3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) antagonism of the GABA potentiation and the learning impairment induced in rats by allopregnanolone.
Allopregnanolone is a progesterone metabolite and GABA-A receptor modulator with benzodiazepine like effects, including decreased learning and memory. In vitro 3beta-hydroxypregnane steroids antagonize allopregnanolone-induced effects, but no antagonism has been shown in vivo. Our purpose was to evaluate 3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) as a blocker of allopregnanolone-induced effects in vivo and in vitro in rats. We tested adult male Wistar rats in the Morris water maze 8 min after daily injections (i.v.) of allopregnanolone 2 mg/kg (n = 21); allopregnanolone : UC1011 2 : 6 (n = 7), 2 : 8 (n = 7), 2 : 20 (n = 14) mg/kg; UC1011 20 mg/kg (n = 14); or vehicle (10% 2-hydroxypropyl-beta-cyclodextrin, n = 4). Studies of chloride ion uptake into cortical and hippocampal membrane preparations were performed. The latency to find the hidden platform was still high in the allopregnanolone-injected group on day 6. Day 3-6 rats injected with allopregnanolone and UC1011 (2 : 20 mg/kg) had lower latency (P < 0.05), compared to the allopregnanolone-injected group. The group that only received UC1011 learned the location of the platform as fast as the controls. There was no significant difference in swim speed between groups. The time spent swimming close to the pool wall was in the allopregnanolone : UC1011 group (2 : 20 mg/kg) significantly decreased (P < 0.05, day 3-6), compared to the allopregnanolone-injected group. The increased chloride ion uptake induced by increasing dosage of allopregnanolone in the presence of 10 micro m GABA was significantly decreased with UC1011 (P < 0.01), in both cortical and hippocampal homogenates. In conclusion, UC1011 can via antagonism at the GABA-A receptor reduce the negative allopregnanolone effect on learning in the water maze.
Turkmen
Sahruh
S
Department of Clinical Science, Obstetrics and Gynecology, Umea Neurosteroid Research Center, 5B level 5, Umea University Hospital, SE-901 85 Umea, Sweden.
Lundgren
Per
P
Birzniece
Vita
V
Zingmark
Elisabeth
E
Backstrom
Torbjorn
T
Johansson
Inga-Maj
IM
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018756:GABA Antagonists / Q000627:therapeutic use*; D018757:GABA Modulators / Q000097:blood / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011276:Pregnanediol / Q000494:pharmacology / Q000627:therapeutic use*; D011280:Pregnanolone / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D018709:Statistics, Nonparametric; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D002712:Chlorides; D018756:GABA Antagonists; D018757:GABA Modulators; C016836:allopregnane-3,20-diol; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone; D011276:Pregnanediol