Effect of adolescent androgen manipulation on psychosis-like behaviour in adulthood in BDNF heterozygous and control mice

Du, X., McCarthny, C.R., Notaras, M., van den Buuse, M., and Hill, R.A. (2019) Effect of adolescent androgen manipulation on psychosis-like behaviour in adulthood in BDNF heterozygous and control mice. Hormones and Behavior, 112. pp. 32-41.

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Rationale: Males are more prone to psychosis, schizophrenia and substance abuse and addiction in adolescence and early adulthood than females. However, the role of androgens during this developmental period is poorly understood.

Objectives: This study aimed to examine how androgens in adolescence influence psychosis-like behaviour in adulthood and whether brain-derived neurotrophic factor (BDNF) is a mediator of these developmental effects.

Methods: Wild-type and BDNF heterozygous male mice were castrated at pre-pubescence and implanted with testosterone or dihydrotestosterone (DHT). In adulthood, we assessed amphetamine- and MK-801-induced hyperlocomotion as a model of psychosis-like behaviour. Western blot analysis was used to quantify levels of the dopamine transporter (DAT) and N-methyl-D-aspartate (NMDA) receptor subunits.

Results: While castration itself had little effect on behaviour, adolescent testosterone, but not DHT, significantly reduced amphetamine-induced hyperlocomotion, whereas both testosterone and DHT reduced the effect of MK-801. These effects were similar in mice of either genotype. In wildtype mice, both testosterone and DHT treatment reduced DAT expression in the medial prefrontal cortex (mPFC) but these effects were absent in BDNF heterozygous mice. There were no effects on NMDA receptor subunit levels.

Conclusions: The differential effect of adolescent testosterone and DHT on amphetamine-induced hyperlocomotion in adulthood suggests involvement of conversion of testosterone to estrogen and subsequent modulation of dopaminergic signalling. In contrast, the similar effect of testosterone and DHT treatment on NMDA receptor-mediated hyperlocomotion indicates it is mediated by androgen receptors. The involvement of BDNF in these hormone effects remains to be elucidated. These results demonstrate that, during adolescence, androgens significantly influence key pathways related to various mental illnesses prevalent in adolescence.

Item ID: 61812
Item Type: Article (Research - C1)
ISSN: 1095-6867
Keywords: androgen, brain-derived neurotrophic factor, dopaminergic pathway, glutamatergic pathway, schizophrenia
Copyright Information: © 2019 Elsevier Inc. All rights reserved.
Funders: NHMRC, NHMRC-ARC, University of Melbourne (UM), Brain and Behavior Research Foundation, USA (BBRF)
Projects and Grants: NHMRC grant 1044887, NHMRC-ARC DementiaResearch Development Fellowship, UM APA scholarship, NHMRC Senior Research Fellowship, BBRF NARSAD Young Investigator Award (grant#22997), NHMRC Career Development Fellowship
Date Deposited: 24 May 2020 19:11
FoR Codes: 52 PSYCHOLOGY > 5202 Biological psychology > 520202 Behavioural neuroscience @ 100%
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