Research report More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides Maura Boldrini 1 , Mark D. Underwood, J. John Mann, Victoria Arango T Department of Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA Department of Psychiatry, Columbia College of Physicians and Surgeons, New York, NY 10032, USA Accepted 26 January 2005 Available online 9 March 2005 Abstract Deficient serotonin neurotransmission in suicide is indicated by reduced brainstem serotonin (5-HT) and 5-hydroxyindoleacetic acid (5- HIAA), fewer 5-HT 1A autoreceptors and reduced cortical serotonin transporter binding in suicide victims. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-HT, and alterations in TPH could explain some of these findings. We sought to determine the amount of TPH immunoreactivity (TPH-IR) in the dorsal (DRN) and median (MRN) raphe nuclei in suicides and controls. Brainstems of suicide victims and controls (n = 11 pairs) were collected at autopsy, matched for age, sex and postmortem interval, frozen and sectioned (20 Am). Immunoautoradiography, using an antibody to label TPH, was performed, slides exposed to film and autoradiograms quantified by a computer-based image analysis system. We examined sections every 1000 Am throughout the whole length of the nucleus, performing statistical analysis only on those subjects for whom the raphe was complete (n = 8 pairs). TPH-IR (ACi/g) was higher in suicides than controls (S: 300.8 F 70.8 vs. C: 259.6 F 40.7, t = 2.57, df = 7, P = 0.04) in the dorsal raphe nucleus (DRN), and not different between suicides and controls (S: 251.3 F 44.2 vs. C: 235.9 F 27.4, t = 1.49, df = 7, P = 0.18) in the MRN. DRN TPH-IR was higher in male suicide victims (MS) compared to male controls (MC; MS: 318.4 F 54.4 vs. MC: 271.9 F 22.5, t = 2.66, df = 6, P = 0.03). The analysis of TPH-IR area and density at each DRN rostrocaudal levels showed higher area and density in suicides compared to controls in the rostral DRN and lower area and density in the caudal DRN. TPH-IR, an index of the amount of TPH enzyme, in the DRN is higher in depressed suicides. More TPH may be an upregulatory homeostatic response to impaired serotonin release or less autoreceptor activation. Alternatively, the serotonin impairment in suicide may be due to hypofunctional serotonin-synthesizing enzyme. D 2005 Published by Elsevier B.V. Theme: Neural Basis of Behavior Topic: Monoamines and Behavior Keywords: Postmortem; Serotonin; Immunoautoradiography; Dorsal raphe nucleus; Human 1. Introduction Suicidal behavior is associated with impaired serotoner- gic function. Low levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) are found in the cerebrospinal fluid (CSF) of depressed suicide attempters compared with psychiatric controls [1,2,8,12,16,37, 47,56,66,68,70], and can predict suicide and suicide attempts [24,48]. Impaired serotonergic neurotransmission in the brain of suicide victims is indicated by lower levels of serotonin (5-HT) and 5-HIAA in the brainstem, as well as fewer presynaptic serotonin transporter (SERT) binding sites and more post-synaptic 5-HT 1A and/or 5-HT 2A receptors in prefrontal cortex of suicide victims [4,5, 0006-8993/$ - see front matter D 2005 Published by Elsevier B.V. doi:10.1016/j.brainres.2005.01.083 T Corresponding author. Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42 New York, NY 10032, USA. Fax: +1 212 543 6017. E-mail address: varango@neuron.cpmc.columbia.edu (V. Arango). 1 Present Affiliation: Department of Neurologic and Psychiatric Sciences, University of Florence, 50134 Florence, Italy. Brain Research 1041 (2005) 19 – 28 www.elsevier.com/locate/brainres