Glucocorticoid receptor-dependent desensitization of 5-HT1A autoreceptors by sleep deprivation: studies in GR-i transgenic mice.
Sleep deprivation for one night induces mood improvement in depressed patients, an action that probably involves the serotonergic (5-HT) system. In animals, sleep deprivation and pharmacologic treatment with antidepressants exert similar effects on 5-HT neurotransmission, notably functional desensitization of 5-HT1A autoreceptors located on 5-HT neurons in the dorsal raphe nucleus (DRN). However, in stressful conditions, corticosterone can also induce a desensitization of these autoreceptors.


OBJECTIVE
To investigate the mechanisms of this adaptation during sleep deprivation and the possible involvement of corticosterone, we studied the effects of an 18-hour sleep deprivation, by forced locomotion, on 5-HT1A receptor-mediated firing response of DRN 5-HT neurons in transgenic mice with impaired glucocorticoid-receptor expression (GR-i) and in wild-type animals. We also examined the effects of chronic treatment with the antidepressant drug fluoxetine in the same paradigm.


RESULTS
In both wild-type and GR-i mice, the 18-hour sleep deprivation or fluoxetine treatment had no effect on the spontaneous firing of 5-HT neurons recorded under anesthesia. However, sleep deprivation decreased the potency of the 5-HT1A agonist 8-OH-DPAT to inhibit 5-HT neuronal firing in wild-type mice, whereas it had no effect in GR-i animals. Conversely, after chronic fluoxetine treatment, the induced reduction of this 5-HT1A autoreceptor-driven response was of larger amplitude in GR-i than in wild-type mice.


CONCLUSIONS
These data suggest that glucocorticoid-receptor activation by corticosterone participates in the antidepressant-like adaptive changes in 5-HT1A autoreceptors in sleep-deprived mice. On the other hand, GR-i animals exhibited enhanced 5-HT1A autoreceptor desensitization induced by fluoxetine, in line with data in other animal models of depression.
Evrard
Alexis
A
UMR 677 INSERM-UPMC, Neuropsychopharmacologie, CHUPitié-Salpêtrière, Paris, France.
Barden
Nicolas
N
Hamon
Michel
M
Adrien
Joëlle
J
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D017660:Autoreceptors / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D012892:Sleep Deprivation / Q000378:metabolism*
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D017660:Autoreceptors; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors