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Modelling the changes induced by chronic desipramine treatment on the factors governing the agonism at prejunctional α<inf>2</inf>-adrenoceptors

Abstract:

1. The adaptational changes induced after chronic desipramine treatment on functional responsiveness of α2-adrenoceptor activation were investigated in prostatic portions of the rat vas deferens. 2. For this purpose, clonidine and xylazine were studied for their effects on twitch contractions elicited by electrical field stimulation of prostatic portions removed 48 h after the last injection to the animals of vehicle or desipramine (10 mg kg-1, i.p.; 14 days). Operational model-fitting and the nested hyperbolic method were used to analyse the effects of irreversible receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 300 nM) on the α2-adrenoceptor-mediated effects of clonidine, either in vehicle- or in desipramine-treated animals. 3. Treatment with desipramine decreased the potency (increased the EC50) of clonidine and xylazine by about 12 and 9 fold respectively. However, the treatment did not modify the maximal effect (α) elicited by either agonist. The estimates of apparent affinity for clonidine did not depend on the method of calculation as the 'null' method and the 'operational' method gave similar answers. Estimates of τ values for both agonists revealed that chronic desipramine treatment resulted in significant decreases in the efficacy of agonists. However, desipramine treatment was not associated with significant changes in the affinity constant for clonidine while for xylazine, the operational model provided a higher estimate of K(A) (lower affinity) after desipramine treatment. 4. The results indicate a large receptor reserve at prejunctional α2-adrenoceptors which is modulated by chronic desipramine treatment. 5. The comparison of results obtained after chronic desipramine exposure with those by using EEDQ suggests that chronic desipramine treatment is not a useful experimental intervention for the purpose of estimating agonist affinities and efficacies.