title: Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.
abstract: Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg i.v.), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg i.v.) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz) to θ (4-8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes significant neurophysiological changes, but does not promote behavioral arousal during general anesthesia. We hypothesize that dextroamphetamine is more likely than atomoxetine to be clinically useful for restoring consciousness in anesthetized patients, mainly due to its stimulation of dopaminergic neurotransmission.
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Kenny
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Taylor
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts, United States of America; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Emery N
authors.initials: EN
authors.lastname: Brown
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ken
authors.initials: K
authors.lastname: Solt
mesh_terms: D000768:Anesthesia, General / Q000379:methods; D000818:Animals; D001143:Arousal / Q000187:drug effects; D000069445:Atomoxetine Hydrochloride / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D003243:Consciousness / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004569:Electroencephalography / Q000187:drug effects; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology; D008774:Methylphenidate / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D000077149:Sevoflurane
chemical_list: D001552:Benzazepines; D008738:Methyl Ethers; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D008774:Methylphenidate; D000077149:Sevoflurane; D000069445:Atomoxetine Hydrochloride; D003913:Dextroamphetamine; D004298:Dopamine; D009638:Norepinephrine; D015742:Propofol