozapine inhibited the binding of [3H]muscimol and [3H]SR 95531 to the GABA recognition site, but this effect only partially correlated with the regional differences in and the potency of clozapine antagonism of GABA-inhibition of [35S]TBPS binding, suggesting that also other than GABA sites may mediate clozapine actions. Autoradiography of [35S]TBPS binding revealed GABA antagonism by clozapine in most brain regions. Main exceptions were cerebellar granule cell and molecular layers, olfactory bulb external plexiform and glomerular layers and primary olfactory cortex, where clozapine antagonized GABA inhibition less than average, and lateral hypothalamic and preoptic areas where its antagonism was greater than average. Recombinant alpha 6 beta 2 gamma 2 receptors, the predominant alpha 6 subunit-containing receptor subtype in cerebellar granule cells, failed to show GABA antagonism by clozapine up to 100 microM. In contrast, recombinant alpha 1 beta 2 gamma 2 receptors, forming the predominant receptor subtype in the brain, were clozapine sensitive. Recombinant alpha 6 beta 2 gamma 2 and alpha 6 beta 3 gamma 2 receptors resulted in clozapine-insensitive receptors, whereas alpha 6 beta 1 gamma 2 receptors were clozapine sensitive. The efficacy of clozapine to antagonize GABA in alpha 1 beta x gamma 2 receptors decreased in the order of alpha 1 beta 1 gamma 2 > alpha 1 beta 2 gamma 2> alpha 1 beta 3 gamma 2. The results indicate that clozapine antagonizes the function of most GABAA receptor subtypes, and that the interaction is determined by the interaction of the alpha and beta subunit variants. GABA antagonism is a unique property of clozapine, not shared by haloperidol, which might be involved in the pharmacological mechanism for the increased seizure susceptibility associated with clozapine treatment.
氯氮平是一种非典型抗精神病药物，在脑囊泡中可通过主要的中枢抑制性受体——A型γ-氨基丁酸（GABAA）受体，功能性地拮抗γ-氨基丁酸诱导的氯离子摄取。微摩尔浓度的氯氮平对GABAA的拮抗作用在大鼠大脑皮质和海马膜中比在小脑膜中更有效，这通过氯氮平逆转GABA对[35S]叔丁基双环磷硫代酸盐（[35S]TBPS）结合的抑制作用得以证明。典型抗精神病药物氟哌啶醇在这些脑区中均未能拮抗GABA，而特异性GABAA拮抗剂2'-（3'-羧基-2',3'-丙基）-3-氨基-6-p-甲氧基苯基吡嗪溴化物（SR 95531）在所有三个脑区中均有效。氯氮平对[35S]TBPS结合的作用不受苯二氮䓬受体拮抗剂氟马西尼的影响。氯氮平抑制[3H]蝇蕈醇和[3H]SR 95531与GABA识别位点的结合，但这种作用仅部分与氯氮平拮抗GABA对[35S]TBPS结合抑制作用的区域差异和效力相关，这表明除了GABA位点外，其他位点也可能介导氯氮平的作用。[35S]TBPS结合的放射自显影显示氯氮平在大多数脑区中拮抗GABA。主要例外是小脑颗粒细胞层和分子层、嗅球外丛状层和肾小球层以及初级嗅觉皮质，在这些区域氯氮平拮抗GABA抑制作用低于平均水平，而在外侧下丘脑和视前区其拮抗作用高于平均水平。重组α6β2γ2受体是小脑颗粒细胞中主要的含α6亚基的受体亚型，在高达100μM的浓度下未显示氯氮平对GABA的拮抗作用。相反，构成大脑中主要受体亚型的重组α1β2γ2受体对氯氮平敏感。重组α6β2γ2和α6β3γ2受体产生对氯氮平不敏感的受体，而α6β1γ2受体对氯氮平敏感。氯氮平拮抗α1βxγ2受体中GABA的效力按α1β1γ2>α1β2γ2>α1β3γ2的顺序降低。结果表明氯氮平拮抗大多数GABAA受体亚型的功能，并且这种相互作用由α和β亚基变体的相互作用决定。GABA拮抗是氯氮平的独特特性，氟哌啶醇不具有此特性，这可能与氯氮平治疗相关的癫痫易感性增加的药理机制有关。
