Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats.
Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats.
复制标题
比较含有 α4-β 亚基的 GABAA 受体调节剂与加波沙朵在大鼠中的辨别刺激效果。
DOI：
10.1007/s00213-016-4243-8
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发表时间：
2016
影响因子：
3.4
通讯作者：
Gerak,LisaR
中科院分区：
文献类型：
--
作者：
Zanettini,Claudio;Pressly,JeffreyD;Ibarra,MiguelH;Smith,KelseyR;Gerak,LisaR
RationaleGaboxadol is a selective agonist at γ-aminobutyric acidA(GABAA) receptors that contain α4-δ subunits, and it produces anxiolytic and sedative effects. Although adverse effects preclude its clinical use, its mechanism of action suggests that those receptors might provide novel therapeutic targets, particularly for modulators of those GABAAreceptor subtypes, by retaining therapeutic effects of gaboxadol and not adverse effects.ObjectivesThe current study compared discriminative stimulus effects of gaboxadol with those of modulators acting at GABAAreceptors containing α4-δ subunits.MaterialsEight rats discriminated 5.6 mg/kg gaboxadol from vehicle while responding under a fixed - ratio 10 schedule for food. Modulators acting at GABAAreceptors containing α4-δ subunits (pregnanolone, ethanol, and flumazenil) and receptors that do not contain those subunits (midazolam) were studied alone; pregnanolone and ethanol were also combined with gaboxadol. In addition, gaboxadol was studied in separate groups discriminating 0.32 mg/kg midazolam, 3.2 mg/kg pregnanolone, or 0.75 g/kg ethanol from vehicle.ResultsGaboxadol produced ≥80 % gaboxadol-lever responding and did not alter rates. No other drug produced, on average, ≥80 % drug-lever responding up to doses that decreased rates, although 1.78 mg/kg midazolam produced 32 % gaboxadol-lever responding. Ethanol and pregnanolone did not enhance the effects of gaboxadol. Rats discriminating midazolam, pregnanolone, or ethanol from vehicle responded predominantly on the vehicle lever after receiving gaboxadol.ConclusionsDrugs that modulate GABAAreceptors containing α4-δ subunits neither mimicked nor enhanced the discriminative stimulus effects of gaboxadol, indicating that at least some effects of gaboxadol are not shared with modulators of that GABAAreceptor subtype.
