Antagonism of picrotoxin-induced changes in dopamine and serotonin metabolism by allopregnanolone and midazolam.
The effects of allopregnanolone and midazolam, given intracerebroventricularly, on the behavioral and biochemical effects of picrotoxin, were examined in a model of neurotoxin-induced seizures, in mice. After acute injections, midazolam (ED(50)=39.8 nmol) and allopregnanolone (ED(50)=11.0 nmol) produced similar and dose-dependent protection against picrotoxin-induced seizures. Picrotoxin given intraperitoneally at the ED(85) dose decreased significantly the concentration of serotonin (5-HT), dopamine (DA), homovanilic acid (HVA) and 3,4-dihydroxyindolacetic acid (DOPAC), in the mouse striatum and the frontal cortex, in the period of time immediately preceding the onset of seizures. A single injection of allopregnanolone more potently, in comparison to midazolam, antagonized the biochemical action of picrotoxin, abolishing its effects on DA, HVA and 5-HT concentration, in the mouse striatum and the frontal cortex. These results for the first time provide a direct argument for an involvement of central dopaminergic and serotonergic systems in the seizure development. The present data add also to the accumulating evidence suggesting a favorable pharmacological profile for some neurosteroids currently considered to have a future role in the management of epilepsy.
Maciejak
Piotr
P
Department of Neurochemistry, Institute of Psychiatry and Neurology, Al. Sobieskiego 9, 02-957 Warsaw, Poland.
Krzaścik
Paweł
P
Członkowska
Agnieszka I
AI
Szyndler
Janusz
J
Bidziński
Andrzej
A
Walkowiak
Jerzy
J
Kostowski
Wojciech
W
Plaznik
Adam
A
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D003292:Convulsants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008845:Microinjections; D008874:Midazolam / Q000494:pharmacology*; D010852:Picrotoxin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011280:Pregnanolone / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000523:psychology; D012701:Serotonin / Q000378:metabolism*
D000596:Amino Acids; D003292:Convulsants; D004298:Dopamine; D018756:GABA Antagonists; D018757:GABA Modulators; D008874:Midazolam; D010852:Picrotoxin; D011280:Pregnanolone; D012701:Serotonin