Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion

Abnormal serotonergic function is implicated in the pathogenesis of affecti ve disorders. We induced transient depressive relapses in volunteer patient s by rapidly depleting plasma tryptophan, the precursor of serotonin (5-HT) , and measured neural activity during different cognitive tasks using posit ron emission tomography (PET). Neural activity in several 5-HT-related brai n areas, e.g., dorsal raphe, habenula, septal region, amygdala, and orbitof rontal cortex, covaried significantly with plasma levels of tryptophan and ratings of depressed mood. Task-specific responses in left amygdala and lef t anterior cingulate were attenuated by tryptophan depletion. We used these PET data to test the hypothesis that projections from the habenula modulat e dorsal raphe activity and that this modulation is enhanced in patients ex periencing a profound mood change following serotonergic challenge. A stron g linear correlation (r(2) > 0.5) between habenula and raphe activity was o bserved in subjects with postdepletion ratings greater than or equal to 10 on a modified Hamilton depression scale, whereas subjects experiencing mild er changes in mood had weaker habenula-raphe coupling (r(2) < 0.5). These d ata support a model of the serotonergic system in which the habenula projec tion to the raphe represents a convergent feedback pathway that controls th e release of 5-HT throughout the brain. In our experiment we were able to e ngage this system in patients who were sensitive to tryptophan depletion. ( C) 1999 Academic Press.