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.
Highlights
Berthold first reported the masculinizing effects of a bloodborne “substance” produced by the testes in male chicks [1]
Numerous studies examining the effects of gonadectomy (GDX), androgen receptor (AR) antagonists, androgen synthesis inhibitors, androgen replacement, and administration of supraphysiological amounts of androgens [i.e., anabolic-androgenic steroids (AAS)] demonstrate that androgens are critical for reproductive behavior [reviewed in Ref. [7]] and aggressive behavior [reviewed in Ref. [8, 9]]
By adding a Tyramide Signal Amplification (TSA) step in the immunohistochemistry protocol, we recently showed that AR protein immunoreactivity (AR-ir) cells are present in the ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) [(33); Figures 3 and 4]
Summary
Berthold first reported the masculinizing effects of a bloodborne “substance” produced by the testes in male chicks [1]. In the last section, we review preclinical and clinical studies demonstrating that GDX, AAS, and perhaps local production of androgens influence executive functions such as behavioral flexibility and inhibitory control. No studies have examined ZIP9 or GPRC6A in mesocorticolimbic nodes, and whole-brain analyses have not reported either transcript in the VTA, NAc, or mPFC in mice [58, 59] or humans [40].
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