Exogenous testosterone and the monoamine-oxidase A polymorphism influence anger, aggression and neural responses to provocation in males

Wagels, Lisa; Votinov, Mikhail; Kellermann, Thilo; Konzok, Julian; Jung, Sonja; Montag, Christian; Schneider, Frank; Eisert, Albrecht; Beyer, Cordian; Habel, Ute

doi:10.1016/j.neuropharm.2019.01.006

Cited by 29 publications

(24 citation statements)

References 68 publications

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“…The polymorphism of the monoamine oxidase A genotype categorized in MAOA-L (long tandem repeats) and MAOA-S (short tandem repeats) variants was determined prior to the study (for full details, see supplementary data). The MAOA polymorphism was included as a covariate in all statistical analyses, because hormonal effects can be modulated by genetic manifestation regarding the MAOA polymorphism 13,[33][34][35][36] .…”

Section: Methodsmentioning

confidence: 99%

Effects of exogenous testosterone application on network connectivity within emotion regulation systems

Votinov

Wagels

Hoffstaedter

et al. 2020

Sci Rep

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Studies with steroid hormones underlined the vital role of testosterone on social-emotional processing. However, there is still a lack of studies investigating whether testosterone modulates network connectivity during resting-state. Here, we tested how the exogenous application of testosterone would affect functional connectivity between regions implicated in emotion regulation. In total, 96 male participants underwent resting-state fMRI scanning. Before the measurement, half of the subjects received 5 g Testim tM gel (containing 50 mg testosterone) and the other half a corresponding amount of placebo gel. Seeds for the connectivity analysis were meta-analytically defined. First, all regions associated with emotion regulation were chosen via Neurosynth (data driven). Among those, specific seeds were selected and categorized based on the neural model of emotion regulation by Etkin and colleagues (Etkin et al., 2015) (theory-guided). Resting-state connectivity analysis revealed decreased connectivity between the right DLPFC and the right amygdala as well as between the VMPFC and the left IPL for the testosterone group compared to the placebo group. A complementary dynamic causal modeling (DCM) analysis on findings from the resting-state connectivity analysis underlined a bidirectional coupling which was decreased close to zero by testosterone administration. Our results demonstrate that testosterone administration disrupts resting-state connectivity within frontosubcortical and fronto-parietal circuits. The findings suggest that even without a specific task (e.g. challenge, reward processing) testosterone modulates brain networks important for social-emotional processing.testosterone administration in both genders and with changing endogenous testosterone levels in puberty 1,16-19 . On the whole, these studies point towards a testosterone-induced reduction of regulatory control (exerted by the prefrontal cortex) over the amygdala 1,17,18 .The first studies in humans that established an important role of testosterone on functional connectivity were performed in the field of electrophysiology 20,21 . A decoupling of midfrontal delta-beta oscillations was linked to the disinhibitory properties of testosterone administration 20 . FMRI studies provided further evidence for a modulatory role of testosterone on brain connectivity. In women, reduced cortico-subcortical connectivity after testosterone administration was observed during a face-matching task 1 . A further study also applying a face-matching task found that testosterone administration reduced the connectivity between the inferior frontal gyrus and the supplementary motor area in female participants 7 . While findings on the effect of a single dose of testosterone on resting-state connectivity are currently lacking, there is some indication of a potential effect provided by the investigation of male anabolic steroid users. In those, modulated connectivity between key areas of the emotion regulation system and large-scale brain networks was observed, compared t...

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Section: Methodsmentioning

confidence: 99%

Effects of exogenous testosterone application on network connectivity within emotion regulation systems

Votinov

Wagels

Hoffstaedter

et al. 2020

Sci Rep

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“…The question that remains here would be why the exogenous manipulation could influence emotions but not behavioral responses. If testosterone administration indeed affects the neural system, which can be assumed based on our previous work (e.g., Wagels et al, 2019b), it is unlikely that this would not affect the dopamine system if endogenous testosterone does. Moreover, endogenous testosterone levels would have changed at the time of the experiment.…”

Section: Discussionmentioning

confidence: 84%

“…In the current study, we aim to test for a possible interaction of testosterone administration with the MAOA VNTR during a non-social frustration task in which we previously found that testosterone increased the affective response anger. Concerning previous findings on the task (Panagiotidis et al, 2017;Wagels et al, 2019b), we assume an increase of anger and increased joystick amplitudes during the frustration block across participants. We reanalyzed the data since we specifically wanted to test if the MAOA VNTR interacts with the exogenously modulated or endogenous testosterone levels in a non-social frustration context, which has not been tested before.…”

Section: Introductionmentioning

confidence: 79%

“…Finally, we observed that individuals who received a single dose of testosterone showed increased risk-taking if they were carriers of a MAOA variant associated with low activity (Wagels et al, 2017b ). In a social provocation task, those individuals showed higher anger paralleled by reduced brain activity in the cuneus during a social provocation task if they did not receive testosterone (Wagels et al, 2019b ). Here testosterone administration increased aggressive behavior independent of the MAOA variant in response to high provocation compared to low provocation (Wagels et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Single-Dose of Testosterone and the MAOA VNTR Polymorphism Influence Emotional and Behavioral Responses in Men During a Non-social Frustration Task

Wagels

Votinov

Hüpen

et al. 2020

Front. Behav. Neurosci.

