Alcoholism is a complex disorder that represents an important contributor to health problems worldwide and that is difficult to encompass with a single preclinical model. Additionally, alcohol (ethanol) influences the function of many neurotransmitter systems, with the interaction at γ-aminobutyric acid A (GABA A ) receptors being integral for ethanol's reinforcing and several withdrawal-related effects. Given that some steroid derivatives exert rapid membrane actions as potent positive modulators of GABA A receptors and exhibit a similar pharmacological profile to that of ethanol, studies in the laboratory manipulated GABAergic steroid levels and determined the impact on ethanol's rewarding-and withdrawal-related effects. Manipulations focused on the progesterone metabolite allopregnanolone (ALLO), since it is the most potent endogenous GABAergic steroid identified. The underlying hypothesis is that fluctuations in GABAergic steroid levels (and the resultant change in GABAergic inhibitory tone) alter sensitivity to ethanol, leading to changes in the positive motivational or withdrawal-related effects of ethanol. This review describes results that emphasize sex differences in the effects of ALLO and the manipulation of its biosynthesis on alcohol reward-versus withdrawal-related behaviors, with females being less sensitive to the modulatory effects of ALLO on ethanol-drinking behaviors but more sensitive to some steroid manipulations on withdrawal-related behaviors. These findings imply the existence of sex differences in the sensitivity of GABA A receptors to GABAergic steroids within circuits relevant to alcohol reward versus withdrawal. Thus, sex differences in the modulation of GABAergic neurosteroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics.

The sheep offers a unique mammalian model in which to study paradoxical same-sex sexual partner preferences. Variations in sexual partner preferences occur spontaneously with as many as 8% of rams in a population exhibiting a sexual preference for other rams (male-oriented). The current review presents an overview and update of the male-oriented ram model and discusses several theories that have been invoked to explain same sex preferences in this species. Although our understanding of the biological determinants and underlying neural substrates of sexual attraction and mate selection are far from complete, compelling evidence is discussed that supports the idea that neural substrates regulating sexual partner preferences are organized during prenatal development. The challenge for future research will be to construct an integrated picture of how hormones, genes, and experience shape sexual partner preference.

The neurosteroid allopregnanolone (ALLO) is a progesterone metabolite that is one of a family of neuroactive steroids (NAS) that are potent positive allosteric modulators of γ-aminobutyric acid A (GABA A ) receptors. These GABAergic NAS are produced peripherally (in the adrenals and gonads) and centrally in the brain. Peripherally produced NAS modulate some effects of ethanol intoxication (e.g., anxiolytic, antidepressant, and anticonvulsant effects) in rodents. We have found that NAS also may be involved in the rebound neural hyperexcitability following a high ethanol dose. Removal of the adrenals and gonads (ADX/GDX) increased withdrawal severity following 4 g/kg ethanol, as measured by handling-induced convulsions (HICs) in male and female DBA/2J mice. NAS are produced through the metabolism of progesterone (PROG), deoxycorticosterone (DOC), or testosterone, which can be blocked with the administration of finasteride (FIN), a 5α-reductase enzyme inhibitor. The current investigation was undertaken to clarify the step(s) in the biosynthetic NAS pathway that were sufficient to restore the acute ethanol withdrawal profile in ADX/GDX mice to that seen in intact animals.Male and female DBA/2J mice underwent ADX/GDX or SHAM surgery. After recovery, separate groups of animals were administered PROG, DOC, PROG+FIN, DOC+FIN, FIN, ALLO, ganaxalone (a synthetic ALLO derivative), corticosterone, or vehicle. Animals were then administered a 4 g/kg ethanol dose and allowed to undergo withdrawal. HICs were measured for 12 hours and again at 24 hours. The results indicate that replacement with PROG and DOC restored the withdrawal profile in ADX/GDX animals to SHAM levels, and that this effect was blocked with coadministration of FIN. Administration of FIN alone increased the withdrawal profile in both SHAM and ADX/GDX males. These findings indicate that the increase in acute withdrawal severity after ADX/GDX may be due to the loss of GABAergic NAS, providing insight into the contribution of endogenous GABAergic NAS to ethanol withdrawal severity. KeywordsNeurosteroids; alcohol; allopregnanolone; progesterone; deoxycorticosterone; finasteride © 2009 IBRO. Published by Elsevier Ltd. All rights reserved.Contact info Katherine Kaufman 3710 SW US Veterans Hospital Rd, R&D 49 Portland, OR 97239 Phone: (503) 220-8262 ex 56643 Fax: (503) 273-5351 kaufmaka@ohsu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 March 10. Published in final edited form as:Neuroscience. Each year in the United Stat...

