Tolerance to the anticonvulsant activity of midazolam and allopregnanolonein a model of picrotoxin seizures

The effects of an intracerebroventricular (i.c.v.) administration of a non- selective full benzodiazepine receptor agonist, midazolam, and a neuroactiv e steroid, allopregnanolone. on picrotoxin-induced seizures and striatal do pamine metabolism, were studied in mice. It was found that acute i.c.v. inj ections of midazolam (ED50 = 38.25 nmol) and allopregnanolone (ED50 = 26.34 nmol) blocked picrotoxin-induced seizures to a similar extent. After repea ted administration at the ED85 doses (midazolam-56.6 nmol, allopregnanolone -94.2 nmol; once or twice daily for 5 days) tolerance developed to the anti convulsant activity of midazolam (ED50 = 94.14 nmol) and allopregnanolone ( ED50 = 186.70 nmol). Acute i.c.v. injections of midazolam and allopregnanol one (at the ED50 doses established in the model of picrotoxin seizures 38.2 5 and 26.34 nmol, respectively), significantly decreased the concentration of dopamine metabolites: 3-methoxytyramine and 3,4-dihydroxyphenylacetic ac id, as well as the dopamine turnover rate (homovanilic acid/dopamine ratio, by about 20%). in the mouse striatum. These findings together with the rec ently published data on the potentiation by midazolam and allopregnanolone of ethanol-induced sleep [Pharmacol. Biochem. Behav. 67 (2000) 345] indicat e a very similar central effect profile of benzodiazepines and neurosteroid s. Moreover, similar efficacy of allopregnanolone and midazolam at the GABA (A) receptors has been found. Overall, the results of the present study, al ong with the possibility of neurosteroid conversion in the brain into other steroid hormones (testosterone, estradiol. aldosterone), add to the accumu lating evidence suggesting a less favorable pharmacological Profile for thi s class of drugs than was previously thought. (C) 2001 Published by Elsevie r Science B.V.