ベンゾジアゼピン系抗不安薬ミダゾラムの扁桃体ノルアドレナリン神経活動への作用
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概要
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The intravenous sedation by benzodiazepine anxiolytics (midazolam, flunitrazepam, diazepam), which is widely used presently in the dental anesthesiology, is an efficient method to reduce the patient's negative emotion, such as fear and/or anxiety. Although benzodiazepine anxiolytics are widely used in dental care, the action mechanism on anxiolytic effect of these drugs has not been clear. The purpose of this study is to elucidate action mechanism on anxiolytic effect of benzodiazepine anxiolytics. In the present study, the author examined the effect of experimental fear and/or anxiety condition (conditioned fear ; replacement to the environment where the rats had received foot shocks previously) on extracellular noradrenaline (NA) levels in the basolateral amygdaloid nucleus (BLA) of the rat using in vivo microdialysis. Since BLA is considered to be important for the provocation of negative emotions and it has been suggested that NA releases in the brain are closely related to the provocation of negative emotions. Male Sprague-Dawley rats were anesthetized with pentobarbital. Rats were implanted with a vertical concentric dialysis probe in BLA, and were cannulated into the external jugular vein. Dialysates were collected every 20 min, and were directly injected for analysis into HPLC-ECD. The NA peak on the chromatogram disappeared following co-administration of tetrodotoxin into the perfusion fluid, which shows that NA in dialisates is released depending upon nerve impulse transmission in NA nerve terminal. The conditioned fear paradigm was employed using the conditioned fear chamber 16 hours after the probe implantation. After obtaining stable basal NA levels in the conditioned fear chamber, this chamber was subdivided into 2 same size boxes by a removable acrylic plate. The rat was placed in either of the 2 subdivided boxes for 20 min. In this box, the rat was exposed to electrical foot shocks on a fixed interval of 30 sec for 20 min. After the foot shock session an acrylic plate was removed, 100 min later the conditioned fear chamber was subdivided into 2 boxes by an acrylic plate again, and the rat was replaced in either of the 2 subdivided boxes without electrical foot shock for exposure to the environmental stimuli previously associated with foot shocks (conditioned fear). During the foot shock session in conditioned fear paradigm, NA increased significantly in BLA. The conditioned fear also caused NA increases in BLA, which indicates that the BLA noradrenergic system is activated not only by various physical stressors, but also by nonphysical stressor. Midazolam (0.1, 0.3mg/kg, i. v), a benzodiazepine anxiolytic attenuated NA increases in BLA induced by conditioned fear. Under the steady state, 0.1mg/kg midazolam had no effect to change NA release in BLA. But 0.3mg/kg midazolam decreased NA release. The present results indicate that the conditioned fear, lacking direct physical stimuli, increases in NA release in BLA, and as stated release is reversed by a benzodiazepine anxiolytic. In conclusion, NA neuronal activity in BLA depression is one of mechanism of benzodiazepine anxiolytic action.
- 1995-10-25