Anxiolytic-like actions of testosterone in the burying behavior test: role of androgen and GABA-benzodiazepine receptors

Fernández‐Guasti, Alonso; Martı́nez-Mota, Lucı́a

doi:10.1016/j.psyneuen.2005.03.006

Cited by 118 publications

(83 citation statements)

References 33 publications

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“…In addition to binding to ERβ, 3α-diol also binds to GBRs to produce anxiolytic-like effects (Gee 1988). Furthermore, androsterone binds only to GBRs (Fernández-Guasti and Martínez-Mota 2005), and may produce anti-anxiety effects similar to 3α-diol in the EPM. However, activation of GBRs is often associated with an amnestic-like decline in cognitive abilities (Maubach 2003); since 3α-diol both decreased anxiety-like behavior and increased cognition, it is unlikely that its anti-anxiety effects were through activation of GBRs.…”

Section: Discussionmentioning

confidence: 99%

“…However, activation of GBRs is often associated with an amnestic-like decline in cognitive abilities (Maubach 2003); since 3α-diol both decreased anxiety-like behavior and increased cognition, it is unlikely that its anti-anxiety effects were through activation of GBRs. Additionally, other studies have shown that attenuation of ERβ with antisense oligonucleotides eliminates both the cognitive and anxiolytic-like benefits associated with 3α-diol (Edinger and Frye 2007a anti-anxiety effects, which are attenuated with the administration of flumazenil, which antagonizes GBRs Fernández-Guasti and Martínez-Mota 2005). Furthermore, other studies have indicated that antagonizing GBRs in the presence of testosterone proprionate, which can be metabolized to androsterone, does not effect anxiolytic-like behavior (Fernández-Guasti and Martínez-Mota 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Drugs were chosen for their varying affinity for different substrates. 3α-diol binds to both ERβ and GBRs (Gee et al 1988), 3β-diol binds just to ERβ (Edinger and Frye 2007a), while androsterone will bind to GBRs (Fernández-Guasti and Martínez-Mota 2005). Radioimmunoassay (RIA) has confirmed that silastic implants provide a continuous amount of hormone to the animal, to produce circulating and brain levels that are comparable to physiological concentrations in intact male rats (Edinger and Frye 2006).…”

Section: Androgen Administrationmentioning

confidence: 99%

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Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats

Osborne

Edinger

Frye

2009

AGE

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Androgen levels decline with aging. Some androgens may exert anti-anxiety and cognitiveenhancing effects; however, determining which androgens have anxiolytic-like and/or mnemonic effects is of interest given the different mechanisms that may underlie some of their effects. For example, the 5α-reduced metabolite of testosterone (T), dihydrotesterone, can be further converted to 5α-androstane,17β-diol-3α-diol (3α-diol) and 5α-androstane,17β-diol-3β-diol (3β-diol), both of which bind with high affinity to the beta isomer of the intracellular estrogen receptor beta (ERβ).However, androsterone, another metabolite of T, does not bind well to ERβ. To investigate the effects of T metabolites, male rats were subjected to gonadectomy then implanted with silastic capsules of 3α-diol, 3β-diol, androsterone, or oil control. After recovery, the rats were tested in elevated plus maze (EPM), light/dark transition (LD), and Morris water maze (MWM). 3α-diol both decreased anxietylike behavior in the EPM and LD, and increased cognition in MWM, while 3β-diol improved cognition in MWM, but had no effects on anxiety behavior, compared to vehicle or androsterone. These data suggest that the actions of 3α-diol and 3β-diol at ERβ may be responsible for some of testosterone's anti-anxiety and cognitive-enhancing effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Androgen Administrationmentioning

confidence: 99%

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Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats

Osborne

Edinger

Frye

2009

AGE

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“…For example, 3α-Diol is a neuroactive steroid, and like other 3α tetrahydrosteroids, is a potent allosteric modulator of GABAa receptors. As a result, 3α-Diol has been implicated in the regulation of a number of different behaviors (Rupprecht and Holsboer, 1999, Rosellini et al, 2001, Fernandez-Guasti and Martinez-Mota 2005, Reddy, 2004. In contrast, 3β-Diol cannot bind the benzodiazepine receptor (unpublished) but, if its actions are similar to other 3β-tetrahydrosteroids, it may be an antagonist of 3α-tetrahydrosteroids at the GABAa receptor (Steckelbroeck et al 2004).…”

Section: Androgen Metabolismmentioning

confidence: 99%

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

Handa

Pak

Kudwa

et al. 2008

Hormones and Behavior

184

122

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The complexity of gonadal steroid hormone actions is reflected in their broad and diverse effects on a host of integrated systems including reproductive physiology, sexual behavior, stress responses, immune function, cognition, and neural protection. Understanding the specific contributions of androgens and estrogens in neurons that mediate these important biological processes is central to the study of neuroendocrinology. Of particular interest in recent years has been the biological role of androgen metabolites. The goal of this review is to highlight recent data delineating the specific brain targets for the dihydrotestosterone metabolite, 5α-androstane, 3β, 17β-diol (3β-Diol). Studies using both in vitro and in vivo approaches provide compelling evidence that 3β-Diol is an important modulator of the stress response mediated by the hypothalmo-pituitary-adrenal axis. Further, the actions of 3β-Diol are mediated by estrogen receptors, and not androgen receptors, often through a canonical estrogen response element in the promoter of a given target gene. These novel findings compel us to re-evaluate the interpretation of past studies and the design of future experiments aimed at elucidating the specific effects of androgen receptor signaling pathways.

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“…Fernandez-Guasti and Martinez-Mota [84], using burying behavior to measure anxiolysis, found that while testosterone reduced anxiety in castrated male rats, two 3α, 5α-reduced metabolites of testosterone (3α-androstanediol and androsterol) did not. Moreover, while flutamide (an androgen receptor blocker) blocked the anxiolytic effects of testosterone, flumazenil (a GABA A receptor blocker) did not.…”

Section: Anxiolysismentioning

confidence: 99%

Reflexive testosterone release: A model system for studying the nongenomic effects of testosterone upon male behavior

Nyby

2008

Frontiers in Neuroendocrinology

100

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Male mammals of many species exhibit reflexive testosterone release in mating situations. In house mice (Mus musculus), the dramatic robustness of such release, occurring primarily in response to a novel female, suggests some function. The resulting testosterone elevations typically peak during copulatory behavior and may serve to activate transitory motivational and physiological responses that facilitate reproduction. However, such a function requires that testosterone be working through either nongenomic, or very quick genomic, mechanisms. The first part of the review describes reflexive sex hormone release in house mice. The second part summarizes research implicating testosterone's fast actions in affecting anxiety, reward, learning, analgesia, and penile reflexes in rodents, all of which could optimize male mating success. The review concludes with a speculative model of how spontaneous and reflexive hormone release might interact to regulate reproductive behavior and why mice appear to be an ideal species for examining testosterone's quick effects.

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Anxiolytic-like actions of testosterone in the burying behavior test: role of androgen and GABA-benzodiazepine receptors

Cited by 118 publications

References 33 publications

Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats

Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

Reflexive testosterone release: A model system for studying the nongenomic effects of testosterone upon male behavior

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