Serotonin and the regulation of mammalian circadian rhythmicity.

The suprachiasmatic nucleus (SCN), the site of the primary mammalian circadian clock, contains one of the densest serotonergic terminal plexes in the brain. Although this fact has been appreciated for some time, only in the last decade has there been substantial approach toward the understanding of the function of serotonin in the circadian rhythm system. The intergeniculate leaflet, which projects to the SCN via the geniculohypothalamic tract, receives serotonergic innervation from the dorsal raphe nucleus, and the SCN receives its serotonergic input from the median raphe nucleus. This separation of serotonergic origins provides the opportunity to investigate the function of the two projections. Loss of serotonergic neurones of the median raphe yields earlier onset and later offset of the nocturnal activity phase, longer duration of the activity phase, and increased sensitivity of circadian rhythm response to light. Despite the simplicity of the origins of serotonergic anatomy with respect to the circadian rhythm system, the actual involvement of serotonin in rhythm modulation is not so obvious. A variety of pharmacological studies have clearly implicated serotonin as a direct regulator of circadian rhythm phase, but others employing different methods suggest that simple elevation of SCN serotonin concentrations does not modify rhythm phase. The most convincing role of serotonin is its apparent ability to modulate sensitivity of the circadian rhythm to light. The putative method for such modulation is via a presynaptic 5-HT1B receptor on the retinohypothalamic tract, the activation of which attenuates photic input to the SCN thereby reducing phase response to light. Serotonin may modulate phase response to benzodiazepines, but does not appear to modify such response to environmentally induced locomotor activity. Current interest in serotonergic modulation of circadian rhythmicity is strong and the research is vigorous. There is an abundance of information about serotonin and circadian rhythm function that lacks a satisfactory framework for its interpretation. The next decade is likely to see the gradual evolution of this framework as the role of serotonin in circadian rhythm regulation is further elucidated.