Discriminative stimulus effects of pregnanolone in rhesus monkeys.
Discriminative stimulus effects of pregnanolone in rhesus monkeys.
复制标题
孕烯醇酮对恒河猴的区别刺激作用。
DOI：
10.1007/s00213-013-3218-2
复制
发表时间：
2014
影响因子：
3.4
通讯作者：
France,CharlesP
中科院分区：
文献类型：
--
作者：
Gerak,LisaR;France,CharlesP
RationaleNeuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABAAreceptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABAA,N-methyl-d-aspartate (NMDA), σ1, or 5-HT3receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators.ObjectiveThe current study established the neuroactive steroid pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABAAreceptors might contribute to its discriminative stimulus effects.MethodsFour rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.ResultsPositive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABAAreceptors, such as extrasynaptic GABAA, NMDA, σ1, and 5-HT3receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity andpA2values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone.ConclusionWhile these results do not exclude the possibility that pregnanolone acts at receptors other than synaptic GABAAreceptors, they indicate a primary and possibly exclusive role of synaptic GABAAreceptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABAAreceptors.
