Anxiolytic-like effect of milnacipran in the four-plate test in mice: mechanism of action.
Milnacipran is a serotonin/noradrenaline reuptake inhibitor (SNRI) which has not yet been systematically studied preclinically or clinically for the treatment of anxiety disorders. In the four-plate test (FPT) which is known to predict anxiolytic-like activity in mice, milnacipran (4, 8, 16 and 32 mg/kg) demonstrated strong anti-punishment effects following acute administration. The anxiolytic-like effect of milnacipran was not reversed by the selective GABA(A) receptor antagonist, flumazenil (2 and 4 mg/kg), the selective alpha1-adrenoceptor antagonist, prazosin (0.5 and 2 mg/kg), the selective alpha2-adrenoceptor antagonist, idazoxan (1 and 4 mg/kg) or the selective 5-HT2B receptor antagonist, SB 206553 (0.1 and 1 mg/kg). In contrast, the selective 5-HT2A receptor antagonist, SR 46349B (0.1 and 1 mg/kg), and the non-selective 5-HT2 receptor antagonist, ketanserin (0.125 and 0.5 mg/kg), completely abolished the anxiolytic-like effect of milnacipran in FPT. Neurochemical depletion of NA or 5-HT completely abolished the activity of milnacipran. These results strongly suggest that activation of 5-HT2A receptors is critically involved in the anxiolytic activity of milnacipran. On the other hand the lack of activity of milnacipran after depletion of NA or 5-HT is consistent with milnacipran acting on the locus coeruleus to induce 5-HT release. The present data suggest a strong connection between 5-HT2A receptors and NA neurotransmission.
Bourin
Michel
M
EA 3256 Neurobiologie de l'anxiété et de la dépression Faculté de Médecine BP 53508, 1, rue Gaston Veil, 44035 Nantes Cedex 01, France. michel.bourin@univ-nantes.fr
Masse
Fabienne
F
Dailly
Eric
E
Hascoët
Martine
M
D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010134:Fenclonine / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D019329:Idazoxan / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D000078764:Milnacipran; D009043:Motor Activity / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011678:Punishment / Q000523:psychology; D011725:Pyridines / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000525:Alprazolam; D014151:Anti-Anxiety Agents; D001596:Benzylamines; D003521:Cyclopropanes; D004298:Dopamine; D010134:Fenclonine; D005442:Flumazenil; D005464:Fluorobenzenes; D019329:Idazoxan; D007211:Indoles; D007650:Ketanserin; D000078764:Milnacipran; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D010636:Phenols; D011224:Prazosin; D011725:Pyridines; D012701:Serotonin; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C076033:SR 46349B; C094868:SB 206553; C012102:DSP 4