Sex hormone-dependent desensitization of 5-HT1A autoreceptors in knockout mice deficient in the 5-HT transporter.
The serotonin transporter (5-HTT) is the target of most antidepressant drugs, whose therapeutic action is related to their facilitatory influence on 5-HT neurotransmission. In this study, we investigated the functional adaptive properties of 5-HT1A autoreceptors, which regulate serotonergic neuronal firing, in knockout mice deficient in 5-HTT. Neurons of the dorsal raphe nucleus (DRN) were recorded extracellularly under chloral hydrate anaesthesia in male and female knockout 5-HTT mice and their wild-type counterparts. The inhibitory response of DRN neurons to intravenous injection of the 5-HT1A agonist 8-OH-DPAT was dramatically reduced in knockout 5-HTT compared with wild-type mice, especially in females. Changes in 8-OH-DPAT-induced hypothermia and autoradiographic labelling of 5-HT1A sites in the DRN confirmed a greater level of desensitization/down-regulation of 5-HT1A autoreceptors in female than in male knockout 5-HTT mice. After gonadectomy, the functional status of 5-HT1A autoreceptors was unchanged in wild-type mice, whereas in knockout 5-HTT, castrated males exhibited a down-regulation, and ovariectomized females an up-regulation of these receptors, as shown by electrophysiological recording and autoradiographic labelling in the DRN, as well as by changes in 8-OH-DPAT-induced hypothermia. Finally, in gonadectomized knockout 5-HTT mice, treatment with testosterone or estradiol restored the DRN neuronal firing sensitivity to 8-OH-DPAT back to sham control level in males or females, respectively. These data indicate that sexual hormones participate in the mechanisms responsible for the desensitization of 5-HT1A autoreceptors in knockout 5-HTT mice. The differential effects of testosterone and estradiol on 5-HT1A-mediated control of 5-HT neurotransmission might be related to the well-established gender differences in the vulnerability to depression.
Bouali
Saoussen
S
INSERM U288, NeuroPsychoPharmacologie Moléculaire Cellulaire et Fonctionalle, France. sbouali@ext.jussieu.fr
Evrard
Alexis
A
Chastanet
Michel
M
Lesch
Klaus-Peter
KP
Hamon
Michel
M
Adrien
Joëlle
J
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001345:Autoradiography; D017660:Autoreceptors / Q000502:physiology*; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002369:Castration / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004572:Electrolysis; D004594:Electrophysiology / Q000379:methods; D004958:Estradiol / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics; D011903:Raphe Nuclei / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012737:Sex Factors; D013739:Testosterone / Q000494:pharmacology
D017660:Autoreceptors; D002352:Carrier Proteins; D012739:Gonadal Steroid Hormones; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C493231:Slc6a4 protein, mouse; D044282:Receptor, Serotonin, 5-HT1A; D013739:Testosterone; D004958:Estradiol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin