Activation and desensitization of presynaptic α2‐adrenoceptors after inhibition of neuronal uptake by antidepressant drugs in the rat vas deferens

Abstract

The isolated field‐stimulated vas deferens of the rat (0.1 Hz, 3 ms, 30–40 V) was used to study the relationship between the in vivo inhibition of neuronal uptake of noradrenaline (NA) by cyclic antidepressant drugs and the subsequent activation/desensitization of presynaptic α2‐adrenoceptors. Receptor activation was indirectly measured by quantifying the ability of each drug to inhibit basal twitch responses after their acute administration. Receptor desensitization was also indirectly measured by quantifying the ability of the drugs to reduce the inhibitory effects of selective α2‐adrenoceptor agonists on the electrically‐induced twitch responses after their long‐term administration. The acute in vivo administration of desipramine and other antidepressants (0.5–10 mg kg−1; i.p.; 2 h) resulted in dose‐dependent inhibitions of the basal twitch responses which were rapidly reversed to control values by idazoxan (10−5 M). In vitro, desipramine and other antidepressants also inhibited in a concentration‐dependent manner (10−9 − 10−5 M) the twitch responses. In rats pretreated 12 h earlier with reserpine (1 mg kg−1; i.p.) or oxypertine (4 mg kg−1; i.p.), desipramine (10 mg kg−1; 2 h) did not induce inhibition of the basal twitch responses or it induced a smaller effect, respectively. For the various antidepressants the degree of inhibition of the basal twitch responses (desipramine > protriptyline > nortriptyline > maprotiline = imipramine > amitriptyline > viloxazine > iprindole > zimelidine) was highly correlated (r = 0.914) with the potency for blockade of [3H]‐NA uptake into rat brain synaptosomes. Clonidine and xylazine inhibited in a concentration‐dependent manner (10−9 − 10−6 M) the twitch responses. The long‐term (7–14 days) administration of antidepressants or cocaine (10 mg kg−1, i.p.) resulted in significant decreases in sensitivity to clonidine or xylazine. Short‐term (3 days) treatment with desipramine did not reduce the sensitivity to clonidine. The results indicate that the acute in vivo inhibition of NA neuronal uptake by antidepressants leads to the activation (through endogenous NA) of presynaptic inhibitory α2‐adrenoceptors which results in inhibition of the twitch responses. In contrast, prolonged in vivo inhibition of NA reuptake is followed by a slow desensitization process of the same receptors which results in a reduction of sensitivity to clonidine. 1986 British Pharmacological Society