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Previous studies suggest that testosterone and several neurotransmitters might interactively influence human aggression. The current study aimed to test potential interactions of a genetic variation linked to the catabolism of serotonin, dopamine, and norepinephrine and exogenous testosterone on the reaction towards non-social provocation. In total, 146 male participants were genotyped for a prominent polymorphism of the monoamine oxidase A (MAOA) gene resulting in a short and long variant. Participants completed a non-social frustration task after receiving either testosterone or a placebo gel in a double-blind setup. Participants performed a non-social frustration task, where they had to direct a virtually moving ball into a barrel by pulling a joystick (neutral block). During a frustration block, the joystick repeatedly did not respond to participants' reactions thereby causing failed trials to which participants reacted with increased anger and stronger pulling of the joystick. We analyzed the effect of testosterone administration on emotion and behavior in individuals who either carried a low (L) or high (H) activity MAOA variant. Testosterone administration increased provocation-related self-reported anger and abolished the association between trait aggression and joystick deflection in the frustration block. In MAOA-H carriers endogenous testosterone levels at baseline were associated with increased joystick deflection in both blocks. There was, however, no interaction of testosterone administration and genotype. Although preliminary, the results rather indicate independent influences of exogenous testosterone administration and MAOA, but support an interaction of endogenous testosterone levels and MAOA genetics in a frustration task. The administration of testosterone seems to act on the subjective emotional experience in a provoking situation, while endogenous testosterone levels increased pulling impulses only in carriers of the MAOA-H variant.

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“…MAO-A was initially recognized as a potential neuromodulator related to human psychiatric disorders. 22 Recently, emerging evidence has revealed that MAO-A plays a role in cancers by mediating the epithelial-mesenchymal transition, proliferation and invasion of cancer cells. 23,24 For example, in human neuroblastoma cells, higher levels of MAO-A results in increased basal ROS levels which promotes autophagy through Bcl-2 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

<p>Monoamine Oxidase A is a Major Mediator of Mitochondrial Homeostasis and Glycolysis in Gastric Cancer Progression</p>

Chen¹,

Li²,

Sun³

et al. 2020

CMAR

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Objective: Monoamine oxidase A (MAO-A) is a mitochondrial protein involved in tumourigenesis in different types of cancer. However, the biological function of MAO-A in gastric cancer development remains unknown. Methods: We examined MAO-A expression in gastric cancer tissues and in gastric cancer cell lines by immunohistochemistry and Western blot analyses. CCK8, FACS and bromodeoxyuridine incorporation assays were performed to assess the effects of MAO-A on gastric cancer cell proliferation. The role of MAO-A in mitochondrial function was determined through MitoSOX Red staining, ATP generation and glycolysis assays. Results: In the present study, we observed that MAO-A was significantly upregulated in gastric cancer tissues and in AGS and MGC803 cells. The observed MAO-A inhibition indicated decreased cell cycle progression and proliferation. Silencing MAO-A expression was associated with suppressed migration and invasion of gastric cancer cells in vitro. Moreover, alleviated mitochondrial damage in these cells was demonstrated by decreased levels of mitochondrial reactive oxygen species and increased ATP generation. MAO-A knockdown also regulated the expression of the glycolysis rate-limiting enzymes hexokinase 2 and pyruvate dehydrogenase. Finally, we observed that the glycolysis-mediated effect was weakened in AGS and MGC803 cells when MAO-A was blocked. Conclusion: The findings of the present study indicate that MAO-A is responsible for mitochondrial dysfunction and aerobic glycolysis, which in turn leads to the proliferation and metastasis of human gastric tumour cells.

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Exogenous testosterone and the monoamine-oxidase A polymorphism influence anger, aggression and neural responses to provocation in males

Cited by 29 publications

References 68 publications

Effects of exogenous testosterone application on network connectivity within emotion regulation systems

Effects of exogenous testosterone application on network connectivity within emotion regulation systems

Single-Dose of Testosterone and the MAOA VNTR Polymorphism Influence Emotional and Behavioral Responses in Men During a Non-social Frustration Task

<p>Monoamine Oxidase A is a Major Mediator of Mitochondrial Homeostasis and Glycolysis in Gastric Cancer Progression</p>

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