RESUMO
Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BPND), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BPND (Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BPND of the high-affinity D2 receptor tracer 18F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BPND bilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BPND in anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.
Assuntos
Alelos , Polimorfismo de Nucleotídeo Único/genética , Putamen/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Estriado Ventral/metabolismo , Adolescente , Adulto , Benzamidas , Dopamina/fisiologia , Feminino , Radioisótopos de Flúor , Determinismo Genético , Ligação Genética , Genótipo , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/genética , Estriado Ventral/diagnóstico por imagem , Adulto JovemRESUMO
Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.
Assuntos
Variação Genética , Individualidade , Monoaminoxidase/genética , Personalidade/genética , Córtex Pré-Frontal/fisiologia , Adulto , Mapeamento Encefálico , Expressão Facial , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Modelos Biológicos , Vias Neurais/irrigação sanguínea , Vias Neurais/fisiologia , Testes Neuropsicológicos , Oxigênio/sangue , Estimulação Luminosa/métodos , Córtex Pré-Frontal/irrigação sanguíneaAssuntos
Catecol O-Metiltransferase/genética , Epistasia Genética , Imageamento por Ressonância Magnética , Córtex Pré-Frontal/irrigação sanguínea , Córtex Pré-Frontal/fisiologia , Proteínas RGS/genética , Análise de Variância , Mapeamento Encefálico , Humanos , Processamento de Imagem Assistida por Computador , Memória de Curto Prazo/fisiologia , Metionina/genética , Mutação/fisiologia , Testes Neuropsicológicos , Oxigênio/sangue , Valina/genéticaRESUMO
This study investigates the possible interactions of antidepressant agents and hallucinogens in humans through structured interviews using a standardized questionnaire. Volunteer subjects recruited through announcements placed on the Internet or other sources were asked to describe the somatic, hallucinatory, and psychological effects of self-administered LSD prior to and during chronic administration of an antidepressant. Twenty-eight out of 32 subjects (88%) who had taken an antidepressant with inhibitory effects on serotonin (5-HT) reuptake (fluoxetine, paroxetine, sertraline, trazodone) for over 3 weeks had a subjective decrease or virtual elimination of their responses to LSD. An additional subject who had taken fluoxetine for only 1 week had an increased response to LSD. These data are in contrast to our previous study that reported increased responses to LSD during chronic administration of tricyclic antidepressants or lithium. Possible mechanisms of action for the effects from serotonergic antidepressants involve 5-HT2 and 5-HT1A receptors, changes in extracellular brain serotonin concentrations, and changes in brain catecholamine systems.
