Although carbamazepine (CBZ) is used therapeutically in the treatment of various neurological and psychiatric conditions, its mechanism of action remains largely unknown. CBZ has now been shown to inhibit the binding of [H-3]PK 11195 to peripheral benzodiazepine receptors (PBRs) in rat brain and ovary membranes in vitro with a potency (IC50, similar to 60 mu M) much lower than that of unlabeled PK 11195 (IC50, similar to 2.0 nM). Administration of CBZ to rats induced dose (25 to 100 mg/kg, i.p.) and time (15 to 60 min) dependent increases in the concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone in both the cerebral cortex and plasma. CBZ also induced steroidogenesis in the brain of adrenalectomized-orchiectomized rats, suggesting that this effect is mediated in a manner independent of peripheral PBRs. The increase in brain concentrations of neuroactive steroids induced by a single injection of CBZ was associated with a marked protective effect against isoniazid-induced convulsions. In contrast, long-term administration of CBZ (50 mg/kg, twice a day for 30 days) induced tolerance to the anticonvulsant action of the drug. This same treatment, however, did not prevent the ability of a challenge dose of CBZ to stimulate steroidogenesis. These results indicate that CBZ-induced steroidogenesis might not be responsible for the anticonvulsant activity of this drug, (C) 2000 Elsevier Science Ltd. All rights reserved.
Steroidogenesis in rat brain induced by short- and long-term administration of carbamazepine
SERRA, MARIANGELA;
2000-01-01
Abstract
Although carbamazepine (CBZ) is used therapeutically in the treatment of various neurological and psychiatric conditions, its mechanism of action remains largely unknown. CBZ has now been shown to inhibit the binding of [H-3]PK 11195 to peripheral benzodiazepine receptors (PBRs) in rat brain and ovary membranes in vitro with a potency (IC50, similar to 60 mu M) much lower than that of unlabeled PK 11195 (IC50, similar to 2.0 nM). Administration of CBZ to rats induced dose (25 to 100 mg/kg, i.p.) and time (15 to 60 min) dependent increases in the concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone in both the cerebral cortex and plasma. CBZ also induced steroidogenesis in the brain of adrenalectomized-orchiectomized rats, suggesting that this effect is mediated in a manner independent of peripheral PBRs. The increase in brain concentrations of neuroactive steroids induced by a single injection of CBZ was associated with a marked protective effect against isoniazid-induced convulsions. In contrast, long-term administration of CBZ (50 mg/kg, twice a day for 30 days) induced tolerance to the anticonvulsant action of the drug. This same treatment, however, did not prevent the ability of a challenge dose of CBZ to stimulate steroidogenesis. These results indicate that CBZ-induced steroidogenesis might not be responsible for the anticonvulsant activity of this drug, (C) 2000 Elsevier Science Ltd. All rights reserved.
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