Midazolam effects on prepulse inhibition of the acoustic blink reflex

Abstract

AimsThe 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.Methods 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). Results The magnitude of PPI was inversely related to the concentration of midazolam. This relationship was described by a sigmoidal E max model, giving an E max of 0.65±0.13, an ED 50 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. Conclusions 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.

The effects of methylphenidate and diazepam on the acoustic startle reflex in stand alone and prepulse trials in healthy volunteers

“…The reduction of PPI could be blocked by the benzodiazepine antagonist flumazenil. It was even suggested that the assessment of PPI may be potentially useful to monitor the sedative effect of benzodiazepines (38). In agreement with this was that our subjects scored higher on the fatigue scales after the intake of diazepam compared to placebo.…”

“…We found that diazepam decreased the amplitude in prepulse trials more after a weak prepulse than after a strong prepulse, probably because it is more easy to reduce a large than a small startle reflex. A reduction of PPI after diazepam was reported in a study with progressively increasing concentrations of midazolam (from 0.02 to 0.14 mg kg-' h-*) in humans (38). The reduction of PPI could be blocked by the benzodiazepine antagonist flumazenil.…”

Prepulse inhibition deficits in patients with panic disorder

“…The effect of antidepressants on startle reactivity is less clear: Phillips et al [2000] showed that amitryptyline, but not fluvoxamine or reboxetine, reduced the startle response; in contrast, Liechti et al [2001] observed an increase in startle reactivity induced by citalopram. Although inconsistent effects of benzodiazepines on startle and PPI have been reported [Abdulajawad et al, 1997;Schachinger et al, 1999]; patients treated with benzodiazepines were excluded from this study. The effect of medication on within-session habituation is not clear.…”

Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice

“…Four FXS subjects were taking anxiolytics. Anxiolytics have been shown to have no effect (diazepam 22 ) or to reduce PPI (midazolam 23 ). The latter effect, however, was associated with sedation and severe reduction in baseline startle responding.…”