Serotonin 5-HT2c agonists mimic the effect of light pulses on circadian rhythms.
The serotonin agonist quipazine has been shown to cause phase shifts in melatonin and activity rhythms and to induce c-fos in the suprachiasmatic nucleus of rats. In this study, in vivo pharmacological characterisation of the phase shifting properties of serotonin agonists has been performed, with a view to determining the receptor sub-types involved. Agonists for the 5-HT2a/2c receptors, (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI, 0.1 mg/k), 1-(3-chlorophenyl)-piperazine HCl (mCPP, 2 mg/kg) and N-(3-trifluoromethylphenyl)-piperazine HCl (TFMPP, 2 mg/kg) injected at CT18 resulted in acute transient inhibition of melatonin production and delays in the onset of production on the following nights of 1.2+/-0.2, 1.7+/-0.3 and 1. 4+/-0.8 h respectively. Drugs specific for 5-HT1a/7 and 5-HT3 receptors failed to affect melatonin production. At a dose of 0.07 micromole/kg, the serotonin antagonist, ritanserin inhibited the DOI induced phase delay whereas ketanserin was ineffective at this dose, providing strong evidence that DOI was acting through 5-HT2c receptors. DOI (0.5 mg/kg) at CT18 provoked a phase delay in the core body temperature rhythm of similar magnitude to that following a light pulse. Administration of DOI but not agonists active at other receptor sites resulted in the appearance of c-Fos in the ventrolateral division of the suprachiasmatic nucleus (SCN) at CT18 but not at CT6. Ritanserin was more potent than ketanserin at inhibiting the DOI induced increase in c-Fos labelled cells in the SCN. When rats were pre-treated with metergoline (15 mg/kg), ritanserin (3 mg/kg) or LY 53,857 (3 mg/kg) prior to a 2 lx/ 1 min light pulse, none of the drugs significantly inhibited the responses to light. The results of these experiments indicate that serotonergic agonists active at the 5-HT2c receptor mimic the effects of light on 2 independent rhythms and activate SCN neurones in the rat.
Kennaway
D J
DJ
Department of Obstetrics and Gynaecology, The University of Adelaide, Frome Road, Adelaide, South Australia, 5005, Australia.
Moyer
R W
RW
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects* / Q000528:radiation effects*; D007650:Ketanserin / Q000494:pharmacology; D008027:Light; D008297:Male; D008550:Melatonin / Q000037:antagonists & inhibitors; D010507:Periodicity; D010775:Photic Stimulation / Q000379:methods; D010879:Piperazines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
D000662:Amphetamines; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D016713:Ritanserin; C018406:1-(3-trifluoromethylphenyl)piperazine; D007650:Ketanserin; D008550:Melatonin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C015068:1-(3-chlorophenyl)piperazine