EXCEED THE SPACE PROVIDED. Serotonin abnormalities in the brainstem and cerebral cortex of alcoholics is hypothesized based on reports of reduced serotonin metabolites inthe cerebrospinal fluid, the efficacyof serotonin agonists and uptake inhibitors in reducingalcoholconsumption inhumansandanimal models andbiochemical abnormalities inalcohol preferring rat strains. During the funded period considerable progress was made and postmortem evidence of alterations in serotonin-synthesizing neurons in the dorsal raphe nucleus (DRN) of alcoholics, including increased densityof neuronal processes, was obtained. In the prefrontal cortex, serotonin receptors were not markedly changed in alcoholics compared to matched controls. A novel immunoautoradiographic method was developed for quantifying tryptophan hydroxylase in frozen brainstem sections. A comprehensive series of postmortem studies of the serotonin system in frozen brainstem and forebrain is proposed to further examine serotonin source neurons in the DRN and target neurons in the lateral and orbital prefrontal cortex and in the anterior cingulate. The brain of 20 matched (age, sex, race, postmortem interval) pairs of cases with DSM-IV criteria for alcoho abuse or dependence and nonpsychiatric controlswill beexamined. Alcohol abuse/dependence will be diagnosed accordingto DSM-IV criteria bypsychological autopsy. Inthe DRN: tryptophan hydroxylase will be measured using immunoautoradiography at the level of the entire DRN (autoradiography) and in individual neurons (emulsion); in adjacent sections, 5-HT, precursors and metabolites will be measured in DRN punches (HPLC), and Serotonin transporter (SERT) sites and 5-HT1A autoreceptor binding in the DRN will be measured by quantitative autoradiography. In the ventrolateral and orbital prefrontal cortex, anterior cingulate and primary motor cortex, measurement of cortical neuron density will be determined using stereology and neuron density will be related to the concentration of serotonin transporter sites, 5-HT1Aand 5-HT2A receptors in the same cortical regionstoderive an index of the concentration of receptors per neuron. The studies are designed to assess the integrity of DRNserotonin neurons and neurons in the prefrontalcortex in alcoholics. The results of the studies should help to clarify whether serotonin receptors or neurons regulate or fail to regulate in alcoholics. PERFORMANCE SITE ========================================Section End===========================================
| Bach, Helene; Arango, Victoria; Kassir, Suham A et al. (2014) Alcoholics have more tryptophan hydroxylase 2 mRNA and protein in the dorsal and median raphe nuclei. Alcohol Clin Exp Res 38:1894-901 |
| Underwood, Mark D; Mann, J John; Huang, Yung-Yu et al. (2008) Family history of alcoholism is associated with lower 5-HT2A receptor binding in the prefrontal cortex. Alcohol Clin Exp Res 32:593-9 |
| Underwood, Mark D; Mann, J John; Arango, Victoria (2007) Morphometry of dorsal raphe nucleus serotonergic neurons in alcoholism. Alcohol Clin Exp Res 31:837-45 |
| Oquendo, Maria A; Russo, Stefani A; Underwood, Mark D et al. (2006) Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide. Biol Psychiatry 59:235-43 |
| Underwood, Mark D; Mann, J John; Arango, Victoria (2004) Serotonergic and noradrenergic neurobiology of alcoholic suicide. Alcohol Clin Exp Res 28:57S-69S |
| Arango, Victoria; Underwood, Mark D; Mann, J John (2002) Serotonin brain circuits involved in major depression and suicide. Prog Brain Res 136:443-53 |
