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.

[1]  J. Hyttel,et al.  Citalopram — Pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity , 1982, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[2]  J. Hyttel,et al.  Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor, citalopram , 2004, Psychopharmacology.

[3]  P. Waldmeier,et al.  AMINE UPTAKE INHIBITORS: CRITERIA OF SELECTIVITY , 1980, Acta psychiatrica Scandinavica.

[4]  K. Overø.  Kinetics of citalopram in test animals; drug exposure in safety studies , 1982, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[5]  G. Goodwin,et al.  Presynaptic serotonin receptor-mediated response in mice attenuated by antidepressant drugs and electroconvulsive shock , 1985, Nature.

[6]  M. Gastpar,et al.  Preliminary studies with citalopram (Lu 10-171), a specific 5-HT-reup-take inhibitor, as antidepressant , 1982, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[7]  Yves Chaput,et al.  Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: Electrophysiological studies in the rat brain , 1986, Naunyn-Schmiedeberg's Archives of Pharmacology.

[8]  E. Øfsti.  Citalopram — A specific 5-HT-reuptake inhibitor — As an antidepressant drug: A phase II multicentre trial , 1982, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[9]  H. Hall,et al.  Acute effects of atypical antidepressants on various receptors in the rat brain. , 2009, Acta pharmacologica et toxicologica.

[10]  G. Nowak,et al.  Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: Effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities , 2004, Psychopharmacology.

[11]  M. Briley,et al.  Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug , 1985, Neuropharmacology.

[12]  S. Stahl,et al.  The pharmacology of depression: studies of neurotransmitter receptors lead the search for biochemical lesions and new drug therapies , 1986 .

[13]  J. Hyttel,et al.  Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor, citalopram , 2004, Psychopharmacology.

[14]  W. Potter,et al.  Species dependence of adaptations at the pre- and postsynaptic serotonergic receptors following long-term antidepressant drug treatment. , 1988 .

[15]  M. Briley,et al.  Sensitivity of the response of 5-HT autoreceptors to drugs modifying synaptic availability of 5-HT , 1988, Neuropharmacology.