Our prior research suggests that serotonergic function is involved in the pathophysiology of seasonal affective disorder (SAD) & the mechanism of action of light therapy. The serotonin agonist m-CPP has produced exaggerated activation & euphoria in untreated SAD patients (PTS), & abnormal hormonal responses have occurred in response to m-CPP & to the 5HT-1A agonist ipsapirone; & metergoline, a serotonin antagonist, though contrary to prediction, reduced SAD symptoms. This year we: A) present sleep log from the metergoline study; B) examine the effects of m-CPP on serotonergic function using positron emission tomography (PET); & D) discuss possible relationships of serotonin-related candidate genes both to SAD & migraine headaches. A) Sleep results from our metergoline study indicated no significant effects of metergoline upon any of the sleep parameters studied. There were effects of light therapy. During light therapy PTS showed a trend towards later sleep onsets, earlier sleep offsets & midpoints, decreased duration, a trend toward decreased nap time, & reduced total sleep time. These findings again conform the powerful effects of bright light on sleep in PTS. B) Given our earlier findings with m-CPP, we sought to assess whether m-CPP also induces changes in cerebral metabolism. We sought to replicate an earlier PET finding showing increased prefrontal & decreased orbitofrontal metabolism. We sought to replicate an earlier reported m-CPP-induced activation - euphoria. PTS & CTS were infused with m-CPP & placebo & administered a PET scan after each infusion. Blood samples for ACTH, cortisol & prolactin were drawn, as well as estradiol, progesterone, FSH and LH for females & on males for FSH, LH & testosterone. The NIMH 25-item self-rating scale was used to measure activation & euphoria. Behaviorally, we again replicated our earlier finding of serotonin-related candidate genes in PTS & CTS. In the past year, we developed new cell lines for addition PTS & CTS. These additional cell lines now await analysis & correlation with clinical profile. We identified a variant of the 5HT2C receptor gene in approximately 14% of CTS. The variant appears to have functional significance in frog oocytes. We plan to test its functional significance in humans by administering m-CPP to CTS with & without the variant & measure a variety of serotonin-related dependent measures. D) Finally, we began a study of the possible genetic basis of migraine headaches that was inspired by: a) the strong familial basis of migraines; b) concordance of migraines & mood disorders; & c) evidence which suggest that serotonergic disturbances are involved in migraines. To date we have established cell lines for 32 migraine patients. Data analysis is forthcoming.