Midazolam effects on prepulse inhibition of the acoustic blink reflex

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Abstract
The eye-blink response following sudden acoustic noise bursts is part of the startle reflex. The magnitude of the startle response can be attenuated by presentation of a weak stimulus before the 'startle-eliciting' stimulus (prepulse inhibition, PPI). PPI is a stable finding in awake humans but may be altered by anaesthetic drugs. We investigated whether the application of benzodiazepines altered the magnitude of PPI in healthy male volunteers. In an open-label noncontrolled investigation, the effect of the benzodiazepine agonist midazolam on PPI was assessed in the absence and presence of the antagonist flumazenil. After an initial control period of 60 min three consecutive periods, each of 60 min, with progressively increasing concentrations 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 was administered intravenuously as a combination of bolus, 50% of total dose and continuous infusion over the 60 min period. Electromyographic (EMG) response of the right orbicularis oculi muscle was used to assess the startle response to noise bursts of 50 ms duration (95 dB(A)). Noise bursts were randomly preceded by nonstartling prepulses (800 Hz sinus, 50 ms duration, 65 dB(A), prepulse to noise interval 120 ms). The magnitude of PPI was calculated by dividing the EMG response to nonprepulsed stimuli by the response to prepulsed stimuli for each individual and period. Eleven subjects participated in the study, two of them were excluded from the statistical analysis because startle responses could not be reliably elicited (final sample size n=9). The magnitude of PPI was inversely related to the concentration of midazolam. This relationship was described by a sigmoidal Emax model, giving an Emax 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, the magnitude of PPI increased by 0.11 (95% CI, 0-0.22, P</=0.04), which is consistent with its mode of action as a benzodiazepine antagonist. In healthy male volunteers the magnitude of PPI varies according to agonism and antagonism of benzodiazepine receptors, suggesting that the assessment of PPI may be potentially useful to monitor the sedative effect of benzodiazepines in the clinical setting.