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Serotonin (5-hydroxytryptamine, 5-HT) shifts the phase of the circadian rhythm in the eye of Aplysia. We have examined the role of cAMP in mediating the effects of 5-HT on the rhythm. The phase shifts produced by 5-HT are mimicked by treatments that should increase intracellular levels of cAMP. An analogue ofcAMP, 8-benzylthio-cAMP, advanced and delayed the rhythm at phases in which 5-HT had similar effects on the rhythm. In addition, two phosphodiesterase inhibitors, Ro-20-1724 and papaverine, caused advance phase shifts where 5-HT advances the rhythm. The phosphodiesterase inhibitors Ro-20-1724 and 3-isobutyl-1-methylxanthine each potentiated the effect of subthreshold doses of 5-HT on the rhythm. The effects of 5-HT and 8-benzylthio-cAMP on the rhythm were nonadditive, indicating that 5-HT and 8-benzylthio-cAMP affect the rhythm through a common pathway. Finally, 5-HT produced large changes (13-fold) in the levels of cAMP in the eye. These results indicate that cAMP mediates the effect of 5-HT on the rhythm. There are two possible roles for cAMP in the circadian system. Either the cAMP system is an intracellular step in an entrainment pathway or it is part of the biological clock. Because 5-HT, 8-benzylthio-cAMP, and three phosphodiesterase inhibitors inhibit impulses from the eye, cAMP may also mediate the inhibition produced by 5-HT, or it might be involved in regulating the frequency of spontaneous impulses throughout the day.Entrainment of circadian rhythms from animals requires that environmental information be processed through one or more neurons. Ultimately, the information must be translated into a form that perturbs the endogenous oscillating mechanism. Our research is focused upon the pathways by which entrainment information acts on circadian oscillators. Serotonin (5-hydroxytryptamine, 5-HT) shifts the phase ofthe circadian rhythm of the isolated eye of Aplysia (1). The characteristics of the phase shifts produced by 5-HT and light indicate that 5-HT is used in a different pathway from the one involved in entrainment of the isolated eye by light-dark cycles (2). We have hypothesized that 5-HT plays a role in transmitting circadian information from the central nervous system to the eye via efferent activity in the optic nerve (1-3). Because it is likely that circadian oscillators involve some part of the metabolic machinery of the cell, some of the final steps of entrainment pathways may be intracellular second messengers. We investigated whether cAMP mediates phase shifting by 5-HT because many different effects of 5-HT in Aplysia appear to involve cAMP (4-12). Preliminary results of some of these studies have appeared elsewhere (13). METHODSEyes were removed from the sea hare Aplysia californica and maintained individually at 15. 5°C in constant darkness throughout the experiment. The recording chambers contained filtered sea water with 30 mM Hepes (pH 7.7), penicillin at 100 units/ ml, and streptomycin at 100 ,ug/ml. The rhythm ofspontaneous nerve impulses was assayed by recording imp...

A putative neurotransmitter, serotonin, may be used to transmit temporal information in the eye of Aplysia, because it can shift the phase of the circadian rhythm of spontaneous optic nerve impulses from the eye and the eye contains a significant quantity of serotonin. Serotonin acts either directly on the cell, or cells, containing the circadian pacemaker or on cells electronically coupled to the pacemaker cells.

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