Long-term administration of monoamine oxidase inhibitors alters the firing rate and pattern of dopamine neurons in the ventral tegmental area.
Monoamine oxidase inhibitors (MAOIs) exert their antidepressant action by increasing the function of the serotonin (5-HT), norepinephrine and dopamine (DA) systems. There is, however, limited electrophysiological data on the effects of MAOIs on DA neurons. The effects of 2-d and 21-d administration of three MAOIs were investigated (clorgyline, selective MAOI-A; deprenyl, selective MAOI-B; phenelzine, non-selective MAOI) on the firing activity of DA neurons in the ventral tegmental area using in-vivo electrophysiology in rats. Short-term clorgyline (1 mg/kg) and phenelzine (2.5 mg/kg) was devoid of effect on DA neurons, whereas prolonged administration significantly decreased their firing rate (by 30% and 20%, respectively), number of bursts (by 80% and 45%, respectively), and percentage of spikes occurring in bursts only in clorgyline-treated rats (70%). Deprenyl (0.25 mg/kg) was without effects. DA firing was restored in clorgyline-treated rats by inhibiting 5-HT synthesis using para-chlorophenylalanine (p-CPA; 300 mg/kg. d for three consecutive days). The 5-HT3 antagonist ondansetron (0.5 mg/kg) was devoid of effect in control rats, but completely reversed the alterations of DA neuronal activity in clorgyline-treated rats. An attenuation of DA neuronal activity was thus produced by prolonged blockade of MAOA activity. The absence of effect of MAOA inhibition after subacute administration suggested an indirect mechanism. This was confirmed by the observation that p-CPA antagonized the effects of clorgyline. Since ondansetron completely reversed the effects of clorgyline on DA neuronal activity, the effects of MAOA inhibition appeared to be mediated by 5-HT3 receptors.
Chenu
Franck
F
Institute of Mental Health Research, University of Ottawa, Ontario, Canada. franck.chenu@rohcg.on.ca
El Mansari
Mostafa
M
Blier
Pierre
P
D000818:Animals; D003010:Clorgyline / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology; D010624:Phenelzine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects; D012642:Selegiline / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D008996:Monoamine Oxidase Inhibitors; D044405:Receptor, Serotonin, 5-HT2C; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D012642:Selegiline; D012701:Serotonin; D003010:Clorgyline; D010624:Phenelzine; D004298:Dopamine; D009638:Norepinephrine