After two weeks of twice-daily administration of amitriptyline to rats, the binding of [3H]clonidine to presynaptic alpha 2-adrenoreceptors was decreased in membranes isolated from 5 areas of the rat brain. After one day of treatment, binding did not differ from saline treated controls. In vitro, a high concentration of amitriptyline caused a competitive inhibition of [3H]clonidine binding but did not alter the number of binding sites. The decrease in the number of alpha 2-adrenoreceptor binding sites after two weeks of amitriptyline treatment would explain the subsensitivity of these receptors which occurs after prolonged administration of antidepressant drugs.

1 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 M2-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 a2-adrenoceptor agonists on the electrically-induced twitch responses after their long-term administra- 4 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 (10mg kg-', 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. 5 The results indicate that the acute in vivo inhibition of NA neuronal uptake by antidepressants leads to the activation (through endogenous NA) ofpresynaptic inhibitory z2-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.

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