Dopaminergic psychostimulants cause arousal from isoflurane-induced sedation without reversing memory impairment in rats

• Published in: British journal of anaesthesia : BJA Vol. 133; no. 4; pp. 793 - 803
• Main Authors: Fettiplace, Michael R., Vincent, Kathleen F., Cho, Angel, Dillon, Emmaline, Stapley, Brendan M., Stewart, Victoria, Solt, Ken
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2024; Elsevier
• Subjects: amnesia; arousal; dopamine; isoflurane; memory; Neuroscience and Neuroanaesthesia; psychostimulant; amnesia; memory; isoflurane; dopamine; psychostimulant; arousal
• ISSN: 0007-0912; 1471-6771; 1471-6771
• DOI: 10.1016/j.bja.2024.05.026

Dopaminergic psychostimulants can restore arousal in anaesthetised animals, and dopaminergic signalling contributes to hippocampal-dependent memory formation. We tested the hypothesis that dopaminergic psychostimulants can antagonise the amnestic effects of isoflurane on visuospatial working memory. Sixteen adult Sprague–Dawley rats were trained on a trial-unique nonmatching-to-location (TUNL) task which assessed the ability to identify a novel touchscreen location after a fixed delay. Once trained, the effects of low-dose isoflurane (0.3 vol%) on task performance and activity, assessed by infrared beam breaks, were assessed. We attempted to rescue deficits in performance and activity with a dopamine D1 receptor agonist (chloro-APB), a noradrenergic reuptake inhibitor (atomoxetine), and a mixed dopamine/norepinephrine releasing agent (dextroamphetamine). Anaesthetic induction, emergence, and recovery from anaesthesia were also investigated. Low-dose isoflurane impaired working memory in a sex-independent and intra-trial delay-independent manner as assessed by task performance, and caused an overall reduction in activity. Administration of chloro-APB, atomoxetine, or dextroamphetamine did not restore visuospatial working memory, but chloro-APB and dextroamphetamine recovered arousal to levels observed in the baseline awake state. Performance did not differ between induction and emergence. Animals recovered to baseline performance within 15 min of discontinuing isoflurane. Low-dose isoflurane impairs visuospatial working memory in a nondurable and delay-independent manner that potentially implicates non-hippocampal structures in isoflurane-induced memory deficits. Dopaminergic psychostimulants counteracted sedation but did not reverse memory impairments, suggesting that isoflurane-induced amnesia and isoflurane-induced sedation have distinct underlying mechanisms that can be antagonised independently.