Inhibitory effect of some neuroactive steroids on cocaine-induced kindling in mice.
Some neuroactive steroids which positively modulate GABAA receptor activity suppress cocaine-induced kindling but a possible involvement of other neurochemical mechanism in their antiepileptogenic effect remains to be elucidated. To this end, in the present study, we evaluated effects of allopregnanolone, a positive modulator of the GABAA receptor; its isomer without GABAergic activity--isopregnanolone and a negative-modulator of GABAergic transmission--dehydroepiandrosterone sulfate on cocaine-induced kindling in mice. Animals were pretreated daily with either vehicle or neuroactive steroid and then given cocaine (45 mg/kg) for 12 days. After a 14-day washout period in which drugs were not administered, the mice were challenged with the same 45 mg/kg dose of cocaine. Isopregnanolone (5 mg/kg) and dehydroepiandrosterone sulfate (20 mg/kg) administered daily with cocaine decreased number of mice exhibiting seizures. Allopregnanolone (5 mg/kg) also showed strong tendency to suppress cocaine kindling, however, its effect did not reach statistical significance. None of the neuroactive steroids had effect on acute cocaine (75 mg/kg ip)-induced clonic seizures. Further biochemical study showed that the veratridine- but not K+ -stimulated release of D-[3H]-aspartate in hippocampal slices was higher in cocaine-kindled mice than in the control group. Isopregnanolone (100 microM) significantly attenuated the veratridine-induced D-[3H]-aspartate release in hippocampi of cocaine-kindled group. These data indicate that positive modulation of the GABAA receptors is not a critical feature of neuroactive steroids that would determine their ability to prevent the cocaine-induced kindling.
Leśkiewicz
Monika
M
Department of Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Budziszewska
Bogusława
B
Jaworska-Feil
Lucylla
L
Kubera
Marta
M
Basta-Kaim
Agnieszka
A
Lasoń
Władysław
W
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D003505:Cyclodextrins / Q000494:pharmacology*; D026603:D-Aspartic Acid / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D047392:beta-Cyclodextrins
D000927:Anticonvulsants; D003292:Convulsants; D003505:Cyclodextrins; D011963:Receptors, GABA-A; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D026603:D-Aspartic Acid; D019314:Dehydroepiandrosterone Sulfate; D011280:Pregnanolone; D003042:Cocaine