Serotonergic serotonin (1A) mixed agonists/antagonists elicit large-magnitude phase shifts in hamster circadian wheel-running rhythms.

The biological clock that generates circadian rhythms in mammals is located within the suprachiasmatic nuclei at the base of the hypothalamus. The circadian clock is entrained to the daily light/dark cycle by photic information from the retina. The retinal input to the clock is inhibited by exogenously applied serotonin agonists, perhaps mimicking an endogenous inhibitory serotonergic input to the clock arriving from the midbrain raphe. In the present study, a unique class of serotonergic compounds was tested for its ability to modulate retinal input to the circadian clock. The serotonergic ligands 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-8-azaspiro(4.5)decane-7,9-dione dihydrochloride (BMY 7378), S 15535, and 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione hydrochloride (MDL 73005 EF) can all be classified as mixed agonists/antagonists at type 1A serotonin receptors. Circadian wheel-running activity rhythms were monitored in Syrian hamsters maintained in constant darkness. Dim white-light pulses administered to the hamsters at circadian time 19 advanced the phase of their running rhythms by 1-2 h. Injection of BMY 7378, S 15535, and to a lesser degree MDL 73005 EF, prior to the light pulses resulted in phase advances from 5 to 6 h, and by as much as 8 h. Neither BMY 7378 nor S 15535 had any effect on light-induced phase delays in hamster activity rhythms at circadian time 14. Further, BMY 7378 is able to phase advance circadian rhythms by approximately 1 h at night even without light exposure. Finally, the effects of BMY 7378 on circadian rhythms is opposite to that observed with the prototypical serotonin 1A agonist (+/-)-8-hydroxy-2-(DI-n-propyl-amino)tetralin hydrobromide (8-OH-DPAT) (8-OH-DPAT elicits non-photic phase advances in the day and inhibits photic-induced phase advances at night). These results suggest that pharmacologically blocking raphe input to the suprachiasmatic circadian clock results in substantially larger photically induced phase advances in wheel-running rhythms. This is further evidence that raphe input to the circadian clock is probably acting to dampen the clock's response to light under certain conditions. The large-magnitude phase shifts, and temporal-activity profile seen with BMY 7378 and S 15535, suggest that compounds with this unique pharmacological profile may be beneficial in the treatment of circadian phase delays recently reported to be a complication resulting from Alzheimer's disease.