Effects of Repeated Administration of Inhaled ...

There is a lack of information on the effects of repeated administration of volatile anesthetics. Effects of repeated inhalation of enflurane, halothane, isoflurane and sevoflurane, on anesthetic effects and brain neurochemicals were investigated in mice. A simplified but quantitative anesthetic apparatus was employed which estimated the minimal alveolar concentration (MAC, ED50) of enflurane, halothane, isoflurane and sevoflurane to be 1.51, 1.29, 1.10 and 1.65 % (at 1 atm), respectively. Test compounds were administered by inhalation until complete anesthesia was established and then kept for one additional min at 1.73 or 2.16 MAC enflurane (0.4 or 0.5 ml), 1.61 or 2.69 MAC halothane (0.3 or 0.5 ml), 1.38 or 2.30 MAC isoflurane (0.3 or 0.5 ml) or 1.88 or 2.36 MAC sevoflurane (0.4 or 0.5 ml) once per day for 5 consecutive days, recording induction time and recovery time. In addition, rotarod performance (see “Materials and Methods”) was tested each day prior to administration of anesthetic. Twenty four hours after the last administration of anesthetic, the brains were removed and acetylcholinesterase (AChE) activity, [3H]quinuclidinyl benzilate (QNB) binding to muscarinic acetylcholine receptor (mAChR) preparation and [3H]haloperidol binding to dopaminergic receptor (D2-R) preparation in the striatum, cerebral cortex and/or hippocampus were measured. All drugs produced a dose-dependent rapid induction. However, halothane at 1.61 MAC and sevoflurane at 1.88 MAC produced prolonged induction times after repeated administrations. Enflurane at 1.73 MAC shortened and sevoflurane at 1.88 MAC prolonged the recovery times after repeated treatment. There were no changes in AChE activity in the three brain regions produced by any anesthetic tested. However, enflurane at 2.16 MAC and sevoflurane at 2.36 MAC reduced striatal [3H]QNB binding and isoflurane at 2.30 MAC reduced cerebral [3H]haloperidol binding. In summary, repeated administrations of halothane and sevoflurane may yield some degree of tolerance and repeated use of enflurane and sevoflurane appear to alter receptor kinetics of mAChRs and D2-R in specific brain areas.