Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
Neuropharmacology (Impact Factor: 5.11). 03/2008; 54(2):365-74. DOI: 10.1016/j.neuropharm.2007.10.006
Source: PubMed


The GABAergic neurosteroid allopregnanolone (ALLO) has been repeatedly shown to have an increased anticonvulsant effect during ethanol withdrawal in rats and in C57BL/6J mice. In contrast, the seizure prone DBA/2J inbred strain and the Withdrawal Seizure-Prone (WSP) selected line exhibited decreased sensitivity to ALLO's anticonvulsant effect during ethanol withdrawal, with no change in sensitivity in the Withdrawal Seizure-Resistant (WSR) line. To date, only male mice have been tested. Thus, the present study examined ALLO sensitivity during ethanol withdrawal in female WSP and WSR mice, since females display less severe physical symptoms of withdrawal and have higher circulating ALLO levels than males. Female WSP and WSR mice were exposed to ethanol vapor or air for 72h. During peak ethanol withdrawal, separate groups of mice were injected with vehicle or ALLO (0, 3.2, 10, or 17mg/kg, i.p.) prior to the timed tail vein infusion of pentylenetetrazol (PTZ). ALLO injection significantly increased the threshold dose for onset to PTZ-induced convulsions, indicating an anticonvulsant effect, in female WSP and WSR mice. During ethanol withdrawal, sensitivity to ALLO's anticonvulsant effect was slightly increased in female WSR mice but was significantly decreased in female WSP mice. This line difference in sensitivity to ALLO during ethanol withdrawal in female mice was similar to that in the male mice. Notably, all seizure prone genotypes tested to date displayed tolerance to the anticonvulsant effect of ALLO during ethanol withdrawal, suggesting that decreased sensitivity of GABA(A) receptors to ALLO may contribute to the increased ethanol withdrawal phenotype.

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Available from: Michelle A Nipper (Tanchuck)
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    • "Several observations have been also obtained on seizures. Indeed, allopregnanolone has been reported to reduce seizures in several experimental models (Beckley et al., 2008; Belelli et al., 1989; Czlonkowska et al., 2000; Frye and Scalise, 2000; Singh et al., 2010) with potency higher than PROG itself (Lonsdale and Burnham, 2007; Lonsdale et al., 2006). Interesting data have been also obtained in Alzheimer's disease. "
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    ABSTRACT: Allopregnanolone, a neuroactive steroid derived from progesterone, is synthesized within the nervous tissue, by means of specific enzymes. Contrary to progesterone and its first metabolite dihydroprogesterone, allopregnanolone is able to interact with GABA-A receptor and not with the classical progesterone receptor. This suggests that the effect of progesterone administration may be due to activation of progesterone receptor, or of GABA-A receptor, or both. However, this is rarely considered in the experimental studies. Here we summarize and discuss the hot topics involving the actions of allopregnanolone within the nervous tissue. One major role of this neuroactive steroid is neuroprotection in case of lesion, ischemia or peripheral neuropathies (i.e. diabetes). In addition, allopregnanolone may reduce the symptoms of neurodegenerative diseases (e.g., Alzheimer, Parkinson, Niemann-Pick type C, multiple sclerosis) in animal models and now translational studies are developed for its therapeutic use. Allopregnanolone may exert a beneficial effect also in case of neuropathic pain and it is also a potential candidate for the treatment of mood and anxiety disorders. Finally, this neuroactive steroid seems to have important physiological roles in the early differentiation of some neural circuits (in particular at hippocampal level), and to reduce stress during pregnancy. In conclusion, it appears that allopregnanolone is a key regulators of physiological functions and may have interesting therapeutic perspectives for neurodegenerative and psychiatric disorders.
    Full-text · Article · Oct 2013 · Progress in Neurobiology
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    • "Interestingly, mice with a point mutation in the a1 gene do not experience the anticonvulsant effect of diazepam against PTZ convulsions (Rudolph et al., 1999), supporting the possibility that a withdrawal-induced decrease in expression of the a1 subunit could be an important neuroadaptation for reducing the efficacy of anticonvulsants such as ALLO. Regardless, additional studies are necessary to determine whether the reduction in GABA A R sensitivity to ALLO's anticonvulsant effect during EtOH withdrawal in WSP mice (Beckley et al., 2008; Finn et al., 2006b; Gililland- Kaufman et al., 2008; present findings) is consistent with selective GABA A R subunit changes. Studies with FIN utilized a different endpoint for assessing the effects of this manipulation of endogenous neurosteroid levels on basal convulsive activity and EtOH withdrawal severity, namely the assessment of HICs over the 48-hour time course of withdrawal. "
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    ABSTRACT: Background: Allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA receptors (GABAA Rs) that affects ethanol (EtOH) withdrawal. Finasteride (FIN), a 5α-reductase inhibitor that blocks the formation of ALLO and other GABAergic neurosteroids, alters EtOH sensitivity. Recently, we found that Withdrawal Seizure-Prone mice from the first genetic replicate (WSP-1) exhibited behavioral tolerance to the anticonvulsant effect of intrahippocampal ALLO during EtOH withdrawal and that intrahippocampal FIN significantly increased EtOH withdrawal severity. The purpose of this study was to determine whether neurosteroid manipulations in the substantia nigra reticulata (SNR) and ventral tegmental area (VTA) produced effects during EtOH withdrawal comparable to those seen with intrahippocampal ALLO and FIN. Methods: Male WSP-1 mice were surgically implanted with bilateral guide cannulae aimed at the SNR or VTA at 2 weeks prior to EtOH vapor or air exposure for 72 hours. 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 EtOH-exposed mice. Separate studies examined the effect of 4 FIN infusions (0 or 10 μg/side/d) during the development of physical dependence on the expression of EtOH withdrawal. Results: ALLO infusion exerted a potent anticonvulsant effect in EtOH-naïve mice, but a diminished anticonvulsant effect during EtOH withdrawal. Administration of FIN into the SNR exerted a delayed proconvulsant effect in EtOH-naïve mice, whereas infusion into the VTA increased EtOH withdrawal duration. Conclusions: Activation of local GABAA Rs 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 EtOH withdrawal. Thus, EtOH withdrawal reduced sensitivity of GABAA Rs to GABAergic neurosteroids in 2 neuroanatomical substrates within the basal ganglia in WSP-1 male mice.
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    • "Another study revealed a cross-tolerance in the neurophysiological effects of allopregnanolone in rats with a history of chronic ethanol exposure (Slawecki et al., 2005). In mice, the anticonvulsant effect of allopregnanolone is also decreased in alcohol withdrawal tested with induction of pentylenetetrazol seizures and this effect was only seen in genotypes with intense ethanol withdrawal (Finn et al., 2000; Beckley et al., 2008). Tolerance developed to the anticonvulsant activity of allopregnanolone on picrotoxin-induced seizures after repeated intracerebroventricular administration of allopregnanolone at the effective doses ED(85) once or twice daily for 5 days (Czlonkowska et al., 2001). "
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    ABSTRACT: Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid -A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors.
    Full-text · Article · Sep 2010 · British Journal of Pharmacology
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