NEUROSTEROID COADMINISTRATION PREVENTS DEVELOPMENT OF TOLERANCE AND AUGMENTS RECOVERY FROM BENZODIAZEPINE WITHDRAWAL ANXIETY AND HYPERACTIVITY IN MICE

Neurosteroids are potent and specific modulators of the GABAA receptor s which regulate the neuronal activity through diverse neurotransmitte r mechanisms. In the present study we investigated the effects of conc omitant treatment with various neurosteroids on the development of tol erance and recovery from withdrawal anxiety and hyperactivity to chron ic benzodiazepines. Long-term treatment of mice with full allosteric m odulator (triazolam 0.25 mg/kg/day for 8 clays) or selective allosteri c modulator (diazepam 20 mg/kg/day for 21 days) of GABA(A) receptor in duced tolerance to behavioral sedation on actimeter and anxiolytic eff ects on plus-maze, and produced a marked withdrawal anxiety and hypera ctivity syndrome upon abrupt cessation of treatment, respectively. Con comitant progesterone (10 mg/kg, s.c.), a neurosteroid precursor; or 4 '-chlordiazepam (0.25 mg/kg, i.p.), a mirochondrial diazepam binding i nhibitor (DBI) receptor (MDR) ligand, prevented the development of tol erance and significantly augmented the recovery from withdrawal-induce d anxiety and hyperlocomotion to diazepam. When administered alone for 21 days, neither progesterone nor 4'-chlordiazepam produced any per s e effects on actimeter or plus-maze when rested on post-withdrawal day s. Coadministration of neurosteroid allopregnanolone (AP) (0.25 and 0. 5 mg/kg), or pregnenolone sulfate (PS) (2 mg/kg), but not dehydroepian drosterone sulfate (2 mg/kg), abolished the development of tolerance a nd attenuated withdrawal-induced anxiety and hyperlocomotion due to tr iazolam, without producing any per se behavioral effects when rested a t 1 and 2 days after the last injection. Coadministration of flumazeni l (5 mg/kg), progesterone (10 mg/kg), 4'-chlordiazepam (0.25 mg/kg), h ydrocortisone (100 mg/kg) or nifedipine (2 mg/kg) also prevented the d evelopment of tolerance and suppressed the triazolam withdrawal syndro me. However; pretreatment with PK11195 (2 mg/kg), a MDR partial antago nist, reversed the effects of 4'-chlordiazepam nt triazolam tolerance and recovery from chronic triazolam. When injected simultaneously nife dipine, a Ca2+ channel antagonist, potentiated the progesterone- and 4 '-chlordiazepam-induced attenuation of triazolam tolerance and withdra wal behavior These findings suggest that coadministration of neuroster oids allopregnanolone, pregnenolone sulfate and progesterone, and MDR ligand 4'-chlordiazepam prevents the development of tolerance to benzo diazepines and augments the recovery from chronic benzodiazepines Thes e results indicate that coadministration of neurosteroids may facilita te discontinuation of benzodiazepines in long-term therapy.