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Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

Kenny JD, Taylor NE, Brown EN, Solt K - PLoS ONE (2015)

Bottom Line: The difference was statistically significant.Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Dextroamphetamine restores righting during continuous sevoflurane general anesthesia, but atomoxetine does not.(A) Rats inhaled sevoflurane at a dose sufficient to maintain loss of righting for at least 25 consecutive minutes. They then received intravenous normal saline or SCH-23390 (0.2 mg/kg). Five minutes later, atomoxetine or dextroamphetamine was administered intravenously. Sevoflurane was maintained at the same dose for ten additional minutes, or until return of righting occurred. (B) Empirical cumulative distribution function for time to righting after the administration of dextroamphetamine. Dextroamphetamine restored righting within 10 minutes in 6/6 rats at doses of 1 mg/kg and 3 mg/kg IV, and in 3/6 rats at a dose of 0.3 mg/kg IV. (C) Atomoxetine did not restore righting within ten minutes of administration in any animals, regardless of the dose (n = 6 each). Even at the highest dose (3 mg/kg IV) atomoxetine did not elicit any behavioral signs of arousal. (D) In rats pretreated with SCH-23390, dextroamphetamine (1 mg/kg IV) did not restore righting in any animals (n = 6).
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pone.0131914.g001: Dextroamphetamine restores righting during continuous sevoflurane general anesthesia, but atomoxetine does not.(A) Rats inhaled sevoflurane at a dose sufficient to maintain loss of righting for at least 25 consecutive minutes. They then received intravenous normal saline or SCH-23390 (0.2 mg/kg). Five minutes later, atomoxetine or dextroamphetamine was administered intravenously. Sevoflurane was maintained at the same dose for ten additional minutes, or until return of righting occurred. (B) Empirical cumulative distribution function for time to righting after the administration of dextroamphetamine. Dextroamphetamine restored righting within 10 minutes in 6/6 rats at doses of 1 mg/kg and 3 mg/kg IV, and in 3/6 rats at a dose of 0.3 mg/kg IV. (C) Atomoxetine did not restore righting within ten minutes of administration in any animals, regardless of the dose (n = 6 each). Even at the highest dose (3 mg/kg IV) atomoxetine did not elicit any behavioral signs of arousal. (D) In rats pretreated with SCH-23390, dextroamphetamine (1 mg/kg IV) did not restore righting in any animals (n = 6).

Mentions: Fig 1A illustrates the protocol for this experiment. After establishing an inhaled concentration of sevoflurane sufficient to maintain loss of righting for 25 minutes, normal saline was administered intravenously. No animals exhibited a behavioral arousal response after the injection of normal saline. Five minutes later, atomoxetine or dextroamphetamine was administered. The final mean inhaled concentration of sevoflurane was 1.7% (95% CI: 1.6 to 1.7%) for both the atomoxetine and dextroamphetamine groups.


Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

Kenny JD, Taylor NE, Brown EN, Solt K - PLoS ONE (2015)

Dextroamphetamine restores righting during continuous sevoflurane general anesthesia, but atomoxetine does not.(A) Rats inhaled sevoflurane at a dose sufficient to maintain loss of righting for at least 25 consecutive minutes. They then received intravenous normal saline or SCH-23390 (0.2 mg/kg). Five minutes later, atomoxetine or dextroamphetamine was administered intravenously. Sevoflurane was maintained at the same dose for ten additional minutes, or until return of righting occurred. (B) Empirical cumulative distribution function for time to righting after the administration of dextroamphetamine. Dextroamphetamine restored righting within 10 minutes in 6/6 rats at doses of 1 mg/kg and 3 mg/kg IV, and in 3/6 rats at a dose of 0.3 mg/kg IV. (C) Atomoxetine did not restore righting within ten minutes of administration in any animals, regardless of the dose (n = 6 each). Even at the highest dose (3 mg/kg IV) atomoxetine did not elicit any behavioral signs of arousal. (D) In rats pretreated with SCH-23390, dextroamphetamine (1 mg/kg IV) did not restore righting in any animals (n = 6).
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pone.0131914.g001: Dextroamphetamine restores righting during continuous sevoflurane general anesthesia, but atomoxetine does not.(A) Rats inhaled sevoflurane at a dose sufficient to maintain loss of righting for at least 25 consecutive minutes. They then received intravenous normal saline or SCH-23390 (0.2 mg/kg). Five minutes later, atomoxetine or dextroamphetamine was administered intravenously. Sevoflurane was maintained at the same dose for ten additional minutes, or until return of righting occurred. (B) Empirical cumulative distribution function for time to righting after the administration of dextroamphetamine. Dextroamphetamine restored righting within 10 minutes in 6/6 rats at doses of 1 mg/kg and 3 mg/kg IV, and in 3/6 rats at a dose of 0.3 mg/kg IV. (C) Atomoxetine did not restore righting within ten minutes of administration in any animals, regardless of the dose (n = 6 each). Even at the highest dose (3 mg/kg IV) atomoxetine did not elicit any behavioral signs of arousal. (D) In rats pretreated with SCH-23390, dextroamphetamine (1 mg/kg IV) did not restore righting in any animals (n = 6).
Mentions: Fig 1A illustrates the protocol for this experiment. After establishing an inhaled concentration of sevoflurane sufficient to maintain loss of righting for 25 minutes, normal saline was administered intravenously. No animals exhibited a behavioral arousal response after the injection of normal saline. Five minutes later, atomoxetine or dextroamphetamine was administered. The final mean inhaled concentration of sevoflurane was 1.7% (95% CI: 1.6 to 1.7%) for both the atomoxetine and dextroamphetamine groups.

Bottom Line: The difference was statistically significant.Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus