Effects of the selective norepinephrine reuptake inhibitor reboxetine on norepinephrine and serotonin transmission in the rat hippocampus.
Given that norepinephrine (NE) and serotonin (5-HT) neurons are implicated in the mechanisms of action of antidepressant drugs and both project to the hippocampus, the impact of acute and long-term administration of the selective NE inhibitor reboxetine was assessed on CA(3) pyramidal neuron firing in this postsynaptic structure. Cumulative injections of reboxetine (1-4 mg/kg, i.v.) dose-dependently increased the recovery time of the firing of these neurons following iontophoretic applications of NE, but not 5-HT. In rats treated with reboxetine for 2.5 mg/kg/day for 21 days, a robust increase in the recovery time following NE applications was observed, and a small but significant prolongation occurred following 5-HT applications. In controls and reboxetine-treated rats, 1 and 5 Hz stimulations of the afferent 5-HT bundle to the hippocampus, which allows determination of terminal 5-HT(1B) autoreceptor sensitivity, produced similar frequency-dependent decreases in pyramidal neuron firing in both groups. However, after low and high doses of clonidine (10 and 400 microg/kg, i.v.), which assesses alpha(2)-adrenergic auto- and heteroreceptor sensitivity, respectively, only the effect of the high dose of clonidine was attenuated. Interestingly, administration of the selective 5-HT(1A) receptor antagonist WAY 100,635 induced a 140% increase in basal pyramidal neuron firing in reboxetine as compared to saline-treated rats. This increase in tonic activation of postsynaptic 5-HT(1A) receptors might be attributable in part to a desensitization of alpha(2)-adrenergic heteroreceptors, presumably resulting from sustained NE reuptake inhibition. These results indicate that even a selective NE reuptake inhibitor can modulate 5-HT transmission.
Szabo
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Neurobiological Psychiatry Unit, McGill University, H3A 1A1, Montréal, Canada.
Blier
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D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D003198:Computer Simulation; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007478:Iontophoresis; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D018759:Adrenergic Uptake Inhibitors; D009025:Morpholines; D010879:Piperazines; D011725:Pyridines; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000077593:Reboxetine; D009638:Norepinephrine