Activation of D1 Dopamine Receptors Induces Emergence from Isoflurane General Anesthesia

Abstract

BACKGROUND A recent study showed that methylphenidate induces emergence from isoflurane anesthesia. Methylphenidate inhibits dopamine and norepinephrine reuptake transporters. The objective of this study was to test the hypothesis that selective dopamine receptor activation induces emergence from isoflurane anesthesia. METHODS In adult rats, we tested the effects of chloro-APB (D1 agonist) and quinpirole (D2 agonist) on time to emergence from isoflurane general anesthesia. We then performed a dose–response study to test for chloro-APB-induced restoration of righting during continuous isoflurane anesthesia. SCH-23390 (D1 antagonist) was used to confirm that the effects induced by chloro-APB are specifically mediated by D1 receptors. In a separate group of animals, spectral analysis was performed on surface electroencephalogram recordings to assess neurophysiological changes induced by chloro-APB and quinpirole during isoflurane general anesthesia. RESULTS Chloro-APB decreased median time to emergence from 330s to 50s. The median difference in time to emergence between the saline control group (n=6) and the chloro-APB group (n = 6) was 222s (95% CI: 77–534s, Mann-Whitney test). This difference was statistically significant (p = 0.0082). During continuous isoflurane anesthesia, chloro-APB dose-dependently restored righting (n = 6) and decreased electroencephalogram delta power (n = 4). These effects were inhibited by pretreatment with SCH-23390. Quinpirole did not restore righting (n = 6) and had no significant effect on the electroencephalogram (n = 4) during continuous isoflurane anesthesia. CONCLUSIONS Activation of D1 receptors by chloro-APB decreases time to emergence from isoflurane anesthesia, and produces behavioral and neurophysiological evidence of arousal during continuous isoflurane anesthesia. These findings suggest that selective activation of a D1 receptor-mediated arousal mechanism is sufficient to induce emergence from isoflurane general anesthesia.

Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia

“…(30). Conversely, chloro-APB, a specific D1 receptor agonist, induced a decrease in δ-power but failed to induce an increase in θ-power, and yet produced profound behavioral arousal during CSSGA (28). Taken together, these results suggest that surface EEG changes may not adequately reflect arousal states, and that efforts should be made to investigate changes in local field potentials and their correlation with surface EEG.…”

“…Using continuous, steady-state general anesthesia (CSSGA), we previously demonstrated that DA transporter (DAT) inhibitors (methylphenidate, dextroamphetamine) and a D1 receptor agonist (chloro-APB) reliably restore conscious behaviors, including the righting reflex in rats anesthetized with isoflurane, propofol, and sevoflurane (27)(28)(29)(30). The ability to reverse the actions of chemically diverse anesthetics such as propofol (an alkyl phenol) and sevoflurane (a halogenated ether) strongly suggests that DAT inhibitors induce reanimation from general anesthesia not by molecular-level antagonism of the anesthetic but rather by stimulating arousal at the level of neural circuits.…”

Dopamine-enhancing Medications to Accelerate Emergence from General Anesthesia

“…The authors conclude that selective activation of D1Rs is sufficient to induce emergence from isoflurane general anesthesia and that D2Rs are not needed. 5 These new data in the setting of isoflurane anesthesia are intriguing and supplement older data reporting similar findings with phenobarbital anesthesia. 6,7 Specifically, Horita et al 7 investigated the effects of a D1R agonist (1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) and a D2R antagonist (raclopride) on duration of phenobarbital anesthesia in rats (administered only 20 min after induction with 40 mg/kg intraperitoneal phenobarbital to reduce pharmacokinetic effects on emergence).…”

“…In this issue of Anesthesiology, Taylor et al 5 report that the dopamine-1 receptor (D1R) agonist 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide but not the D2R agonist quinpirole reduces the time to emergence from isoflurane anesthesia in rats by 85% compared with placebo. The authors conclude that selective activation of D1Rs is sufficient to induce emergence from isoflurane general anesthesia and that D2Rs are not needed.…”

Mechanisms of Anesthetic Emergence: Evidence for Active Reanimation

“…This study suggests that the locus coeruleus dampens thiopental anesthesia but facilitates ketamine anesthesia and argues for a role of the locus coeruleus in mediating the action of anesthetics. [42]. These results indicate that methylphenidate may be useful in reversing general anesthetic-induced unconsciousness and respiratory depression at the end of surgery, and potentially may be used in day-surgery patients.…”