Reevaluation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs.
The effects of antidepressant drugs on central 5-HT receptor activity were studied in rats and mice. Antidepressant drugs were evaluated for their ability to displace 3H-5-HT and 3H-d-LSD from membrane binding sites in the dorsal neocortex of rats in vitro and for their ability to block 5-HTP and d-LSD induced behavioral effects in mice. The degree of blockade of head-twitches in mice produced by the antidepressants was highly correlated with their affinity for 3H-d-LSD binding sites. A number of antidepressant drugs such as amitriptyline, nortriptyline, mianserine, doxepine, nomifensine and dibenzepine appear to possess marked 5-HT receptor blocking activity at some type of 5-HT receptors in brain. New antidepressant drugs such as zimelidine, which specifically inhibit 5-HT reuptake and do not block 5-HT receptor sites, may after chronic treatment also reduce the functional activity of 5-HT systems by producing adaptive changes in postsynaptic 5-HT mechanisms. Thus, a new indoleamine hypothesis of depression is presented: the therapeutic action of antidepressant drugs may in part be due to a reduced functional acitivity of some central 5-HT systems.
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000503:physiopathology*; D006801:Humans; D007700:Kinetics; D008238:Lysergic Acid Diethylamide / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008711:Metergoline / Q000494:pharmacology; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*
D000928:Antidepressive Agents; D011985:Receptors, Serotonin; D008711:Metergoline; D012701:Serotonin; D008238:Lysergic Acid Diethylamide; D009638:Norepinephrine