Rates of serotonin synthesis were measured in the human brain using positron emission tomography. The sensitivity of the method is indicated by the fact that measurements are possible even after a substantial lowering of synthesis induced by acute tryptophan depletion. Unlike serotonin levels in human brain, which vary greatly in different brain areas, rates of synthesis of the indolamine are rather uniform throughout the brain. The mean rate of synthesis in normal males was found to be 52% higher than in normal females; this marked difference may be a factor relevant to the lower incidence of major unipolar depression in males. Low brain serotonin (5-HT) levels or function have been implicated in various types of psychopathology, including depression, suicide, aggression, anxiety, and bulimia (for reviews see refs. 1-3). Until recently, the principal methods for studying serotonin metabolism in human brain were determination of the metabolite of serotonin 5-hydroxyindole-3-acetic acid (5-HIAA) in cerebrospinal fluid (CSF) and postmortem measurements of brain serotonin and 5-HIAA. Both methods have limitations. In particular, neither provides a direct measure of serotonin synthesis in the living brain. Recently, a method for measuring serotonin synthesis in the brain of living mammals has been developed (4-5) and tested successfully in dogs (6). The method uses positron emission tomography (PET) and ␣-[11 C]methyl-L-tryptophan as a tracer. The tracer is converted in part to ␣-[11 C]methylserotonin, which accumulates in serotonin neurons, because it is not a substrate for monoamine oxidase and does not cross the bloodbrain barrier.We report here in vivo measurements of serotonin synthesis in the brain of healthy volunteers. Both male and female subjects were studied because CSF studies suggest that the rate of brain serotonin metabolism is higher in females than in males (7-8), and because the incidence of major unipolar depression is higher in women (9). We measured rates of serotonin synthesis under two conditions: at baseline and after acute tryptophan depletion (ATD). For ATD, subjects ingest a tryptophan-free mixture of all the essential amino acids. This induces protein synthesis, which incorporates body stores of free tryptophan into protein, thus reducing the level of this amino acid in tissues, including brain (10). Because tryptophan is the precursor of serotonin, its reduction is thought to lower the rate of serotonin synthesis in brain (11-12). ATD was used in the present study for several reasons. First, low serotonin levels have been proposed to relate to various types of psychopathology (for reviews see refs. 1-3), so any useful method of in vivo measurements of the serotonin synthesis rate must have a demonstrated capability for measuring low rates of serotonin synthesis. Second, ATD induces a transient reappearance of depressive symptoms in patients under treatment with antidepressants (13). Moreover, ATD also produces a mild lowering of mood in normal subjects with a family history of de...

Impulsive-aggressive personality disorders and alcohol abuse/dependence were two independent predictors of suicide in major depression, and impulsive and aggressive behaviors seem to underlie these risk factors. A developmental hypothesis of suicidal behavior, with impulsive and aggressive behaviors as the starting point, is discussed.

Microdialysis experiments in rodents indicate that ethanol promotes dopamine release predominantly in the nucleus accumbens, a phenomenon that is implicated in the reinforcing effects of drugs of abuse. The aim of the present study was to test the hypothesis in humans that an oral dose of ethanol would lead to dopamine release in the ventral striatum, including the nucleus accumbens. Six healthy subjects underwent two [(11)C]raclopride PET scans following either alcohol (1 ml/kg) in orange juice or orange juice alone. Subjective mood changes, heart rate, and blood-alcohol levels were monitored throughout the procedure. Personality traits were evaluated using the tridimensional personality questionnaire. PET images were co-registered with MRI and transformed into stereotaxic space. Statistical parametric maps of [(11)C]raclopride binding potential change were generated. There was a significant reduction in [(11)C]raclopride binding potential bilaterally in the ventral striatum/nucleus accumbens in the alcohol condition compared to the orange juice condition, indicative of increased extracellular dopamine. Moreover, the magnitude of the change in [(11)C]raclopride binding correlated with the alcohol-induced increase in heart rate, which is thought to be a marker of the psychostimulant effects of the drug, and with the personality dimension of impulsiveness. The present study is the first report that, in humans, alcohol promotes dopamine release in the brain, with a preferential effect in the ventral striatum. These findings support the hypothesis that mesolimbic dopamine activation is a common property of abused substances, possibly mediating their reinforcing effects.

BackgroundMost studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations.Methodology/Principal FindingsWe performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data.Conclusions/SignificanceThe observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.