TY - JOUR
T1 - Epipregnanolone and a novel synthetic neuroactive steroid reduce alcohol self-administration in rats
AU - O'Dell, L. E.
AU - Purdy, R. H.
AU - Covey, D. F.
AU - Richardson, H. N.
AU - Roberto, M.
AU - Koob, G. F.
N1 - Funding Information:
The authors thank Dr. Eric Zorrilla for his comments on this manuscript, and Mike Arends for his excellent editorial assistance. We also thank Ron T. Smith and Molly Brennan for their technical assistance. This research was supported by National Institutes of Health Grants AA06420 and AA12602 from the National Institute on Alcohol and Alcoholism to The Scripps Research Institute (GFK, LEO), and GM 47969 from the National Institute of General Medicine to Washington University School of Medicine (DFC). This research was also supported by The Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute. This is publication number 16826-NP from The Scripps Research Institute.
PY - 2005/7
Y1 - 2005/7
N2 - This study was designed to compare the effects of several neuroactive steroids with varying patterns of modulation of γ-aminobutyric acid (GABA)A and NMDA receptors on operant self-administration of ethanol or water. Once stable responding for 10% (w/v) ethanol was achieved, separate test sessions were conducted in which male Wistar rats were allowed to self-administer ethanol or water following pre-treatment with vehicle or one of the following neuroactive steroids: (3β,5β)-3-hydroxypregnan-20-one (epipregnanolone; 5, 10, 20 mg/kg; n = 12), (3α,5β)-20-oxo-pregnane- 3-carboxylic acid (PCA; 10, 20, 30 mg/kg n = 10), (3α,5β)-3- hydroxypregnan-20-one hemisuccinate (pregnanolone hemisuccinate; 5, 10, 20 mg/kg; n = 12) and (3α,5α)-3-hydroxyandrostan-17-one hemisuccinate (androsterone hemisuccinate; 5, 10, 20 mg/kg; n = 11). The effect of the 3β-epimer of PCA, (3β,5β)-20-oxo-pregnane-3-carboxylic acid (10, 20, 30 mg/kg; n = 9), on ethanol self-administration was also examined. The compounds were administered using a Latin-square design 45 min prior to the weekly test sessions. The effects of the 30 mg/kg dose of the steroidal hemisuccinates on ethanol intake were also examined 5 min after administration of these drugs. Both epipregnanolone and PCA attenuated ethanol self-administration. However, neither of the hemisuccinate compounds significantly altered this behavior. The steroidal hemisuccinates (30 mg/kg; n = 7) were also tested 5 min before behavior testing and had no effect on ethanol intake 5 min after administration. The 3β-epimer of PCA also failed to alter ethanol intake. None of the test compounds altered water intake. In electrophysiological studies, the effects of PCA and androsterone hemisuccinate on evoked GABAA receptor-mediated inhibitory postsynaptic currents (GABAA-IPSCs) was examined in brain slices of the amygdala. PCA had a stimulatory effect at concentrations of 5 and 25 μM. Androsterone hemisuccinate had no agonist activity. The ability of epipregnanolone and PCA to alter ethanol intake appears to be related to different inhibitory actions of these compounds on either GABAA or NMDA receptors, respectively. Thus, dual modulation of these systems by selected neuroactive steroids may offer potential for modifying the reinforcing effects of alcohol.
AB - This study was designed to compare the effects of several neuroactive steroids with varying patterns of modulation of γ-aminobutyric acid (GABA)A and NMDA receptors on operant self-administration of ethanol or water. Once stable responding for 10% (w/v) ethanol was achieved, separate test sessions were conducted in which male Wistar rats were allowed to self-administer ethanol or water following pre-treatment with vehicle or one of the following neuroactive steroids: (3β,5β)-3-hydroxypregnan-20-one (epipregnanolone; 5, 10, 20 mg/kg; n = 12), (3α,5β)-20-oxo-pregnane- 3-carboxylic acid (PCA; 10, 20, 30 mg/kg n = 10), (3α,5β)-3- hydroxypregnan-20-one hemisuccinate (pregnanolone hemisuccinate; 5, 10, 20 mg/kg; n = 12) and (3α,5α)-3-hydroxyandrostan-17-one hemisuccinate (androsterone hemisuccinate; 5, 10, 20 mg/kg; n = 11). The effect of the 3β-epimer of PCA, (3β,5β)-20-oxo-pregnane-3-carboxylic acid (10, 20, 30 mg/kg; n = 9), on ethanol self-administration was also examined. The compounds were administered using a Latin-square design 45 min prior to the weekly test sessions. The effects of the 30 mg/kg dose of the steroidal hemisuccinates on ethanol intake were also examined 5 min after administration of these drugs. Both epipregnanolone and PCA attenuated ethanol self-administration. However, neither of the hemisuccinate compounds significantly altered this behavior. The steroidal hemisuccinates (30 mg/kg; n = 7) were also tested 5 min before behavior testing and had no effect on ethanol intake 5 min after administration. The 3β-epimer of PCA also failed to alter ethanol intake. None of the test compounds altered water intake. In electrophysiological studies, the effects of PCA and androsterone hemisuccinate on evoked GABAA receptor-mediated inhibitory postsynaptic currents (GABAA-IPSCs) was examined in brain slices of the amygdala. PCA had a stimulatory effect at concentrations of 5 and 25 μM. Androsterone hemisuccinate had no agonist activity. The ability of epipregnanolone and PCA to alter ethanol intake appears to be related to different inhibitory actions of these compounds on either GABAA or NMDA receptors, respectively. Thus, dual modulation of these systems by selected neuroactive steroids may offer potential for modifying the reinforcing effects of alcohol.
KW - Alcohol
KW - Epipregnanolone
KW - Ethanol
KW - Neuroactive steroid
KW - Rat
KW - Self-administration
UR - http://www.scopus.com/inward/record.url?scp=22044432443&partnerID=8YFLogxK
U2 - 10.1016/j.pbb.2005.03.020
DO - 10.1016/j.pbb.2005.03.020
M3 - Article
C2 - 15950269
AN - SCOPUS:22044432443
SN - 0091-3057
VL - 81
SP - 543
EP - 550
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
IS - 3
ER -