The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli.

Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports.

Progestogens' effects and mechanisms for object recognition memory across the lifespan.

This review explores the effects of female reproductive hormones, estrogens and progestogens, with a focus on progesterone and allopregnanolone, on object memory. Progesterone and its metabolites, in particular allopregnanolone, exert various effects on both cognitive and non-mnemonic functions in females. The well-known object recognition task is a valuable experimental paradigm that can be used to determine the effects and mechanisms of progestogens for mnemonic effects across the lifespan, which will be discussed herein.

The pregnane xenobiotic receptor, a prominent liver factor, has actions in the midbrain for neurosteroid synthesis and behavioral/neural plasticity of female rats.

A novel factor of interest for growth/plasticity in the brain is pregnane xenobiotic receptor (PXR). PXR is a liver factor known for its role in xenobiotic clearance and cholesterol metabolism. It is expressed in the brain, suggesting a potential role for plasticity, particularly involving cholesterol-based steroids and neurosteroids.

Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor.

Neurosteroids are cholesterol-based hormones that can be produced in the brain, independent of secretion from peripheral endocrine glands, such as the gonads and adrenals. A focus in our laboratory for over 25 years has been how production of the pregnane neurosteroid, allopregnanolone, is regulated and the novel (i.e.

Female mice with deletion of Type One 5α-reductase have reduced reproductive responding during proestrus and after hormone-priming.

The capacity to form progesterone (P₄)'s 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP; a.k.a.

Progesterone facilitates exploration, affective and social behaviors among wildtype, but not 5α-reductase Type 1 mutant, mice.

Progesterone (P4) facilitates exploration, anxiety and social behaviors in estrogen (E2)-primed mice. Some of these effects may be due to actions of its 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP). In order to address the role of P4 and its metabolite, 3α,5α-THP, a mouse model was utilized.

Progesterone, compared to medroxyprogesterone acetate, to C57BL/6, but not 5α-reductase mutant, mice enhances object recognition and placement memory and is associated with higher BDNF levels in the hippocampus and cortex.

Progesterone (P4) may influence cognition in part through actions of its 5α-reduced metabolite, allopregnanolone. Ovariectomized mice that were C57BL/6 wildtype (WT), or deficient in the 5α-reductase Type 1 enzyme (5α-reductase knockout; 5αRKO), were administered vehicle, P4, allopregnanolone, or medroxyprogesterone acetate (MPA) after training in the object recognition or placement tasks. WT mice administered P4 or allopregnanolone performed significantly better in the object recognition and placement tasks than did WT mice administered vehicle or MPA.

Motivated behaviors and levels of 3α,5α-THP in the midbrain are attenuated by knocking down expression of pregnane xenobiotic receptor in the midbrain ventral tegmental area of proestrous rats.

Introduction: Progesterone (P4 ) and its product, 5α-pregnan-3α-ol-20-one (3α,5α-THP), act in the midbrain ventral tegmental area (VTA) to alter motivated behaviors, such as mating, and motor and anxiety behavior. Of interest is whether 3α,5α-THP formation requires the pregnane xenobiotic receptor (PXR), which is expressed in the midbrain of rats.

Aim: The role of PXR in the midbrain for 3α,5α-THP formation, which precedes modulation of motivated behaviors, was investigated.

Type 1 5α-reductase may be required for estrous cycle changes in affective behaviors of female mice.

There are estrous cycle differences in affective behaviors of rodents that are generally attributed to cyclic variations in estradiol, progesterone (P) and its metabolites. A question is the role of the steroid metabolism enzyme, 5α-reductase, for these estrous cycle differences. To address the requirement of 5α-reductase, estrous cycle variations in the behavior of wildtype mice and their littermates that are deficient in the 5α-reductase type 1 enzyme (5αRKO mice) were examined.

Mnemonic effects of progesterone to mice require formation of 3alpha,5alpha-THP.

Ovarian hormones organize and activate neural circuits for reproduction and may also mediate cognition. Research has focused on estradiol's mnemonic effects, albeit progesterone covaries with estradiol and its mechanisms for cognition require attention. Studies tested the hypothesis that cognitive effects of progesterone occur subsequent to its metabolism to 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), which does not bind progestin receptors.

Trilostane exerts antidepressive effects among wild-type, but not estrogen receptor [beta] knockout mice.

Women with estrogen receptor (ER) positive breast cancer, who are treated with the ER blocker, tamoxifen, have an increased risk of depression. Trilostane, a 3b-hydroxysteroid dehydrogenase inhibitor, is now being used to treat tamoxifen-insensitive breast cancer. In-vitro assays show that trilostane may have actions through ERb.

Estradiol or diarylpropionitrile decrease anxiety-like behavior of wildtype, but not estrogen receptor beta knockout, mice.

Clinical and basic studies demonstrate that estrogen (E-sub-2)-based therapies influence anxiety and mood, but the receptor targets (e.g., a or ss isoform of the estrogen receptor, ER) for these effects requires further investigation.

Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice.

Testosterone (T) and its metabolites may underlie some beneficial effects for anxiety and cognition, but the mechanisms for these effects are unclear. T is reduced to dihydrotestosterone (DHT), which can be converted to 5alpha-androstane,3alpha,17beta-diol (3alpha-diol) and/or 5alpha-androstane-3beta,17beta-diol (3beta-diol). Additionally, T can be converted to androstenedione, and then to androsterone.

Estradiol or diarylpropionitrile administration to wild type, but not estrogen receptor beta knockout, mice enhances performance in the object recognition and object placement tasks.

Cognitive processes mediated by the hippocampus and cortex are influenced by estradiol (E(2)); however, the mechanisms by which E(2) has these effects are not entirely clear. As such, studies were conducted to begin to address the role of actions at the beta form of the intracellular estrogen receptor (ERbeta) for E(2)'s cognitive effects in adult female mice. We investigated whether E(2) improved performance of wild type (WT) and ERbeta knockout (betaERKO) mice in tasks considered to be mediated by the cortex and hippocampus, the object recognition and object placement tasks.