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Repeated administration of milnacipran induces rapid desensitization of somatodendritic 5-HT1A autoreceptors but not postsynaptic 5-HT1A receptors

Life Science Research Center for Pharmacology, Asahi Kasei Corporation, Ohito, Shizuoka; Asahi Kasei Corporation 9-1 Kanda, Mitoshiro-cho Chiyoda-ku Tokyo 101-8481; mochizuki.db{at}om.asahi-kasei.co.jp

Tadami Hokonohara

Koh Kawasaki

Life Science Research Center for Pharmacology, Asahi Kasei Corporation, Ohito, Shizuoka

Naomasa Miki

Department of Pharmacology, Osaka University Medical School, Suita, Osaka, Japan

The effects of the repeated administration of milnacipran, a serotonin (5-HT)-noradrenaline reuptake inhibitor (SNRI), on the functional status of somatodendritic 5-HT_1A receptors, and postsynaptic 5-HT_1A 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-HT_1A 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-HT_1A receptors, but not postsynaptic 5-HT_1A receptors, rapidly desensitize in response to the repeated administration of milnacipran.

Key Words: antidepressants • desensitization • dorsal raphe nucleus • 5-HT1A autoreceptor • milnacipran • serotonin and noradrenaline reuptake inhibitor

Journal of Psychopharmacology, Vol. 16, No. 3, 253-260 (2002)
DOI: 10.1177/026988110201600311


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