McMahon Lance R, France Charles P
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Psychopharmacology (Berl). 2005 Apr;178(4):400-9. doi: 10.1007/s00213-004-2022-4. Epub 2004 Oct 14.
Interactions among compounds at GABA(A) receptors might have important implications for the therapeutic and other effects of positive GABA(A) modulators (e.g. benzodiazepines).
This study examined whether a midazolam discriminative stimulus is modified by GABA(A) agonists that act at sites other than benzodiazepine sites.
Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABA(A) receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABA(A) receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam.
When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1-3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32-1 mg/kg), gaboxadol (3.2-10 mg/kg) and progabide (10-32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive.
Direct-acting GABA(A) receptor agonists are qualitatively different from positive GABA(A) modulators in rhesus monkeys trained to discriminate midazolam. Although GABA(A) receptor agonists and modulators can enhance the actions of benzodiazepines at the GABA(A) receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl(-) flux at the GABA(A) receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.
GABA(A)受体上化合物之间的相互作用可能对GABA(A)阳性调节剂（如苯二氮䓬类药物）的治疗及其他效应具有重要意义。
本研究考察作用于苯二氮䓬类药物作用位点以外部位的GABA(A)激动剂是否会改变咪达唑仑辨别刺激。
辨别咪达唑仑（0.32mg/kg皮下注射）的恒河猴接受直接作用的GABA(A)受体激动剂（如蝇蕈醇和加波沙朵）、间接作用的GABA(A)受体激动剂（普罗加比）、乙醇、另一种苯二氮䓬类药物（三唑仑）、一种巴比妥类药物（戊巴比妥）或一种神经活性甾体（孕烷醇酮），单独给药以及与咪达唑仑联合给药。
单独给药时，三唑仑（0.1mg/kg）、戊巴比妥（17.8mg/kg）和孕烷醇酮（5.6mg/kg）引发高水平的咪达唑仑杠杆反应，乙醇（1 - 3g/kg）引发中等水平的咪达唑仑杠杆反应，蝇蕈醇（0.32 - 1mg/kg）、加波沙朵（3.2 - 10mg/kg）和普罗加比（10 - 32mg/kg）引发低水平的咪达唑仑杠杆反应。当与低于完全有效剂量的咪达唑仑联合给药时，普罗加比（32mg/kg）和乙醇（1g/kg），而非蝇蕈醇和加波沙朵，增强了咪达唑仑辨别刺激。三唑仑、孕烷醇酮和戊巴比妥增加了咪达唑仑引发咪达唑仑杠杆反应的效力，且这些联合用药的效应是相加的。
在经过训练辨别咪达唑仑的恒河猴中，直接作用的GABA(A)受体激动剂在性质上与GABA(A)阳性调节剂不同。尽管GABA(A)受体激动剂和调节剂可增强苯二氮䓬类药物在GABA(A)受体复合物上的作用，但相同药物不一定会改变苯二氮䓬类药物的辨别刺激效应。这些结果强调了药物改变GABA(A)受体复合物处Cl(-)通量的机制的重要性，这不仅是药物作用的决定因素，也是药物相互作用以及任何特定药物是否增强苯二氮䓬类药物行为效应的决定因素。
