Sustained administration of bupropion alters the neuronal activity of serotonin, norepinephrine but not dopamine neurons in the rat brain.
Bupropion is widely used in the treatment of depression. There are, however, limited data on its long-term effects on monoaminergic neurons and therefore the mechanism of its delayed onset of action is at present not well understood. The present study was conducted to examine the effects of prolonged bupropion administration on the firing activity of dorsal raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area (VTA) neurons. Spontaneously firing neurons were recorded extracellularly in rats anesthetized with chloral hydrate. Bupropion (30 mg/kg/day) was administered using subcutaneously implanted minipumps. In the DRN, the firing rate of serotonin (5-HT) neurons was significantly increased after 2, 7 and 14 days of administration. The suppressant effect of LSD was significantly diminished after the two-day regimen, indicating a desensitization of 5-HT1A autoreceptors. In the LC, the firing rate of norepinephrine (NE) neurons was significantly attenuated after a 2-day regimen, but recovered progressively over 14 days of administration. The suppressant effect of clonidine on NE neuronal firing was significantly attenuated in rats treated with bupropion for 14 days, indicating a desensitization of alpha2-adrenoceptors. In the VTA, neither 2 nor 14 days of bupropion administration altered the firing and burst activity of dopamine neurons. These results indicate that bupropion, unlike 5-HT reuptake inhibitors, promptly increased 5-HT neuronal activity, due to early desensitization of the 5-HT1A autoreceptor. The gradual recovery of neuronal firing of NE neurons, due to the desensitization of alpha2-adrenoceptors, in the presence of the sustained increase in 5-HT neuronal firing, may explain in part the delayed onset of action of bupropion in major depression.
El Mansari
Mostafa
M
University of Ottawa Institute of Mental Health Research, Room 7407, 1145 Carling Avenue, Ottawa, Ontario, Canada K1Z 7K4. mostafa.elmansari@rohcg.on.ca
Ghanbari
Ramez
R
Janssen
Shannon
S
Blier
Pierre
P
D000818:Animals; D016642:Bupropion / Q000494:pharmacology*; D004298:Dopamine / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004594:Electrophysiology; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D012701:Serotonin / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D018765:Dopamine Uptake Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D016642:Bupropion; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine