Benzodiazepine receptor mediated discriminative cues: effects of GABA-ergic drugs and inverse agonists.
Benzodiazepine receptor mediated discriminative cues: effects of GABA-ergic drugs and inverse agonists.
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DOI：
10.1016/0024-3205(83)90293-x
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发表时间：
1983-11
期刊：
影响因子：
6.1
通讯作者：
E. B. Nielsen;J. Valentine;A. Holohean;J. B. Appel
中科院分区：
文献类型：
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作者：
E. B. Nielsen;J. Valentine;A. Holohean;J. B. Appel
用苯二氮卓类（BZ）受体反向激动剂N′-甲基-β-咔啉-3-甲酰胺（FG 7142）或甲基-6，7-二甲氧基-4-乙基-β-咔啉-3-羧酸酯（DMCM）对大鼠进行双层药物辨别程序。FG 7142（30 mg/kg）未能获得辨别性刺激控制，尽管它确实抑制了反应。成功训练同一组动物区分地西泮（DZP，2.5 mg/kg）和溶媒。GABA激动剂4，5，6，7-四氢-异恶唑并[5，4-c]吡啶-3-醇（THIP，1-3 mg/kg）增强DZP提示; THIP单独产生媒介物适当的响应。此外，氯硝西泮（0.2 mg/kg）和利氮卓（5 mg/kg）替代DZP（效力分别为DZP的7.5和0.25倍）。在拮抗试验中，FG 7142（5-17.5 mg/kg），β-咔啉-3-甲酸甲酯（β-CCM，2.5 mg/kg），尼古丁（0.3 mg/kg）、哈龙（5 mg/kg）和纳洛酮（10 mg/kg）不起作用，荷包牡丹碱（2 mg/kg）和DMCM（1 mg/kg）部分阻断，BZ受体拮抗剂Ro 15-1788（40 mg/kg）可完全阻断DZP的辨别刺激效应。在训练辨别DMCM（0.2 mg/kg）和溶剂的动物中，荷包牡丹碱（2 mg/kg）的替代率为95%; DZP（1-5 mg/kg）完全拮抗DMCM。这些结果表明，DZP线索是由GABA偶联BZ受体介导的，GABA可以调节BZ在其受体位点的功效。然而，由于反向BZ受体激动剂（FG 7142、DMCM和β-CCM）在拮抗DZP方面最多仅略微有效，因此DZP线索可能由BZ受体的不同亚类介导。
Rats were exposed to a two-layer drug discrimination procedure using the benzodiazepine (BZ) receptor inverse agonists N′-methyl-β-carboline-3-carboxamide (FG 7142) or methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM). FG 7142 (30 mg/kg) failed to acquire discriminative stimulus control, although it did suppress responding. The same group of animals was trained successfully to discriminate diazepam (DZP, 2.5 mg/kg) from vehicle. The DZP cue was potentiated by the GABA agonist 4,5,6,7-tetrahydro-isoxazolo [5, 4-c] pyridin-3-ol (THIP, 1–3 mg/kg); THIP alone produced vehicle-appropriate responding. In addition, clonazepam (0.2 mg/kg) and chlordiazepoxide (5 mg/kg) substituted for DZP (with potencies of 7.5 and 0.25 times that of DZP, respectively). In antagonism tests, FG 7142 (5–17.5 mg/kg), methyl-β-carboline-3-carboxylate (β-CCM, 2.5 mg/kg), nicotine (0.3 mg/kg), harmaline (5 mg/kg) and naltrexone (10 mg/kg) did not effect, bicuculine (2 mg/kg) and DMCM (1 mg/kg) partially blocked, and the BZ receptor antagonist Ro 15–1788 (40 mg/kg) completely blocked the discriminative stimulus effects of DZP. In animals trained to discriminate DMCM (0.2 mg/kg) from vehicle, 95% substitution occured with bicuculline (2 mg/kg); DZP (1–5 mg/kg) completely antagonized DMCM. These results indicate that the DZP cue is mediated by GABA-coupled BZ receptors and that GABA may modulate the efficacy of a BZ at its receptor site. However, since inverse BZ receptor agonists (FG 7142, DMCM and β-CCM) were, at best, only marginally effective in antagonizing DZP, the DZP cue may be mediated by a distinct subclass of BZ receptors.