Discriminative stimulus properties of the selective and highly potent α 2-adrenoceptor agonist, S18616, in rats: Mediation by the α 2A subtype, and blockade by the atypical antidepressants, mirtazapine and mianserin

Abstract

The novel spiroimidazoline, S18616, a potent and efficacious agonist at α 2-adrenoceptors (ARs), shows >100-fold selectivity versus α 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% “S18616” 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 sub-maximal substitution (67%). Guanfacine (0.16–1.25) and guanabenz (0.00063–0.04), preferential agonists at α 2A-ARs, revealed full substitution for S18616. In contrast, the α 1-AR agonists, cirazoline and ST587 (both 0.04–0.63), did not substitute. The α 2-AR antagonists, RX821,002, atipamezole (both 0.0025–0.04) and idazoxan (0.04–0.63) blocked the S18616 DS, whereas the α 1-AR antagonists, prazosin (0.16–0.63) and WB4101 (0.04–0.63), were inactive. Prazosin is also a preferential antagonist at α 2B/2C- versus α 2A-ARs and a further preferential α 2B/2C-AR antagonist, BRL41,992 (0.63–2.5), was likewise ineffective. In contrast, the α 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 α 2A-ARs, dose-dependently blocked the S18616 DS. In conclusion, S18616 elicits a robust DS in rats that principally reflects engagement of α 2A-ARs. This novel procedure should prove useful in the characterisation of psychoactive drugs which interact with α 2-ARs.