Ž . European Journal of Pharmacology 425 2001 121–127 www.elsevier.comrlocaterejphar Tolerance to the anticonvulsant activity of midazolam and allopregnanolone in a model of picrotoxin seizures Agnieszka I. Czlonkowska a , Pawel Krza ¸scik a , Halina Sienkiewicz-Jarosz b , ´ Marek Siemia ¸tkowski c , Janusz Szyndler a , Piotr Maciejak d , Andrzej Bidzinski d , ´ Adam Plaznik a,d, ) ´ a Department of Experimental and Clinical Pharmacology, Medical UniÕersity, Krakowskie Przedmiescie 26 r 28, 00-927 Warsaw, Poland ´ b Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Al. Sobieskiego 1 r 9, Poland c Department of Pharmacology and Physiology of the NerÕous System, Institute of Psychiatry and Neurology, 02-957 Warsaw, Al. Sobieskiego 1 r 9, Poland d Department of Neurochemistry, Institute of Psychiatry and Neurology, 02-957 Warsaw, Al. Sobieskiego 1 r 9, Poland Received 25 May 2001; received in revised form 29 June 2001; accepted 3 July 2001 Abstract Ž . The effects of an intracerebroventricular i.c.v. administration of a non-selective full benzodiazepine receptor agonist, midazolam, and a neuroactive steroid, allopregnanolone, on picrotoxin-induced seizures and striatal dopamine metabolism, were studied in mice. It was Ž . Ž . found that acute i.c.v. injections of midazolam ED s38.25 nmol and allopregnanolone ED s26.34 nmol blocked picrotoxin-in- 50 50 Ž duced seizures to a similar extent. After repeated administration at the ED doses midazolam—56.6 nmol, allopregnanolone—94.2 85 . Ž . nmol; once or twice daily for 5 days tolerance developed to the anticonvulsant activity of midazolam ED s94.14 nmol and 50 Ž . Ž allopregnanolone ED s186.70 nmol . Acute i.c.v. injections of midazolam and allopregnanolone at the ED doses established in the 50 50 . model of picrotoxin seizures: 38.25 and 26.34 nmol, respectively , significantly decreased the concentration of dopamine metabolites: Ž 3-methoxytyramine and 3,4-dihydroxyphenylacetic acid, as well as the dopamine turnover rate homovanilic acidrdopamine ratio; by . about 20% , in the mouse striatum. These findings together with the recently published data on the potentiation by midazolam and w Ž . x allopregnanolone of ethanol-induced sleep Pharmacol. Biochem. Behav. 67 2000 345 indicate a very similar central effect profile of benzodiazepines and neurosteroids. Moreover, similar efficacy of allopregnanolone and midazolam at the GABA receptors has been A found. Overall, the results of the present study, along with the possibility of neurosteroid conversion in the brain into other steroid Ž . hormones testosterone, estradiol, aldosterone , add to the accumulating evidence suggesting a less favorable pharmacological profile for this class of drugs than was previously thought. q 2001 Published by Elsevier Science B.V. Ž . Keywords: Picrotoxin-induced seizure; Midazolam; Allopregnanolone; Intra cerebroventricular injection; Dopamine turnover rate; Striatum; Mouse 1. Introduction Neurosteroids are potent and specific endogenous mod- ulators of GABA receptors, which regulate many brain A functions. Recently, some new compounds with improved oral bioavailability and reduced metabolic liability have Ž been developed Wieland et al., 1997; Ga ¸sior et al., 1999, . 2000; Reddy and Rogawski, 2000a; Vanover et al., 2000 . These derivatives of naturally occurring metabolites of ) Corresponding author. Department of Experimental and Clinical Pharmacology, Medical University, Krakowskie Przedmiescie 26r28, ´ 00-927 Warsaw, Poland. Tel.rfax: q 48-22-842-7644. Ž . E-mail address: adaplaz@yahoo.com A. Plaznik . ´ steroid hormones are currently considered as having a future role in the management of epilepsy, anxiety, insom- Ž . nia, migraine and drug dependence Ga ¸sior et al., 1999 . However, certain obstacles still hamper the clinical use of analogs of endogenously occurring neurosteroids. For ex- ample, their anticonvulsant activity must be maintained with chronic dosing. Although it is now well established that neuroactive steroids produce many central effects on acute administra- tion, there is conflicting information regarding the effects of neuroactive steroids when administered repeatedly. On the one hand, there are experimental data indicating that tolerance develops rapidly to the central actions of neuro- steroids. For example, chronic dosing with minaxolone wŽ . 2b,3a ,5a , 11a -2-ethoxy-3-hydroxy-11, N, N-dimethyl- 0014-2999r01r$ - see front matter q 2001 Published by Elsevier Science B.V. Ž . PII: S0014-2999 01 01183-9