Modification of behavioral effects of drugs in mice by neuroactive steroids.
BACKGROUND
Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABA(A) receptor. A synthetically derived neuroactive steroid, ganaxolone (3alphahydroxy-3beta-methyl-5alpha-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration.


OBJECTIVE
The present study explored possible reversal by ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges.


METHODS
Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with ganaxolone.


RESULTS
Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bicuculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ.


CONCLUSIONS
The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA.
Drug Development Group, Behavioral Neuroscience Laboratory, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
J T
JT
Ungard
M
M
Beekman
M
M
Gasior
R B
RB
Carter
D
D
Dijkstra
J M
JM
Witkin
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011284:Pregnenolone / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013256:Steroids / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000927:Anticonvulsants; D000697:Central Nervous System Stimulants; D003292:Convulsants; D018765:Dopamine Uptake Inhibitors; D011619:Psychotropic Drugs; D013256:Steroids; D005680:gamma-Aminobutyric Acid; D011284:Pregnenolone; C105051:ganaxolone; D011280:Pregnanolone; D003042:Cocaine; D010433:Pentylenetetrazole