Serotonin autoreceptor subsensitivity and antidepressant activity.

Release of [3H]serotonin elicited by electrical stimulation from rat hypothalamus and its modulation through autoreceptors has been studied after chronic administration of two antidepressants, citalopram, specific inhibitor of serotonin uptake, and milnacipran (previously called midalcipran, F 2207) which blocks the uptake of serotonin and noradrenaline to the same extent. The amount of [3H]serotonin released by electrical stimulation was enhanced and the inhibitory effect of the agonist, LSD (lysergic acid diethylamide), reduced in rats treated with citalopram at 10 and 50 mg/kg per day for 21 days. These effects existed at both doses but were accentuated at the higher dose. Thus a chronic treatment with citalopram provokes a down-regulation of the serotonergic autoreceptor, allowing an increase of serotonin neurotransmission. After 21 days treatment with milnacipran, at 50 mg/kg per day, none of the parameters studied were modified. These data suggest that down-regulation of the serotonin autoreceptor is not a universally applicable hypothesis to explain the action of all antidepressants acting on the uptake of serotonin.