Chronic treatment with desipramine facilitates its effect on extracellularnoradrenaline in the rat hippocampus: studies on the role of presynaptic alpha(2)-adrenoceptors

Adaptive phenomena such as desensitization of autoreceptors are considered an important factor in the achievement of therapeutic efficacy of antidepre ssant drugs after chronic treatment. We have studied whether a chronic trea tment with desipramine had a greater effect than a single dose on the extra cellular concentrations of noradrenaline in the dorsal hippocampus. Adminis tration of 10 mg/kg i.p. desipramine once daily for 14 days significantly r aised the basal extracellular noradrenaline in the dorsal hippocampus 24 h but not 48 h after the last drug injection. A challenge dose of desipramine increased extracellular noradrenaline in rats treated chronically with veh icle and desipramine. The effect was significantly higher in rats treated c hronically with desipramine 48 h but not 24 h after the last injection. An intraperitoneal administration of the alpha (2)-adrenoceptor agonist clo nidine at the dose of 10 mug/kg significantly reduced extracellular noradre naline in the control group but not in animals chronically treated with des ipramine whereas 30 mug/kg clonidine produced a similar decrease in both gr oups. Three concentrations of clonidine (0.05, 0.5 and 1 muM) infused into the hippocampus significantly reduced extracellular noradrenaline to a simi lar extent in rats chronically treated with saline or desipramine. Fourty-e ight hours after the last injection of the chronic treatment, [H-3]RX-82100 2 binding to alpha (2)-adrenoceptors in the rat locus coeruleus measured by autoradiography was not significantly modified. A slight (17%) but signifi cant decrease of neuronal uptake of [H-3]noradrenaline was found in synapto some preparations from dorsal hippocampus of rats chronically treated with desipramine, but this was likely due to a decrease in affinity. The results suggest that a repeated treatment with desipramine (10 mg/kg i. p. once daily fur 14 days) facilitates its effect on extracellular noradren aline in the dorsal hippocampus and induces adaptive changes probably invol ving desensitization of alpha (2)-adrenoceptors, with no changes in their d ensity, on noradrenergic neurons in the locus coeruleus.