Finasteride is the first 5á-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5á-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5á-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3á-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of ã-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA A receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual-and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5á-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely re- 53
This essay highlights recommendations to make academic biology more inclusive of LGBTQ+ individuals. These recommendations are drawn from the literature and the collective experience of the 26-member author team.
The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of g -aminobutyric acid A (GABA A ) receptors. Earlier work indicates that sensitivity to the anticonvulsant effect of ALLO was enhanced during ethanol (EtOH) withdrawal in rats and in C57BL/6 mice, an inbred strain with mild EtOH withdrawal. In contrast, ALLO sensitivity was reduced during EtOH withdrawal in DBA/2 mice, an inbred strain with severe EtOH withdrawal. Thus, the present studies examined ALLO sensitivity during EtOH withdrawal in another animal model of EtOH withdrawal severity, the Withdrawal SeizureProne (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines. Male mice were exposed to EtOH vapor or air for 72 h. During peak withdrawal, animals were injected with ALLO [0, 3.2, 5, 10 or 17 mg/kg, intraperitoneally (i.p.)] and tested for their sensitivity to the anticonvulsant effect. In separate studies, potentiation of GABA-stimulated chloride uptake by ALLO (10 nM to 10 mM) was assessed in microsacs prepared from mouse brain mice during peak withdrawal. Notably, WSP mice were cross-tolerant to the anticonvulsant effect of ALLO during EtOH withdrawal (i.e. significant decrease in the efficacy of ALLO) when compared with values in airexposed mice. In contrast, sensitivity to the anticonvulsant effect of ALLO was unchanged during EtOH withdrawal in the WSR line. Functional sensitivity of GABA A receptors to ALLO was significantly decreased during EtOH withdrawal in WSP mice in a manner consistent with the change in behavioral sensitivity to ALLO. These findings suggest that mice selectively bred for differences in EtOH withdrawal severity are differentially sensitive to ALLO during EtOH withdrawal.
The progesterone derivative allopregnanolone (ALLO) rapidly potentiates γ-aminobutyric acid A (GABA A ) receptor mediated inhibition. The present studies determined whether specific manipulation of neurosteroid levels in the hippocampus would alter seizure susceptibility in an animal model genetically susceptible to severe ethanol (EtOH) withdrawal, Withdrawal SeizureProne (WSP) mice. Male WSP mice were surgically implanted with bilateral guide cannulae aimed at the CA1 region of the hippocampus one week prior to measuring seizure susceptibility to the convulsant pentylenetetrazol (PTZ), given via timed tail vein infusion. Bilateral intra-hippocampal infusion of ALLO (0.1 g/side) was anticonvulsant, increasing the threshold dose of PTZ for onset to myoclonic twitch and face and forelimb clonus by 2-3 fold. In contrast, infusion of the 5α-reductase inhibitor finasteride (FIN; 2 g/side), which decreases endogenous ALLO levels, exhibited a proconvulsant effect. During withdrawal from chronic EtOH exposure, WSP mice were tolerant to the anticonvulsant effect of intra-hippocampal ALLO infusion, consistent with published results following systemic injection. Finally, administration of intra-hippocampal FIN given only during the development of physical dependence significantly increased EtOH withdrawal severity, measured by handling-induced convulsions. These findings are the first demonstration that bidirectional manipulation of hippocampal ALLO levels produces opposite behavioral consequences that are consistent with alterations in GABAergic inhibitory tone in drug naïve mice. Importantly, EtOH withdrawal rendered WSP mice less sensitive to ALLO's anticonvulsant effect and more sensitive to FIN's proconvulsant effect, suggesting an alteration in the sensitivity of hippocampal GABA A receptors in response to fluctuations in GABAergic neurosteroids during ethanol withdrawal.
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