Mitochondrial diazepam-binding inhibitor receptor complex agonists antagonize dizocilpine amnesia: putative role for allopregnanolone.
In rats trained to retain a passive avoidance response or to retrieve a learned task in the radial and water maze tests, a pretreatment with 2-hexyl-3-indoleacetamide (FGIN-1-27) (IC50 57 mumol/kg p.o.) or 4' chlorodiazepam (4'CD) (15 mumol/kg i.p.), two steroidogenic ligands at the mitochondria diazepam-binding inhibitor receptor complex (MDRC), antagonized the performance deficit elicited by dizocilpine (0.3 mumol/kg i.p.), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The 1-(2-chlorophenyl)-N-methyl-N-(-1-methyl-propyl)-3-isoquinoline carboxamide (PK-11195), an antagonist at MDRC in vivo, failed to modify the disruptive effect of dizocilpine in the passive avoidance response but reversed the FGIN-1-27- or 4' CD-induced antagonism of dizocilpine behavioral actions. Pretreatment with pregnenolone sulfate (48 mumol/kg i.p.), 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one (THDOC) (15 mumol/kg i.v.) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) (15 mumol/kg i.v.) also reduced the passive avoidance retention deficit elicited by dizocilpine. The (17-beta)-17-[[bis(1-methylethyl)amino[carbonyl]androstane-3,5-diene-3- carboxylic acid (SKF-105111), a 5 alpha-reductase inhibitor, blocked the antagonism of dizocilpine behavioral actions by pregnenolone sulfate or by FGIN-1-27 but not those caused by THDOC or allopregnanolone either in normal or adrenalectomized-castrated rats. Thus, it is inferred that the amnesic effect of dizocilpine is counteracted by FGIN-1-27, 4'CD and pregnenolone sulfate because of their ability to increase brain accumulation of allopregnanolone.
Fidia-Georgetown Institute for the Neurosciences, Georgetown University Medical School, Washington, District of Columbia.
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Romeo
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Cheney
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Zivkovic
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Costa
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Guidotti
D000647:Amnesia / Q000139:chemically induced* / Q000517:prevention & control*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D007210:Indoleacetic Acids / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D011280:Pregnanolone / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000502:physiology*; D012601:Scopolamine / Q000494:pharmacology / Q000633:toxicity; D013256:Steroids / Q000494:pharmacology / Q000502:physiology; D014316:Tritium
D007210:Indoleacetic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; C078199:diazepam-binding inhibitor receptor; D014316:Tritium; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; D016291:Dizocilpine Maleate; D011280:Pregnanolone; D012601:Scopolamine