Testosterone's anti-anxiety and analgesic effects may be due in part to actions of its 5α-reduced metabolites in the hippocampus

Edinger, Kassandra L.; Frye, Cheryl A.

doi:10.1016/j.psyneuen.2004.11.001

Cited by 134 publications

(103 citation statements)

References 89 publications

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“…As such, in our laboratory, we have used gonadectomized adult male rodents, which have their primary endogenous sources of androgens, such as testosterone and its metabolite (i.e., 3a-androstanediol, a neurosteroid that is a positive modulator of GABA A receptors), the testes, removed (2 ± 1 s spent on the open arms of the plus maze), as negative controls. Androgen-replete rodents, those that are gonadally intact (28 ± 6 s) or gonadectomized and replaced with testosterone (4 mg kg À1 subcutaneously; 36 + 5 s, which produces physiological circulating testosterone and 3a-androstanediol levels) serve as positive controls 40,41 . PROCEDURE 1| Make sure maze is cleaned and dried before use and that video-tracking system is ready to be used.…”

Section: Methodsmentioning

confidence: 99%

“…We have used single exposure to the elevated plus maze with success to determine response to novelty/anxiety behavior of rodents in different hormone conditions to determine the antianxiety effects of steroid hormones, such as estrogen, progestins and androgens 22,[40][41][42][43][44][45][46][47][48][49][50] . The materials, methods and typical results obtained are as follows.…”

Section: Predictive Validity Of the Elevated Plus Mazementioning

confidence: 99%

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The use of the elevated plus maze as an assay of anxiety-related behavior in rodents

2007

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The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an open arm, and entries/duration in each arm are recorded by a video-tracking system and observer simultaneously for 5 min. Other ethological parameters (i.e., rears, head dips and stretchedattend postures) can also be observed. An increase in open arm activity (duration and/or entries) reflects anti-anxiety behavior. In our laboratory, rats or mice are exposed to the plus maze on one occasion; thus, results can be obtained in 5 min per rodent. INTRODUCTIONThe elevated plus maze has been described as a simple method for assessing anxiety responses of rodents by File and co-workers 1 . A task, using a Y-shaped apparatus that included an elevated open alley, which produced a strong approach-avoidance conflict, and an enclosed alley, which did not, was first described by Montgomery 2 . This task was modified into an elevated maze with four arms (two open and two enclosed) that are arranged to form a plus shape and was described by Handley and Mithani 3 . These authors described the assessment of anxiety behavior of rodents by using the ratio of time spent on the open arms to the time spent on the closed arms. Unlike other behavioral assays used to assess anxiety responses that rely upon the presentation of noxious stimuli (i.e., electric shock, food/water deprivation, loud noises, exposure to predator odor, etc.) that typically produce a conditioned response, the elevated plus maze relies upon rodents' proclivity toward dark, enclosed spaces (approach) and an unconditioned fear of heights/open spaces (avoidance) 4 .There is great diversity in possible applications of the elevated plus maze. To name a few, prescreening of newly developed pharmacological agents for treatment of anxiety-related disorders can be carried out. The anxiolytic and anxiogenic effects of pharmacological agents, drugs of abuse and hormones can be investigated. The effects of reproductive senescence/aging and/or pre-, peri-or postnatal exposure to various stressors can be assessed. Furthermore, beyond its utility as a model to detect anxiolytic effects of benzodiazepine-related compounds, the elevated plus maze can be used as a behavioral assay to study the brain sites (e.g., limbic regions, hippocampus, amygdala, dorsal raphe nucleus, etc. 5,6 ) and mechanisms (e.g., GABA, glutamate, serotonin, hypothalamic-pituitary-adrenal axis neuromodulators, etc. 1,3,[7][8][9][10][11][12] ) underlying anxiety behavior. Indeed, the elevated plus maze has been used as a model of state, unconditioned anxiety for over two decades, and there are now over 2,000 papers related to this topic. Because a lengthy discussion of these key findings is beyond the scope of this protocol, readers are referred to several excellent an...

