Effect of acute, short- and long-term milnacipran administration on rat locus coeruleus noradrenergic and dorsal raphe serotonergic neurons.
The effect of milnacipran on the firing activity of dorsal raphe serotonin (5-HT) neurons and locus coeruleus norepineprine (NE) neurons was assessed using extracellular unitary recording in chloral hydrate anesthetized rats. A 2-day treatment with milnacipran (20 or 60 mg/kg/day, s.c.) markedly decreased the firing rate of NE neurons, and it remained reduced after a 7- or a 14-day treatment. Although the suppressant effect of the alpha2-adrenergic agonist clonidine on the firing rate of NE neurons was markedly reduced following long-term milnacipran (60 mg/kg/day x 14 days, s.c.), that of NE remained unchanged. The firing rate of 5-HT neurons was reduced following a 2-day treatment with milnacipran (20 mg/kg/day, s.c.), but there was a partial recovery after a 7-day treatment (20 mg/kg/day, s.c.) and a complete one after a 14-day treatment (20, 40 or 60 mg/kg/day, s.c.). The suppressant effect of 5-HT and of the 5-HT1A agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) on the firing rate of 5-HT neurons was also unaltered after milnacipran (60 mg/kg/day x 14 days, s.c.). The latter milnacipran treatment did not affect the uptake of [3H]5-HT but it inhibited that of [3H]NE by 30% in hippocampal slices. The NE system was thus investigated in an attempt to explain the effects of milnacipran on the firing activity of 5-HT neurons. Acute injection of milnacipran suppressed the firing activity of 5-HT neurons (with an ED50 of 5.7+/-1.5 mg/kg, i.v.), but not in NE-denervated rats. Furthermore, the inhibitory effect of clonidine on 5-HT neuron firing activity was markedly reduced by the long-term milnacipran treatment, whereas the inhibition of electrically evoked release of [3H]NE as well as that of [3H]5-HT produced by the alpha2-adrenoceptor agonist UK 14.304 from preloaded mesencephalic slices containing the dorsal raphe was unaltered. The latter results indicate that the alpha2-adrenergic autoreceptor and heteroreceptor were unaffected in the raphe area by milnacipran. In conclusion, milnacipran had profound effects on the function of 5-HT and NE neurons, and the mechanism by which 5-HT neurons regained their normal firing during milnacipran treatment appeared to implicate the NE system.
Neurobiological Psychiatry Unit, McGill University, Montreal, Quebec, Canada.
R
R
Mongeau
M
M
Weiss
C
C
de Montigny
P
P
Blier
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000494:pharmacology; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D007279:Injections, Subcutaneous; D007700:Kinetics; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology*; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology; D000078764:Milnacipran; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013134:Spiperone / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000068438:Brimonidine Tartrate; D003000:Clonidine; D003521:Cyclopropanes; D003891:Desipramine; D008238:Lysergic Acid Diethylamide; D000078764:Milnacipran; D009638:Norepinephrine; D011810:Quinoxalines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013134:Spiperone; D005680:gamma-Aminobutyric Acid