SEROTONIN 5-HT2C AGONISTS MIMIC THE EFFECT OF LIGHT-PULSES ON CIRCADIAN-RHYTHMS

The serotonin agonist quipazine has been shown to cause phase shifts i n melatonin and activity rhythms and to induce c-fos in the suprachias matic nucleus of rats. In this study, in vivo pharmacological characte risation of the phase shifting properties of serotonin agonists has be en performed, with a view to determining the receptor sub-types involv ed. Agonists for the 5-HT2a/2c receptors, +/-)-1-(4-iodo-2,5-dimethoxy phenyl)-2-aminopropane hydrochloride (DOI, 0.1 mg/k), 1-(3-chloropheny l)-piperazine HCl (mCPP, 2 mg/kg) and N-(3-trifluoromethylphenyl)-pipe razine HCl (TFMPP, 2 mg/kg) injected at CT18 resulted in acute transie nt inhibition of melatonin production and delays in the onset of produ ction 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 fa iled to affect melatonin production. At a dose of 0.07 mu mole/kg, the serotonin antagonist, ritanserin inhibited the DOI induced phase dela y whereas ketanserin was ineffective at this dose, providing strong ev idence that DOI was acting through 5-HT2c receptors. DOI (0.5 mg/kg) a t CT18 provoked a phase delay in the core body temperature rhythm of s imilar magnitude to that following a light pulse. Administration of DO I but not agonists active at other receptor sites resulted in the appe arance of c-Fos in the ventrolateral division of the suprachiasmatic n ucleus (SCN) at CT18 but not at CT6. Ritanserin was more potent than k etanserin at inhibiting the DOI induced increase in c-Fos labelled cel ls 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 li ght pulse, none of the drugs significantly inhibited the responses to light. The results of these experiments indicate that serotonergic ago nists active at the 5-HT2c receptor mimic the effects of Light on 2 in dependent rhythms and activate SCN neurones in the rat. (C) 1998 Elsev ier Science B.V. All rights reserved.