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Section: Methodsmentioning

confidence: 99%

Section: Predictive Validity Of the Elevated Plus Mazementioning

confidence: 99%

The use of the elevated plus maze as an assay of anxiety-related behavior in rodents

2007

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“…Testing occurred in a single room, in a sequential manner, with no breaks between individual tasks (other than time needed to clean apparatus and move rats from one task to the next). Although, it is possible that exposure to prior tests may influence performance in subsequent tasks, previous reports comparing males tested in a battery of anxiety tasks versus individual anxiety tasks did not reveal differences on behavioral or endocrine (5α-reduced androgens) measures [35]. It took approximately 45-50 min for each rat to be tested through the battery described below.…”

Section: Behavioral Testingmentioning

confidence: 99%

Infusions of 3α,5α-THP to the VTA enhance exploratory, anti-anxiety, social, and sexual behavior and increase levels of 3α,5α-THP in midbrain, hippocampus, diencephalon, and cortex of female rats

Frye

Rhodes

2008

Behavioural Brain Research

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Abstract17β-Estradiol (E 2 ) and progesterone (P 4 ) influence the onset and duration of sexual behavior and are also associated with changes in behaviors that may contribute to mating, such as exploration, anxiety, and social behaviors (socio-sexual behaviors). In the midbrain ventral tegmental area (VTA), the P 4 metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), modulates lordosis of E 2 -primed rodents; 3α,5α-THP can also influence anxiety and social behaviors. To examine if 3α,5α-THP in the VTA mediates socio-sexual behaviors, we infused 3α,5α-THP to the VTA of diestrous and proestrous rats. As expected, proestrous, compared to diestrous, rats showed more exploratory (open field), anxiolytic (elevated plus maze), pro-social (partner preference, social interaction), and sexual (paced mating) behavior and had increased E 2 , P 4 , dihydroprogesterone (DHP), and 3α,5α-THP in serum, midbrain, hippocampus, diencephalon, and cortex. Infusions of 3α,5α-THP to the VTA, but not control sites, such as the substantia nigra (SN) or central grey (CG), of diestrous rats produced behavioral and endocrine effects akin to that of proestrous rats and increased DHP and 3α,5α-THP levels in midbrain, hippocampus, and diencephalon. Levels of DHP and 3α,5α-THP, but neither E 2 nor P 4 concentrations, in midbrain, hippocampus, diencephalon, and/or cortex were positively correlated with socio-sexual behaviors. Thus, 3α,5α-THP infusions to the VTA, but not SN or CG, can enhance socio-sexual behaviors and increase levels in midbrain, hippocampus, and diencephalon.

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“…2,3 Recently, several reports have described that the pharmacological doses of testosterone (T) and its metabolite, 5α-androstane-3α,17β-diol (3α,5α-Adiol), elicit anesthetic and anxiolytic effects in animal models. 4,5 3α,5α-Adiol is structurally similar to AP (both are 3α-hydroxy-5α-reduced steroids), so it also has an allosteric activity at the GABAA receptors. 5 Thus, 3α,5α-Adiol can play a key physiological role in mediating the effect of T on the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 3α,5α-Adiol is structurally similar to AP (both are 3α-hydroxy-5α-reduced steroids), so it also has an allosteric activity at the GABAA receptors. 5 Thus, 3α,5α-Adiol can play a key physiological role in mediating the effect of T on the central nervous system. AP and related neurosteroids in the brain have been recently measured by liquid chromatography (LC)-mass spectrometry (MS) coupled with electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) due to its selectivity, versatility and simultaneous multi-analyte quantification capability.…”

Section: Introductionmentioning

confidence: 99%

Studies on Neurosteroids XXI: An Improved Liquid Chromatography–Tandem Mass Spectrometric Method for Determination of 5α-Androstane-3α,17β-diol in Rat Brains

et al. 2007

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A sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS/MS) method for the determination of the rat brain 5α-androstane-3α,17β-diol (3α,5α-Adiol) has been developed and validated. The brain extract was purified using solid-phase extraction cartridges, derivatized with isonicotinoyl azide, and subjected to LC-MS/MS. The method was accurate and reproducible, and the limit of quantitation was 0.1 ng/g tissue when a 100-mg tissue sample was used. The change in the brain 3α,5α-Adiol level by immobilization stress was also analyzed using the developed method.

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Testosterone's anti-anxiety and analgesic effects may be due in part to actions of its 5α-reduced metabolites in the hippocampus

Cited by 134 publications

References 89 publications

The use of the elevated plus maze as an assay of anxiety-related behavior in rodents

The use of the elevated plus maze as an assay of anxiety-related behavior in rodents

Infusions of 3α,5α-THP to the VTA enhance exploratory, anti-anxiety, social, and sexual behavior and increase levels of 3α,5α-THP in midbrain, hippocampus, diencephalon, and cortex of female rats

Studies on Neurosteroids XXI: An Improved Liquid Chromatography–Tandem Mass Spectrometric Method for Determination of 5α-Androstane-3α,17β-diol in Rat Brains

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