Modulation of the extracellular 5-hydroxytryptamine brain concentrations by the serotonin and noradrenaline reuptake inhibitor, milnacipran. Microdialysis studies in rats.
We examined the effects of the administration of milnacipran, a dual inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake on the 5-HT output in rat brain. Local milnacipran administration increased the 5-HT output in frontal cortex and the midbrain raphe nuclei 7- and 10-fold by a Ca(2+)- and tetrodotoxin-dependent mechanism. However, the subcutaneous administration of milnacipran (1-60 mg/kg s.c.) elevated the 5-HT output much less in these areas (200-230% of baseline at 60 mg/kg). In hypothalamus, 10 mg/kg s.c. raised 5-HT levels to 170%. The 5-HT1A antagonist WAY-100635 caused a small potentiation of the effects of milnacipran. The baseline 5-HT output was unaffected by 2-week treatments with milnacipran (30 and 60 mg/kg.day). The distinct regional profile and the lack of enhancement of its effects by WAY-100635 and prolonged treatment suggest that milnacipran does not exert its antidepressant action through an enhancement of the serotonergic function.
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Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, Spain.
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005625:Frontal Lobe / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis; D000078764:Milnacipran; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology
D002118:Calcium; D003521:Cyclopropanes; D000078764:Milnacipran; D009638:Norepinephrine; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013779:Tetrodotoxin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide