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Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. L(A)L(A); triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(-703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.
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Dopamine is known as the main neurotransmitter modulating the activation of the reward system of the brain. The DRD2 TaqIA polymorphism is associated with dopamine D2 receptor density which plays an important role in the context of reward. Persons carrying an A1 allele have a lower D2 receptor density and a higher risk to show substance abuse. The present study was designed to investigate the influence of the DRD2 TaqIA polymorphism and the selective D2 receptor agonist bromociptine on the activation of the reward system by means of functional magnetic resonance imaging (fMRI). In a double-blind crossover study with 24 participants we found an increase of reward system activation from placebo to bromocriptine only in subjects carrying the A1 allele. Furthermore, only A1 carrier showed an increase of performance under bromocriptine. The results are interpreted as reflecting a specific sensitivity for dopamine agonists in persons carrying an A1 allele and may complement actual data and theories of the development of addiction disorders postulating a higher genetic risk for substance abuse in carrier of the A1 allele.
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Absorption represents a disposition to experience altered states of consciousness characterized by intensively focused attention. It is correlated with hypnotic susceptibility and includes phenomena ranging from vivid perceptions and imaginations to mystical experiences. Based on the assumption that drug-induced and naturally occurring mystical experiences share common neural mechanisms, we hypothesized that Absorption is influenced by the T102C polymorphism affecting the 5-HT2a receptor, which is known to be an important target site of hallucinogens like LSD. Based on the pivotal role ascribed to the prefrontal executive control network for absorbed attention and positive symptoms in schizophrenia, it was further hypothesized that Absorption is associated with the VAL158MET polymorphism of the catechol-O-methyltransferase (COMT) gene affecting the dopaminergic neurotransmitter system. The Tellegen Absorption Scale was administered to 336 subjects (95 male, 241 female). Statistical analysis revealed that the group with the T/T genotype of the T102C polymorphism, implying a stronger binding potential of the 5-HT2a receptor, indeed had significantly higher Absorption scores (F = 10.00, P = 0.002), while no main effect was found for the COMT polymorphism. However, the interaction between T102C and COMT genotypes yielded significance (F = 3.89; P = 0.049), underlining the known functional interaction between the 5-HT and the dopaminergic system. These findings point to biological foundations of the personality trait of Absorption.
Erkunden
Eintragsart
Sprache
- Englisch (3)
Thema
- *Polymorphism, Genetic
- Adolescent (1)
- Adult (3)
- Alleles (2)
- Attention/*physiology (1)
- Brain/blood supply/*drug effects/physiology (1)
- Brain Mapping/methods (1)
- Brain/pathology/physiology (1)
- Bromocriptine/*pharmacology (1)
- Catechol O-Methyltransferase/*genetics (1)
- Conditioning, Psychological/physiology (1)
- Cross-Sectional Studies (1)
- Dopamine Agonists/*pharmacology (1)
- Double-Blind Method (1)
- Environment (1)
- Epistasis, Genetic (1)
- Extinction, Psychological/physiology (1)
- *Fear (1)
- Feedback, Psychological/drug effects/physiology (1)
- Female (3)
- Gene Frequency (1)
- Genetic Predisposition to Disease (1)
- Genotype (2)
- Hallucinations/genetics/*physiopathology (1)
- Humans (3)
- Image Processing, Computer-Assisted/methods (1)
- Magnetic Resonance Imaging/methods (2)
- Male (3)
- Models, Genetic (1)
- Oxygen/blood (1)
- Phenotype (1)
- Reaction Time/drug effects/genetics (1)
- Receptor, Serotonin, 5-HT2A/*genetics (1)
- Receptors, Dopamine D2/*genetics (1)
- Reverse Transcriptase Polymerase Chain Reaction/methods (1)
- *Reward (1)
- Schizophrenia/genetics/physiopathology (1)
- Serotonin/*metabolism (1)
- Skin/pathology (1)
- Wounds and Injuries (1)