Background Allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA receptors (GABAARs) that affects ethanol withdrawal. Finasteride (FIN), a 5α-reductase inhibitor that blocks the formation of ALLO and other GABAergic neurosteroids, alters ethanol sensitivity. Recently, we found that Withdrawal Seizure-Prone mice from the first genetic replicate (WSP-1) exhibited behavioral tolerance to the anticonvulsant effect of intra-hippocampal ALLO during ethanol withdrawal and that intra-hippocampal FIN significantly increased ethanol withdrawal severity. The purpose of the present study was to determine whether neurosteroid manipulations in the substantia nigra reticulata (SNR) and ventral tegmental area (VTA) produced effects during ethanol withdrawal comparable to those seen with intra-hippocampal ALLO and FIN. Methods Male WSP-1 mice were surgically implanted with bilateral guide cannulae aimed at the SNR or VTA at two weeks prior to ethanol vapor or air exposure for 72 hrs. Initial studies examined the anticonvulsant effect of a single ALLO infusion (0, 100 or 400 ng/side) at a time corresponding to peak withdrawal in the air- and ethanol-exposed mice. Separate studies examined the effect of four FIN infusions (0 or 10 µg/side/day) during the development of physical dependence on the expression of ethanol withdrawal. Results ALLO infusion exerted a potent anticonvulsant effect in ethanol-naïve mice, but a diminished anticonvulsant effect during ethanol withdrawal. Administration of FIN into the SNR exerted a delayed proconvulsant effect in ethanol-naïve mice, whereas infusion into the VTA increased ethanol withdrawal duration. Conclusions Activation of local GABAARs in the SNR and VTA via ALLO infusion is sufficient to exert an anticonvulsant effect in naïve mice and to produce behavioral tolerance to the anticonvulsant effect of ALLO infusion during ethanol withdrawal. Thus, ethanol withdrawal reduced sensitivity of GABAARs to GABAergic neurosteroids in two neuroanatomical substrates within the basal ganglia in WSP-1 male mice.

Recent findings suggest that the ability of ethanol (EtOH) to increase the levels of neurosteroids with potent γ-aminobutyric acid (GABA)ergic properties can influence measures of EtOH sensitivity. Earlier studies determined that removal of the adrenals and gonads diminished the steroidogenic effect of EtOH and significantly increased acute EtOH withdrawal severity in two inbred mouse strains that differed in withdrawal severity, suggesting the contribution of anticonvulsant GABAergic steroids to acute withdrawal in intact animals. Thus, the goal of the present studies was to investigate the consequence of steroid removal on acute EtOH withdrawal through excision of the adrenals and gonads, in another genetic animal model of EtOH withdrawal differences, the Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) selected lines. Male and female WSP and WSR mice underwent surgical removal of the adrenals and gonads or no organ removal (SHAM). One to two weeks later, baseline handling-induced convulsions (HICs) were assessed, mice were given a 4 g/kg dose of ethanol, and HICs were measured hourly for 12 hours and then at 24 hours. The combination surgery significantly increased EtOH withdrawal in WSP and WSR female mice, as measured by area under the curve (AUC) and peak HIC scores. AUC was significantly positively correlated with plasma corticosterone levels and significantly negatively correlated with progesterone levels. In contrast, surgical status did not alter withdrawal severity in male WSP and WSR mice. Overall, the increase in acute ethanol withdrawal severity in female WSP and WSR mice following adrenalectomy and gonadectomy corroborate our recent evidence that withdrawal from a high dose of EtOH can be modulated by anticonvulsant steroids produced in the periphery.