Androgen Regulation of the Mesocorticolimbic System and Executive Function

Abstract

Multiple lines of evidence indicate that androgens, such as testosterone, modulate the mesocorticolimbic system and executive function. This review integrates neuroanatomical, molecular biological, neurochemical, and behavioral studies to highlight how endogenous and exogenous androgens alter behaviors, such as behavioral flexibility, decision making, and risk taking. First, we briefly review the neuroanatomy of the mesocorticolimbic system, which mediates executive function, with a focus on the ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Second, we present evidence that androgen receptors (AR) and other steroid receptors are expressed in the mesocorticolimbic system. Using sensitive immunohistochemistry and quantitative polymerase chain reaction (qPCR) techniques, ARs are detected in the VTA, NAc, mPFC, and OFC. Third, we describe recent evidence for local androgens (“neuroandrogens”) in the mesocorticolimbic system. Steroidogenic enzymes are expressed in mesocorticolimbic regions. Furthermore, following long-term gonadectomy, testosterone is nondetectable in the blood but detectable in the mesocorticolimbic system, using liquid chromatography tandem mass spectrometry. However, the physiological relevance of neuroandrogens remains unknown. Fourth, we review how anabolic-androgenic steroids (AAS) influence the mesocorticolimbic system. Fifth, we describe how androgens modulate the neurochemistry and structure of the mesocorticolimbic system, particularly with regard to dopaminergic signaling. Finally, we discuss evidence that androgens influence executive functions, including the effects of androgen deprivation therapy and AAS. Taken together, the evidence indicates that androgens are critical modulators of executive function. Similar to dopamine signaling, there might be optimal levels of androgen signaling within the mesocorticolimbic system for executive functioning. Future studies should examine the regulation and functions of neurosteroids in the mesocorticolimbic system, as well as the potential deleterious and enduring effects of AAS use.

Exogenous testosterone increases status-seeking motivation in men with unstable low social status

“…Furthermore, testosterone's influence on motivation might result via actions on the dopaminergic system. Research in rats have shown high density androgen receptors on dopaminergic neurons in mesolimbic areas (Creutz and Kritzer, 2004), and exogenous testosterone to increase dopamine synthesis and release (de Souza Silva et al, 2009;Purves-Tyson et al, 2014), and discount effort for high reward (Tobiansky et al, 2018). Moreover, in humans, dopamine receptor availability in the ventral striatum is correlated with status in humans (Martinez et al, 2010).…”

Testicular hormones mediate robust sex differences in impulsive choice in rats

“…Consistent with the absence of estrous cycle effects on choice behavior, ovariectomies did not alter task performance, suggesting that if ovarian hormones contribute to the greater impulsive choice observed in females, their effects may be organizational rather than activational. Alternatively, local androgen synthesis in the brain ( Tobiansky et al, 2018 ) might compensate for loss of circulating ovarian hormones to allow maintenance of pre-surgical patterns of choice behavior in females.…”

Androgenic Morality? Associations of sex, oral contraceptive use and basal testosterone levels with moral decision making

“…These mesocorticolimbic structures are crucial for decision making with dopamine signaling playing a key role for various executive functions (overview: Klein et al, 2019;Logue and Gould, 2014). Congruently, androgens have been shown to modulate structure and neurochemistry of the mesocorticolimbic system including dopamine signaling and thus to influence executive functions (review: Tobiansky et al, 2018b). In addition, aromatase the enzyme that converts testosterone to estradiolis expressed in mesocorticolimbic regions (Tobiansky et al, 2018a) and estrogen receptors have been found in the VTA, NAc and mPFC (Perez et al, 2003).…”