Functional correlation between allopregnanolone and [35S]-TBPS binding in the brain of rats exposed to isoniazid, pentylenetetrazol or stress.
1. The relation between changes in the cerebral cortical concentration of allopregnanolone and gamma-aminobutyric acid (GABA) type A receptor function after intracerebroventricular injection of this neurosteroid was investigated in male rats. 2. Intracerebroventricular administration of allopregnanolone (1.25 to 15 micrograms) produced a maximal increase (100 fold at the highest dose) in cortical allopregnanolone concentration within 5 min; the concentration remained significantly increased at 15 and 30 min, before returning to control values by 60 min. 3. The same treatment induced a rapid and dose-dependent decrease in the binding of t-[35S]-butylbicyclophosphorothionate ([35S]-TBPS) to cerebral cortical membranes measured ex vivo, an effect mimicked by the benzodiazepine midazolam but not by the 3 beta-hydroxyepimer of allopregnanolone. The time course of changes in [35S]-TBPS binding paralleled that of brain allopregnanolone concentration. 4. In a dose-dependent manner, allopregnanolone both delayed the onset of convulsions and inhibited the increase in [35S]-TBPS binding to cortical membranes induced by isoniazid. The potency of allopregnanolone in inhibiting [35S]-TBPS binding in isoniazid-treated rats was approximately four times that in control animals. 5. The ability of allopregnanolone to decrease [35S]-TBPS binding in isoniazid-treated rats also correlated with its anticonvulsant activity against pentylenetetrazol-induced seizures as well as its inhibitory effect on the increase in [35S]-TBPS binding induced by foot shock. 6. The results indicate that the in vivo administration of allopregnanolone enhances the function of GABAA receptors in rat cerebral cortex and antagonizes the inhibitory action of stress and drugs that reduce GABAergic transmission.
Concas
A
A
Department of Experimental Biology, University of Cagliari, Italy.
Mostallino
M C
MC
Perra
C
C
Lener
R
R
Roscetti
G
G
Barbaccia
M L
ML
Purdy
R H
RH
Biggio
G
G
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D003292:Convulsants / Q000378:metabolism*; D018757:GABA Modulators / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007538:Isoniazid; D008297:Male; D010433:Pentylenetetrazole; D011280:Pregnanolone / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced; D013312:Stress, Physiological / Q000378:metabolism; D013997:Time Factors
D000995:Antitubercular Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D018757:GABA Modulators; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone; D007538:Isoniazid; D010433:Pentylenetetrazole