EVALUATION OF IN-VIVO INTERACTIONS IN MICE BETWEEN FLURAZEPAM AND 2 NEUROACTIVE STEROIDS

The development of neuroactive steroids as anticonvulsant medications may be useful both as a primary treatment and as an adjuvant to other anticonvulsants. They may be limited, however, by sedative and ataxic side effects. In the current study, 3(alpha)-hydroxy-5(beta)-pregnan-2 0-one and alfaxalone, two prototypic neuroactive steroids, were shown to potentiate the ability of flurazepam to antagonize electrically pre cipitated tonic hindlimb extension in mice at doses that by themselves had little antiseizure efficacy. While alfaxalone alone lacked motor incoordinating effects at a dose (18.0 mg/kg) that potentiated the ant iseizure efficacy of flurazepam, the same dose of 3(alpha)-hydroxy-5(b eta)-pregnan-20-one possessed both the ability to potentiate flurazepa m's anticonvulsant effect and disrupt mouse rotorod performance. The d ata suggest that allosteric interactions that have been described in v itro between neuroactive steroids and other modulators of the GABA(A) receptor complex may have relevance for the intact animal. Finally, th e data also suggest that neuroactive steroids could be developed as sh ort-lived adjuvant antiseizure medications in certain critical situati ons (e.g., medication-refractory status epilepticus). However, the mot or incoordinating effects resulting from the combination of neuroactiv e steroids and flurazepam suggest that their usefulness as adjuvant me dications in the chronic therapy of seizure disorders may be limited. Copyright (C) 1996 Elsevier Science Inc.