5α-reduced androgens may have actions in the hippocampus to enhance cognitive performance of male rats

Frye, Cheryl A.; Edinger, Kassandra L.; Seliga, Angela; Wawrzycki, JoAnna M

doi:10.1016/j.psyneuen.2003.10.004

Cited by 87 publications

(72 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In rodents, gonadectomy (GDX) decreases cognitive performance of male rats (Ceccarelli & Scaramuzzino, 2001;Frye & Seliga, 2001). Androgen replacement to GDX rats restores performance in the inhibitory avoidance Frye, Edinger, Seliga, & Wawrzycki, 2004;Frye & Seliga, 2001), object recognition tasks (Ceccarelli & Scaramuzzino, 2001), and conditioned contextual fear tasks (Edinger, Lee, & Frye, 2004). These findings suggest that androgen-depletion causes deficits in cognitive performance which can be ameliorated through T-replacement.…”

Section: Introductionmentioning

confidence: 92%

Androgens’ effects to enhance learning may be mediated in part through actions at estrogen receptor-β in the hippocampus

Edinger

Frye

2007

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

Testosterone (T) may enhance cognitive performance. However, its mechanisms are not well understood. First, we hypothesized that if T's effects are mediated in part through actions of its 5α-reduced metabolites, dihydrotestosterone (DHT) and/or 3α-androstanediol (3α-diol) in the hippocampus, then T, DHT, and 3α-diol-administration directly to the hippocampus should enhance learning and memory in the inhibitory avoidance task. In order to test this hypothesis, gonadectomized (GDX) male rats were administered T, DHT, or 3α-diol via intrahippocampal inserts immediately following training in the inhibitory avoidance task. We found that T tended to increase, and DHT and 3α-diol significantly increased, performance in the inhibitory avoidance task compared to vehicle-administered GDX rats. Second, we hypothesized that, if androgens' effects are due in part to actions of 3α-diol in the hippocampus, then systemic or intrahippocampal administration of 3α-diol should significantly enhance cognitive performance of GDX male rats. Third, we hypothesized that, if androgen metabolites can have actions at estrogen receptors (ERs) in the hippocampus, then administration of ER antisense oligonucleotides (AS-ODNs) directly to the hippocampus of GDX, 3α-diol replaced, rats would decrease learning in the inhibitory avoidance task. We found that intrahippocampal administration of AS-ODNs for ERβ, but not ERα, significantly decreased learning and memory of 3α-diol replaced rats. Together, these findings suggest that T's effects to enhance learning and memory may take place, in part, through actions of its metabolite, 3α-diol, at ERβ in the dorsal hippocampus.

show abstract

Section: Introductionmentioning

confidence: 92%

Androgens’ effects to enhance learning may be mediated in part through actions at estrogen receptor-β in the hippocampus

Edinger

Frye

2007

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

show abstract

“…The major disadvantage is that the protocol appears to be not suitable for analysis of very low or physiological concentrations of 3α-androstanediol. This problem can be partly rectified by several approaches, including the use of analysis by difference approach to estimate the normal levels of 3α-androstanediol to those previously reported (Frye et al, 2004). There are several better alternatives to improve the sensitivity such as extraction of a large volume of plasma, injection of a large aliquot into the HPLC column, and reconstitution of the sample extract into a smaller volume of HPLC mobile phase to increase the analyte concentration.…”

Section: Advantages and Limitations Of 3α-androstanediol Assaymentioning

confidence: 99%

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Reddy¹

2008

Neurochemistry International

View full text Add to dashboard Cite

Steroid hormones play a key role in the pathophysiology of several brain disorders. Testosterone modulates neuronal excitability, but the underlying mechanisms are obscure. There is emerging evidence that testosterone-derived "androgenic neurosteroids", 3α-androstanediol and 17β-estradiol, mediate the testosterone effects on neural excitability and seizure susceptibility. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17β-estradiol. Reduction of testosterone by 5α-reductase generates 5α-dihydrotestosterone, which is then converted to 3α-androstanediol, a powerful GABA A receptormodulating neurosteroid with anticonvulsant properties. Although the 3α-androstanediol is an emerging neurosteroid in the brain, there is no specific and sensitive assay for determination of 3α-androstanediol in biological samples. This article describes the development and validation of mass spectrometric assay of 3α-androstanediol, and the molecular mechanisms underlying the testosterone modulation of seizure susceptibility. A liquid chromatography-tandem mass spectrometry assay to measure 3α-androstanediol is validated with excellent linearity, specificity, sensitivity, and reproducibility. Testosterone modulation of seizure susceptibility is demonstrated to occur through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. The proconvulsant effect of testosterone is associated with increases in plasma 17β-estradiol concentrations. The 5α-reduced metabolites of testosterone, 5α-dihydrotestosterone and 3α-androstanediol, had powerful anticonvulsant activity. Overall, the testosterone-derived neurosteroids 3α-androstanediol and 17β-estradiol could contribute to the net cellular actions of testosterone in the brain. Because 3α-androstanediol is a potent positive allosteric modulator of GABA A receptors, it could serve as an endogenous neuromodulator of neuronal excitability in men. The 3α-androstanediol assay is an important tool in this area because of the growing interest in the potential to use adjuvant aromatase inhibitor therapy to improve treatment of epilepsy.

show abstract

“…some circumstances, improve PA memory in rats (Frye and Lacey 2001;Frye et al 2004). Also, in adult male rats, systemic DHT treatment reverses castration-induced impairment in PA memory (Frye and Seliga 2001).…”

Section: Discussionmentioning

confidence: 94%

Testosterone and dihydrotestosterone differentially improve cognition in aged female mice

Benice¹,

Raber²

2009

Learn. Mem.

View full text Add to dashboard Cite

Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to 24-mo-old gonadally intact female mice treated for 6 wk with silastic capsules containing either testosterone (T) or dihydrotestosterone (DHT) or empty capsules (placebo). Compared with placebo-treated mice, spatial memory retention in the water maze was enhanced by testosterone treatment, but not DHT treatment. In contrast, DHT treatment improved passive avoidance (PA) retention, while T treatment only did so marginally. These data support that androgen supplementation in old female mice improves cognitive performance differentially depending upon the type of hormone treatment and cognitive task.

show abstract

5α-reduced androgens may have actions in the hippocampus to enhance cognitive performance of male rats

Cited by 87 publications

References 45 publications

Androgens’ effects to enhance learning may be mediated in part through actions at estrogen receptor-β in the hippocampus

Androgens’ effects to enhance learning may be mediated in part through actions at estrogen receptor-β in the hippocampus

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Testosterone and dihydrotestosterone differentially improve cognition in aged female mice

Contact Info

Product

Resources

About