Chronic voluntary ethanol intake hypersensitizes 5-HT(1A) autoreceptors in C57BL/6J mice.
Alcoholism is a complex disorder involving, among others, the serotoninergic (5-HT) system, mainly regulated by 5-HT(1A) autoreceptors in the dorsal raphe nucleus. 5-HT(1A) autoreceptor desensitization induced by chronic 5-HT reuptake inactivation has been associated with a decrease in ethanol intake in mice. We investigated here whether, conversely, chronic ethanol intake could induce 5-HT(1A) autoreceptor supersensitivity, thereby contributing to the maintenance of high ethanol consumption. C57BL/6J mice were subjected to a progressive ethanol intake procedure in a free-choice paradigm (3-10% ethanol versus tap water; 21 days) and 5-HT(1A) autoreceptor functional state was assessed using different approaches. Acute administration of the 5-HT(1A) receptor agonist ipsapirone decreased the rate of tryptophan hydroxylation in striatum, and this effect was significantly larger (+75%) in mice that drank ethanol than in those drinking water. Furthermore, ethanol intake produced both an increased potency (+45%) of ipsapirone to inhibit the firing of 5-HT neurons, and a raise (+35%) in 5-HT(1A) autoreceptor-mediated stimulation of [(35)S]GTP-gamma-S binding in the dorsal raphe nucleus. These data showed that chronic voluntary ethanol intake in C57BL/6J mice induced 5-HT(1A) autoreceptor supersensitivity, at the origin of a 5-HT neurotransmission deficit, which might be causally related to the addictive effects of ethanol intake.
Kelaï
Sabah
S
UPMC Univ Paris 06, UMR-5677, Neuropsychopharmacologie, Paris, France.
Renoir
Thibault
T
Chouchana
Laurent
L
Saurini
Françoise
F
Hanoun
Naïma
N
Hamon
Michel
M
Lanfumey
Laurence
L
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000428:Alcohol Drinking / Q000503:physiopathology*; D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D004195:Disease Models, Animal; D005518:Food Preferences / Q000187:drug effects*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014364:Tryptophan / Q000378:metabolism
D011743:Pyrimidines; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006897:Hydroxyindoleacetic Acid; C043077:ipsapirone; D014364:Tryptophan; D006916:5-Hydroxytryptophan