Vesicular monoamine transporter 2 (VMAT2) binding in the human dorsal and median raphe nuclei of depressed suicides

Objectives: The vesicular monoamine transporter 2 (VMAT2) sequesters serotonin into vesicles for recycling and release. Depressed suicides have more brainstem serotonin neurons and tryptophan hydroxylase (TPH)/neuron, the rate-limiting enzyme in serotonin biosynthesis. Studies in depressed suicide attempters indicate low CSF 5-HIAA, indicating deficient serotonin release. We investigated VMAT2 binding in the brainstem of depressed suicides as a potential cause of serotonin loss. Methods: Autoradiography was performed in postmortem human brain sections using ³H-dihydrotetrabenazine ([³H]DHTBZ), which specifically binds to VMAT2. Sections from rostral and caudal levels of the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN), were analyzed from 13 matched triplets (N=39) of Major Depressive Disorder (MDD) suicides, MDD cases who died of natural causes, and nonsuicide controls without psychiatric disorders. To determine the anatomical distribution of VMAT2, autoradiography was conducted every millimeter throughout the brainstem of a single control subject. Results: Specific [³H]DHTBZ binding within the DRN and MRN overlapped with the immunoautoradiographic localization of TPH. Specific [³H]DHTBZ binding did not differ by sex or race, and binding did not correlate with age. In depressed suicides, [³H]DHTBZ binding in the caudal MRN (32.7 ± 3.4 fmol/mg tissue) was lower relative to depressed (48.7 +/- 8.0 fmol/mg tissue) and psychiatrically healthy controls (51.9 ± 6.0 fmol/mg tissue). [³H]DHTBZ binding was not different in the rostral MRN or in the DRN (p>0.05). Conclusions: VMAT2 localization in the human brainstem is consistent with the critical role of VMAT2 in serotonin transport and highlights the importance of VMAT2 in mood regulation. Less VMAT2 in the caudal MRN of depressed suicides would favor loss of serotonin with each action potential leading to a deficiency of available serotonin for release and signaling. These results augment PET studies implicating altered VMAT2 binding in the ventral brainstem in psychiatric disease. Funding Sources: MH40210, MH090964, and T32MH015144.