Effect of acute, short- and long-term milnacipran administration on rat locus coeruleus noradrenergic and dorsal raphe serotonergic neurons

• Published in: Neuropharmacology Vol. 37; no. 7; pp. 905 - 918
• Main Authors: Mongeau, Raymond, Weiss, Michel, de Montigny, Claude, Blier, Pierre
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-07-1998; Elsevier
• Subjects: 5-HT neurons; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Adrenergic alpha-Agonists - pharmacology; Adrenergic Uptake Inhibitors - administration & dosage; Adrenergic Uptake Inhibitors - pharmacology; Animals; Biological and medical sciences; Biological Transport; Brimonidine Tartrate; Clonidine - pharmacology; Cyclopropanes - administration & dosage; Cyclopropanes - pharmacology; Desipramine - pharmacology; Dorsal raphe; Drug Administration Schedule; gamma-Aminobutyric Acid - pharmacology; Hippocampus - drug effects; Hippocampus - physiology; Hypothalamus - drug effects; Hypothalamus - physiology; Injections, Subcutaneous; Kinetics; Locus coeruleus; Locus Coeruleus - drug effects; Locus Coeruleus - physiology; Lysergic Acid Diethylamide - pharmacology; Male; Medical sciences; Mesencephalon - drug effects; Mesencephalon - physiology; Milnacipran; NE neurons; Neurons - drug effects; Neurons - physiology; Neuropharmacology; Norepinephrine - metabolism; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Quinoxalines - pharmacology; Raphe Nuclei - drug effects; Raphe Nuclei - physiology; Rats; Rats, Sprague-Dawley; Serotonin - metabolism; Serotonin - pharmacology; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - pharmacology; Spiperone - pharmacology; Time Factors; Milnacipran; NE neurons; Dorsal raphe; 5-HT neurons; Locus coeruleus; α2-Adrenergic receptor; Rat; Serotonin; Psychotropic; Brain stem; Rodentia; Central nervous system; Electrophysiology; Midbrain; Reuptake inhibitor; In vitro; In vivo; Vertebrata; Mammalia; 5-HT1A Serotonine receptor; Animal; Antidepressant agent; Subcutaneous administration; Norepinephrine; Raphe nucleus; Mechanism of action
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(98)00083-5

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
α
2-adrenergic agonist clonidine on the firing rate of NE neurons was markedly reduced following long-term milnacipran (60 mg/kg/day×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-HT
1A 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×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 ED
50 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
α
2-adrenoceptor agonist UK 14.304 from preloaded mesencephalic slices containing the dorsal raphe was unaltered. The latter results indicate that the
α
2-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.