Serotonin and the regulation of mammalian circadian rhythmicity

The suprachiasmatic nucleus (SCN), the site of the primary mammalian circad ian clock, contains one of the densest serotonergic terminal plexes in the brain. Although this fact has been appreciated for some time, only in the l ast decade has there been substantial approach toward the understanding of the function of serotonin in the circadian rhythm system. The intergenicula te leaflet, which projects to the SCN via the geniculohypothalamic tract, r eceives serotonergic innervation from the dorsal raphe nucleus, and the SCN receives its serotonergic input from the median raphe nucleus. This separa tion of serotonergic origins provides the opportunity to investigate the fu nction 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 circa dian rhythm response to light. Despite the simplicity of the origins of ser otonergic anatomy with respect to the circadian rhythm system, the actual i nvolvement of serotonin in rhythm modulation is not so obvious. A variety o f pharmacological studies have clearly implicated serotonin as a direct reg ulator of circadian rhythm phase, bur others employing different methods su ggest that simple elevation of SCN serotonin concentrations does not modify rhythm phase. The most convincing role of serotonin is its apparent abilit y to modulate sensitivity of the circadian rhythm to Light. The putative me thod for such modulation is via a presynaptic 5-HT1B receptor on the retino hypothalamic 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 t o environmentally induced locomotor activity. Current interest in serotoner gic modulation of circadian rhythmicity is strong and the research is vigor ous. There Is an abundance of information about serotonin and circadian rhy thm function that lacks a satisfactory framework for its interpretation. Th e next decade is likely to see the gradual evolution of this framework as t he role of serotonin in circadian rhythm regulation is further elucidated.