Two actions are better than one: avoiding self-inhibition of serotonergic neurones enhances the effects of serotonin uptake inhibitors.
The serotonin (5-HT)-increasing action of 5-HT uptake or monoamine oxidase inhibitors is limited by a negative feedback at somatodendritic level. The excess 5-HT produced by these antidepressant drugs in the interstitial space of the midbrain raphe activates somatodendritic 5-HT1A autoreceptors, thereby attenuating terminal 5-HT release. This effect is maximal in forebrain areas innervated by the dorsal raphe nucleus and can be prevented by the administration of non-selective [(-)pindolol, (-)tertatolol] and selective (WAY-100635) 5-HT1A antagonists. In keeping with these observations, the combined administration of selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A antagonists increase the cortical and striatal extracellular 5-HT concentration more than the former alone. Also, concurrent inhibition of the 5-HT and noradrenaline transporters with 20 mg/kg imipramine increases cortical extracellular 5-HT concentration more than SSRI doses which maximally block the 5-HT transporter. Moreover, the effects of fluoxetine on frontal cortex 5-HT are potentiated by a dose of desipramine that does not modify extracellular 5-HT by itself. Given the relevance of increased serotonergic transmission in the treatment of depression, these experimental data indicate that dual-action antidepressant treatments may be more effective than those which selectively inhibit the 5-HT transporter.
Romero
L
L
Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, CSIC.
Bel
N
N
Casanovas
J M
JM
Artigas
F
F
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D017551:Microdialysis; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors