Repeated administration of milnacipran induces rapid desensitization of somatodendritic 5-HT1A autoreceptors but not postsynaptic 5-HT1A receptors.
The effects of the repeated administration of milnacipran, a serotonin (5-HT)-noradrenaline reuptake inhibitor (SNRI), on the functional status of somatodendritic 5-HT1A receptors, and postsynaptic 5-HT1A receptors were explored using electrophysiological approaches in rats. In-vitro electrophysiological recordings in the dorsal raphe nucleus showed that 5-HT inhibited the firing of serotonergic neurones, and the selective 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635), reversed the inhibitory effect of 5-HT. The potency of 5-HT to inhibit the firing of serotonergic neurones was slightly attenuated after 3 days of treatment with milnacipran (30 mg/kg, p.o., twice daily), and significantly attenuated after 7 or 14 days treatment at the same dose. The tricyclic antidepressant, imipramine, did not significantly modify the inhibitory effect of 5-HT. After 7 days treatment at 30 mg/kg, p.o., once daily, milnacipran reduced the potency of 5-HT to inhibit the firing of serotonergic neurones, whereas the selective serotonin reuptake inhibitors, fluvoxamine and fluoxetine (60 and 30 mg/kg, p.o., once daily, respectively), did not modify it under these conditions. Treatment with milnacipran (30 mg/kg, p.o., twice daily) for 14 days did not change the inhibition of the CA1 field potential in rat hippocampal slices by 5-HT. These data suggest that somatodendritic 5-HT1A receptors, but not postsynaptic 5-HT1A receptors, rapidly desensitize in response to the repeated administration of milnacipran.
Mochizuki
Daisuke
D
Life Science Research Center for Pharmacology, Asahi Kasei Corporation, Ohito, Shizuoka, Japan. mochizuki.db@om.asahi-kasei.co.jp
Hokonohara
Tadami
T
Kawasaki
Koh
K
Miki
Naomasa
N
D000818:Animals; D017660:Autoreceptors / Q000187:drug effects*; D046508:Culture Techniques; D003521:Cyclopropanes / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D000078764:Milnacipran; D009638:Norepinephrine / Q000819:agonists*; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D017660:Autoreceptors; D003521:Cyclopropanes; D000078764:Milnacipran; D009638:Norepinephrine; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017367:Selective Serotonin Reuptake Inhibitors