Abstract
Previous results from our laboratory have indicated that small intravenous doses of the α2-adrenergic agonist Clonidine increase serotonin (5-HT) neurotransmission by attenuating the release of endogenous norepinephrine (NE), as a result of the activation of α2-adrenergic autoreceptor on NE neurons, and that high doses of Clonidine decrease 5-HT neurotransmission by directly activating α2-adrenergic heteroreceptors on 5-HT terminals. The aim of the present study was to assess whether antidepressant treatments that increase the synaptic concentration of NE or 5-HT alter the ability of Clonidine to modulate 5-HT neurotransmission through these two α2-adrenoceptors. Rats were treated for 3 weeks with 0.75 mg/kg per day of befloxatone (a reversible inhibitor of monoamine oxidase A), 10 mg/kg per day of nisoxetine (a selective NE reuptake inhibitor), 10 mg/kg per day of paroxetine (a selective 5-HT reuptake inhibitor) or saline using subcutaneous osmotic minipumps (removed 48 hours before the experiment). No significant change in the effect of the small dose of Clonidine (10 µg/kg, IV) was found following the befloxatone, the nisoxetine, or the paroxetine treatments. The reduction of 5-HT neurotransmission by the high dose of Clonidine (400 µg/kg, IV) was no longer present in rats treated with nisoxetine or befloxatone, but was unaltered in those treated with paroxetine. Furthermore, in rats preheated with the NE neurotoxin 6-hydroxydopamine, a long-term treatment with befloxatone failed to alter the reducing effect of the high dose of Clonidine but abolished the reducing effect of the low dose of Clonidine. These results suggest that antidepressant drugs that increase NE synaptic concentration induce a desensitization of α2-heteroreceptor on 5-HT terminals.
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Mongeau, R., de Montigny, C. & Blier, P. Electrophysiologic Evidence for Desensitization of α2-Adrenoceptors on Serotonin Terminals Following Long-Term Treatment with Drugs Increasing Norepinephrine Synaptic Concentration. Neuropsychopharmacol 10, 41–51 (1994). https://doi.org/10.1038/npp.1994.6
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DOI: https://doi.org/10.1038/npp.1994.6
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