Reduced signal transduction by 5-HT4 receptors after long-term venlafaxine treatment in rats.
OBJECTIVE
The 5-HT(4) receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT(4) receptor-mediated signalling events.


METHODS
The effects of 21 days treatment (p.o.) with high (40 mg·kg(-1)) and low (10 mg·kg(-1)) doses of venlafaxine, were evaluated at different levels of 5-HT(4) receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg(-1), 21 days) was also evaluated on 5-HT(4) receptor density.


RESULTS
Treatment with a high dose (40 mg·kg(-1)) of venlafaxine did not alter 5-HT(4) mRNA expression, but decreased the density of 5-HT(4) receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg(-1)) while it was attenuated in rats treated with 40 mg·kg(-1) of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT(4) receptor density.


CONCLUSIONS
Our data indicate a functional desensitization of 5-HT(4) receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake.
Vidal
R
R
Instituto de Biomedicina y Biotecnología (IBBTEC) (UC-CSIC-IDICAN), Santander, Cantabria, Spain.
Valdizan
E M
EM
Vilaró
M T
MT
Pazos
A
A
Castro
E
E
D000200:Action Potentials / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D003511:Cyclohexanols / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D017966:Pyramidal Cells / Q000502:physiology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D000077593:Reboxetine; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000069470:Venlafaxine Hydrochloride
D018759:Adrenergic Uptake Inhibitors; D018687:Antidepressive Agents, Second-Generation; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003511:Cyclohexanols; D009025:Morpholines; D044422:Receptors, Serotonin, 5-HT4; D000069470:Venlafaxine Hydrochloride; D000077593:Reboxetine; C055971:zacopride; D000262:Adenylyl Cyclases