Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain

Abstract

Rationale: Adolescence is a developmental period of complex neurobiological change and heightened vulnerability to psychiatric illness. As a result, understanding factors such as sex and stress hormones which drive brain changes in adolescence, and how these factors may influence key neurotransmitter systems implicated in psychiatric illness, is paramount.

Objectives: In this review, we outline the impact of sex and stress hormones at adolescence on dopamine neurotransmission, a signaling pathway which is critical to healthy brain function and has been implicated in psychiatric illness. We review normative developmental changes in dopamine, sex hormone, and stress hormone signaling during adolescence and throughout postnatal life, then highlight the interaction of sex and stress hormones and review their impacts on dopamine neurotransmission in the adolescent brain.

Results and conclusions: Adolescence is a time of increased responsiveness to sex and stress hormones, during which the maturing dopaminergic neural circuitry is profoundly influenced by these factors. Testosterone, estrogen, and glucocorticoids interact with each other and have distinct, brain region-specific impacts on dopamine neurotransmission in the adolescent brain, shaping brain maturation and cognitive function in adolescence and adulthood. Some effects of stress/sex hormones on cortical and subcortical dopamine parameters bear similarities with dopaminergic abnormalities seen in schizophrenia, suggesting a possible role for sex/stress hormones at adolescence in influencing risk for psychiatric illness via modulation of dopamine neurotransmission. Stress and sex hormones may prove useful targets in future strategies for modifying risk for psychiatric illness.

Fig. 1

Dopamine signaling in the brain, and the production of glucocorticoid, androgenic, and estrogenic steroids by the HPA and HPG axes. Darker and lighter shading indicate superficial and deep structures, respectively. Abbreviations: HPA hypothalamic-pituitary-gonadal, HPA hypothalamic-pituitary-adrenal, PFC prefrontal cortex, NAc nucleus accumbens, VTA ventral tegmental area, SN substantia nigra, CRH corticotropin-releasing hormone, AVP arginine vasopressin, ACTH adrenocorticotropic hormone, GnRH gonadotropin-releasing hormone, LH luteinizing hormone, FSH follicle-stimulating hormone, TH tyrosine hydroxylase, L-DOPA L-3,4-dihydroxyphenylalanine, AAAD aromatic l-amino acid decarboxylase, MAOA/B monoamine oxidase A/B, COMT catechol-O-methyl transferase, DOPAC dihydroxyphenylacetic acid, 3-MT 3-methoxytyramine, HVA homovanillic acid

Fig. 2

a–c Developmental changes in expression of mRNA transcripts and proteins in the dopamine and stress signaling pathways in the human PFC. Dollar sign, molecules whose protein abundance is plotted; asterisk, molecules whose mRNA transcript abundance (confirmed by qPCR) is plotted; ampersand, unpublished microarray data (Weickert et al., unpublished). Abbreviations: TH tyrosine hydroxylase, MAOA/B monoamine oxidase A/B, DR dopamine receptor, AR androgen receptor, ER estrogen receptor, GR glucocorticoid receptor. Data drawn from Gunnar et al. (2009), Kiess et al. (1995), Naninck et al. (2011), Rothmond et al. (2012), Sinclair et al. (2011), and Sippell et al. (1980)

Fig. 3

Summary of the effects of stress and sex hormones on dopaminergic signaling in the PFC and striatum. For comparison purposes, dopamine abnormalities found in schizophrenia are also presented. References and details of summarized studies are described in the text and Table 1. Black arrows within shaded boxes indicate findings in adolescents, thick white arrows indicate findings made in young adults or adults that have yet to be demonstrated in adolescents, and thick purple arrows indicate findings in schizophrenia. Number sign, stress effects seen in disrupted in schizophrenia 1 (DISC1) mutant mice but not wild-type mice in the same chronic isolation stress paradigm. For immunohistochemistry images, white arrowheads indicate cells immunoreactive for both steroid receptors and TH, arrows indicate cells immunoreactive for TH only, and stars indicate cells immunoreactive for steroid receptors only. Scale bars represent 40 μm. Images provided by Owens and Purves-Tyson (unpublished). Abbreviations: PFC prefrontal cortex, NAc nucleus accumbens, SN substantia nigra, VTA ventral tegmental area, AS acute stress, CS chronic stress, H human, P primate, R rodent, AD adolescent, YA young adult, A adult, DR dopamine receptor, DAT dopamine transporter, MAOA monoamine oxidase A, TH tyrosine hydroxylase, WM working memory