Electrophysiological characterization of the effect of long-term duloxetine administration on the rat serotonergic and noradrenergic systems.
Duloxetine is a dual serotonin (5-HT)/norepinephrine (NE) re-uptake blocker with antidepressant potential. In the present in vivo electrophysiological study, the changes in the function of the rat 5-HT and NE systems after 2- and 21-day administration of duloxetine (20 mg/kg/day) were assessed in the dorsal hippocampus and the dorsal raphe nucleus (DRN). The firing rate of DRN neurons was decreased after 2 days of duloxetine, but returned to the control level after 21-day administration. This recovery of firing rate was presumably due to the desensitization of the DRN somatodendritic 5-HT1A autoreceptors found after long-term duloxetine administration. Overall serotonergic tone was assessed by examining the ability of the 5-HT1A antagonist WAY 100635 to alter hippocampal firing. WAY 100635 increased hippocampal firing rates in 21-day treated rats to a greater extent than in 2-day treated or control rats, suggesting that long-term administration induced an increase in endogenous levels of 5-HT in postsynaptic regions. This increase in 5-HT levels was accompanied by selective changes in the 5-HT and NE systems induced by long-term duloxetine administration, i.e., the desensitization of the alpha-2 adrenergic heteroreceptor on 5-HT terminals and the continued blockade of the 5-HT transporters. In contrast, the sensitivity of the alpha-2 adrenergic and terminal 5-HT1B autoreceptors, as well as that of the postsynaptic 5-HT1A receptor after 21-day treatment was unchanged. Therefore, this study demonstrates that duloxetine increases serotonergic tone in a limbic forebrain structure and may therefore be effective in the treatment of depression.
Rueter
L E
LE
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
De Montigny
C
C
Blier
P
P
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D000068736:Duloxetine Hydrochloride; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000502:physiology*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D011725:Pyridines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D027981:Symporters; D013876:Thiophenes / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D002352:Carrier Proteins; D003000:Clonidine; D000068736:Duloxetine Hydrochloride; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; D013876:Thiophenes; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide