Progestins mediate the onset and duration of lordosis, the mating posture of female rodents, through actions in the hypothalamus and ventral tegmental area. In the hypothalamus, progesterone has traditional, "genomic" actions via intracellular progestin receptors. In the ventral tegmental area, 3α-hydroxy-5α-pregnan-20-one has "non-genomic" actions independent of progestin receptors to facilitate lordosis that involve GABA A /benzodiazepine receptors, NMDA type glutamate receptors, and/or dopamine receptors. 3α-Hydroxy-5α-pregnan-20-one levels also change with behavioral and/ or environmental stimuli and may have a role in other reproductively-relevant behaviors, such as affiliation, exploration, and anxiety (socio-sexual behaviors). Data are reviewed that support the notion that: 1) effects of 3α-hydroxy-5α-pregnan-20-one in the midbrain ventral tegmental area facilitate lordosis and other reproductively-relevant behaviors. 2) 3α-Hydroxy-5α-pregnan-20-one, formed in the ventral tegmental area from metabolism of progestins, produced peripherally by endocrine glands, or centrally from biosynthesis in glial cells mediates socio-sexual behaviors. 3) 3α-Hydroxy-5α-pregnan-20-one's actions at GABA A /benzodiazepine receptors, NMDA type glutamate receptors, and dopamine receptors in the ventral tegmental area are important for lordosis; however, effects at these substrates on socio-sexual behaviors have not been elucidated. Given 3α-hydroxy-5α-pregnan-20-one's involvement in stress responses, its putative role as a homeostatic regulator and in the pathophysiology and treatment of neuropsychiatric disorders is discussed. Keywords steroidogenesis; GABA A receptors; NMDA receptors; dopamine; stress response; mood Our research focuses on the mechanisms of progestins' actions in the midbrain ventral tegmental area (VTA) that mediate the onset and duration of sexual behavior of female rodents. To date, the majority of our investigations have utilized a model system in which progestins' mechanisms are manipulated in the VTA and/or the hypothalamus of ovariectomized (OVX), estrogen (E)-primed rodents. The effects on lordosis, the stereotypic posture which female * Correspondence to: C. A. Frye, Department of Psychology, Social Science 369, the University at Albany-SUNY, 1400 Washington Avenue, Albany, NY 12222, USA. Tel: +1-518-442-4836; fax: +1-518-442-4867. E-mail address: cafrye@cnsunix.albany.edu (C. A. Frye). NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 September 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript rodents assume to enable mating to occur (given appropriate hormonal and environmental stimulation), are then used as a bioassay to indicate which mechanisms of progestins are required for lordosis. This approach has revealed that progesterone (P) has classic actions through intracellular progestin receptors (PRs-"genomic" actions) in the hypothalamus to initiate lordosis, but P's metabolite, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP),...

Although androgen secretion is reduced with aging, and may underlie decrements in cognitive and affective performance, the effects and mechanisms of androgens to mediate these behaviors are not well understood. Testosterone (T), the primary male androgen, is aromatized to estrogen (E(2)), and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17beta-diol (3alpha-diol). To ascertain whether actions of the neuroactive metabolite of T, 3alpha-diol, mediates cognitive and affective behaviors, intact, aged male C57/B6 mice (24 month old) as well as young, intact and gonadectomized (GDX; 12 week old) mice were administered s.c. T, 3alpha-diol, E(2), or sesame oil vehicle (1 mg/kg; n=4-5/group) at weekly intervals and 1 h later mice were tested in the activity box, roto-rod, open field, elevated plus maze, zero maze, mirror maze, dark-light transition, forced swim, or Vogel tasks. Mice were trained in the inhibitory avoidance or conditioned contextual fear and were administered hormones following training and then were tested. After the last test occasion, tissues were collected for evaluation of hormone levels and effects on gamma-aminobutyric acid (GABA)-stimulated chloride flux. T, 3alpha-diol, or E(2) increased anti-anxiety and antidepressant behavior of aged, intact mice in the open field, light-dark transition, mirror maze, and forced swim tasks. T or 3alpha-diol, but not E(2), enhanced anti-anxiety behavior in the elevated plus maze, zero maze, and the Vogel task, and increased motor behavior in the activity monitor, latency to fall in the Roto-rod task, and cognitive performance in the hippocampally-mediated, but not the amygdala-mediated, portion of the conditioned fear task and in the inhibitory avoidance task. Anti-anxiety and enhanced cognitive performance was associated with regimen that increased plasma and hippocampal 3alpha-diol levels and GABA-stimulated chloride flux. Similar patterns were seen among young, adult GDX but not in intact mice. Thus, 3alpha-diol can enhance affective and cognitive behavior of male mice.

The effects of P to decrease anxiety behavior of younger and older mice do not require classic PRs and may involve actions of 3alpha,5alpha-THP at GBRs.

Rationale-Greater incidence of anxiety and depressive disorders of women compared to men may be due in part to progesterone (P) and its neuroactive metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), acting in limbic regions, such as the amygdala.Objective-If P's metabolism via 5α-reduction to 3α,5α-THP in the amygdala is critical for antianxiety and antidepressive behavior, then blocking 5α-reductase in the amygdala of female rats is likely to attenuate the antianxiety and anti-depressive effects of high progestin levels from both endogenous and exogenous sources.Methods-Naturally receptive female rats with high endogenous estrogen (E 2 ) and P and ovariectomized (ovx) rats administered E 2 (10 μg) and P (500 μg) subcutaneously were administered finasteride (10 μg/μl), a Type II 5α-reductase inhibitor, or vehicle to the amygdala. Anxiety behavior (open field, elevated plus maze, defensive freezing) and depressive behavior (Porsolt forced swim test) were assessed.Results-There were similar effects of finasteride administration to the amygdala to attenuate antianxiety behavior in naturally receptive and ovx, hormone-primed rats. Conclusions-Thus, formation and subsequent actions of 3α,5α-THP in the amygdala may be important for antianxiety and antidepressive effects.

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