Midazolam effects on prepulse inhibition of the acoustic blink reflex

Aims The eye-blink response following sudden acoustic noise bursts is part of the startle reflex. The magnitude of the startle response can be attenua ted by presentation of a weak stimulus before the 'startle-eliciting' stimu lus (prepulse inhibition, PPI). PPI is a stable finding in awake humans but may be altered by anaesthetic drugs. We investigated whether the applicati on of benzodiazepines altered the magnitude of PPI in healthy male voluntee rs. Methods In an open-label noncontrolled investigation, the effect of the ben zodiazepine agonist midazolam on PPI was assessed in the absence and presen ce of the antagonist flumazenil. After an initial control period of 60 min three consecutive periods, each of 60 min, with progressively increasing co ncentrations of midazolam were studied (0.02, 0.06, 0.14 mg kg(-1) h(-1)). A final 60 min period during the administration of flumazenil (0.004 mg kg( -1) h(-1)) and while the agonist was still present was also studied. Drug w as administered intravenuously as a combination of bolus, 50% of total dose and continuous infusion over the 60 min period. Electromyographic (EMG) re sponse of the light orbicularis oculi muscle was used to assess the startle response to noise bursts of 50 ms duration (95 dB(A)). Noise bursts were r andomly preceded by nonstartling prepulses (800 Hz sinus, 50 ms duration, 6 5 dB(A), prepulse to noise interval 120 ms). The magnitude of PPI was calcu lated by dividing the EMG response to nonprepulsed stimuli by the response to prepulsed stimuli for each individual and period. Eleven subjects partic ipated in the study, two of them were excluded from the statistical analysi s because startle responses could not be reliably elicited (final sample si ze n=9). Results The magnitude of PPI was inversely related to the concentration of midazolam. This relationship was described by a sigmoidal E-max model, givi ng an E-max of 0.65+/-0.13, an ED50 of 33.9+/-10.9 ng ml(-1) and gamma of 3 .5+/-1.0. During infusion of flumazenil and in the presence of midazolam, t he magnitude of PPI increased by 0.11 (95% CI, 0-0.22, P less than or equal to 0.04), which is consistent with its mode of action as a benzodiazepine antagonist. Conclusions In healthy male volunteers the magnitude of PPI varies accordin g to agonism and antagonism of benzodiazepine receptors, suggesting that th e assessment of PPI may be potentially useful to monitor the sedative effec t of benzodiazepines in the clinical setting.