Discriminative stimulus properties of the selective and highly potent α2-adrenoceptor agonist, S18616, in rats:: Mediation by the α2A subtype, and blockade by the atypical antidepressants, mirtazapine and mianserin

被引:14
作者
Dekeyne, Anne [1 ]
Millan, Mark J. [1 ]
机构
[1] Inst Rech Servier, Ctr Rech Croissy, Dept Psychopharmacol, F-78290 Paris, France
关键词
drug discrimination; antidepressant; S18616; alpha(2)-adrenoceptors; adrenergic;
D O I
10.1016/j.neuropharm.2006.05.012
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The novel spiroimidazoline, S18616, a potent and efficacious agonist at alpha(2)-adrenoceptors (ARs), shows > 100-fold selectivity versus alpha(1)-ARs, imidazoline receptors and all other sites examined. Herein, we characterized its discriminative stimulus (DS) properties in rats trained to recognise S18616 (0.01 mg/kg, s.c.) from saline. S18616 dose-dependently (0.0063-0.01) and "fully" (>= 80% "SI8616" lever selection) substituted for itself Full substitution was also acquired for the agonist, UK14,304 (0.04-0.16), while the partial agonist, clonidine (0.01-0.08), yielded submaximal substitution (67%). Guanfacine (0.16-1.25) and guanabenz (0.00063-0.04), preferential agonists at alpha(2A)-ARs, revealed full substitution for S18616. In contrast, the alpha(2A)-AR agonists, cirazoline and ST587 (both 0.04-0.63), did not substitute. The alpha(2)-AR antagonists, RX821,002, atipamezole (both 0.0025-0.04) and idazoxan (0.04-0.63) blocked the S18616 DS, whereas the alpha(1)-AR antagonists, prazosin (0.16-0.63) and WB4101 (0.04-0.63), were inactive. Prazosin is also a preferential antagonist at alpha(2B/2C-) versus alpha(2A)-ARs and a further preferential alpha(2B/2C)-AR antagonist, BRL41,992 (0.63-2.5), was likewise ineffective. In contrast, the alpha(2A)-AR antagonist, BRL44,408 (0.04-0.16), dose-dependently abolished the S18616 DS. Finally, the "atypical" antidepressants, mirtazapine (0.16-10.0) and mianserin (0.63-10.0), which behave as antagonists at alpha(2A)-ARs, dose-dependently blocked the S18616 DS. In conclusion, S18616 elicits a robust DS in rats that principally reflects engagement of alpha(2A)-ARs. This novel procedure should prove useful in the characterisation of psychoactive drugs which interact with alpha(2)-ARs. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:718 / 726
页数:9
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