ENHANCED ALPHA(2A)-AUTORECEPTOR RESERVE FOR CLONIDINE-INDUCED BY RESERPINE AND CHOLINOMIMETIC AGENTS IN THE RAT VAS-DEFERENS

1 The adaptive changes in the functional parameters of the presynaptic alpha(2A)-adrenoceptors in rat vas deferens were examined after treat ments with the monoamine depleter reserpine or with the direct/indirec t cholinomimetic agents pilocarpine and neostigmine. 2 For this purpos e, we studied the inhibition induced by the alpha(2)-adrenoceptor agon ist clonidine on the twitch contraction of the vas deferens elicited b y electrical field stimulation, in animals that had been treated with acute (single dose), short-term (for 4 days) and chronic (for 11 days) regimens of reserpine (0.25 mg kg(-1), s.c., every 48 h), pilocarpine (10 mg kg(-1), i.p., every 12 h) or neostigmine (0.1 mg kg(-1), i.p., every 12 h). The irreversible receptor alkylating agent N-ethoxycarbo nyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 300 nM) was used to block par tially the alpha(2A)-adrenoceptor-mediated effect of clonidine. 3 In c ontrol (untreated) animals, clonidine inhibited concentration-dependen tly the twitch response of the vas deferens (pEC(50)=8.66) with a maxi mal effect near 100%. The apparent affinity constant for clonidine was estimated with the nested hyperbolic methodology (pK(A)=7.10). The an alysis of the occupancy-effect relation for clonidine revealed a large receptor reserve at alpha(2A)-adrenoceptors. 4 Acute, short-term and chronic treatments with reserpine increased the sensitivity of alpha(2 A)-adrenoceptors to clonidine (decreased the EC50) by about 3, 4 and 9 fold, respectively, and also increased the pool of receptor reserve f or this agonist (decreased the K-E) by 4, 10 and 10 fold, respectively . Receptor affinity values were not changed after treatments. 5 Short- term and chronic, but not acute, treatments with pilocarpine and neost igmine increased the sensitivity of alpha(2A)-adrenoceptors to clonidi ne (decreased the EC50) by about 3 and 2 fold, respectively, and also increased the pool of receptor reserve for this agonist (decreased the K-E) by 2 and 3 fold, respectively. Receptor affinity values were not changed after these treatments.6 These results indicate that an enhan cement of the receptor reserve for clonidine might account for the sup ersensitivity of alpha(2A)-adrenoceptors induced by reserpine, pilocar pine or neostigmine treatments in the rat vas deferens.