Intra-raphe benzodiazepines enhance rat locomotor activity: interactions with GABA.

Intracranial dose response relationships for the water-soluble benzodiazepines, chlordiazepoxide, flurazepam and midazolam, were performed by injecting the drugs through cannulae chronically indwelling in the median raphe nucleus of male albino rats. Drugs were administered in doses of 0.0, 0.22, 0.44, 0.88 and 1.75 nmole in 0.5 microliters saline. Both midazolam and flurazepam produced hyperactivity which was most prominent within the first 30 minutes post-injection. Flurazepam, furthermore, proved twice as potent as midazolam. Chlordiazepoxide, in contrast, was without effect at any of the doses tested. This observation supports the view that chlordiazepoxide is a pro-drug which must be metabolized to form an active metabolite. In another experiment, animals received either saline or a sub-effective dose (0.22 nmole) of flurazepam or midazolam into the median raphe nucleus 5 minutes prior to either a subeffective dose of muscimol (0.22 nmole) or saline. Only the combinations of a benzodiazepine plus muscimol produced hyperactivity. These combinations, moreover, produced effects as robust as those of a 4-fold higher dose of muscimol alone (0.88 nmole). Other animals received either saline or bicuculline methiodide (0.88 nmole). Bicuculline did not affect activity level, but completely blocked the hyperkinetic effects of muscimol. These data suggest that the hyperactivity effect of intra-raphe muscimol is due to activation of GABA receptors within the midbrain raphe, rather than at distant sites. In addition, the data suggest that the intra-raphe administration of certain benzodiazepines produces hyperactivity by facilitating GABA transmission.