Stimulating one of two dopamine-producing regions in the brain was able to arouse animals receiving general anesthesia with either isoflurane or propofol. In the August issue of Anesthesiology, investigators from Massachusetts General Hospital (MGH) report that rats anesthetized with continuous doses of either agent would move, raise their heads and even stand up in response to electrical stimulation delivered to the ventral tegmental area (VTA). Stimulation of the other major dopamine-releasing area, the substantia nigra, did not induce the animals to wake up.
“Dopamine cells in the VTA are involved in cognition, motivation and reward, while cells in the substantia nigra are important for movement; and our results showed that VTA cells may also be involved in dopamine’s known arousal function.” explains Ken Solt, MD, of the MGH Department of Anesthesia, Critical Care and Pain Medicine, corresponding author of the report. “Clinically, emergence from general anesthesia is still a passive process during which we just wait for the drugs to wear off and the patient to wake up, a process that can take from a few minutes to an hour or longer. Finding a way to safely arouse patients from anesthesia could both improve operating room efficiency and, even more importantly, may reduce problems such as postoperative delirium and cognitive dysfunction.”
Previous studies by Solt and his colleagues have shown that administration of the stimulant drug methylphenidate (Ritalin), known to enhance dopamine-mediated neurotransmission, aroused animals receiving general anesthesia with either inhaled isoflurane or intravenous propofol. An additional study found that activating dopamine receptors also induced reanimation in anesthetized animals, but since older evidence implied that dopamine had no significant role in maintaining wakefulness, the MGH team designed the current study to investigate more directly the role of the brain’s major dopamine-releasing structures in emergence from anesthesia.
Tiny electrodes were placed in either the VTA or the substantia nigra of anesthetized rats. Application of a mild electric current stimulates only the tissues directly adjacent to the electrodes, inducing dopamine release. Both groups of animals received continuous isoflurane anesthesia at a dose sufficient to maintain unconsciousness; but while electrical stimulation of the VTA successfully reanimated all animals in which electrodes were correctly positioned, stimulation of the substantia nigra produced no arousal response. Several days later the experiment was repeated using propofol in the animals that had reanimated with VTA stimulation, and again VTA stimulation restored conscious behaviors. A subsequent experiment showed that EEG recordings from anesthetized animals shifted to patterns associated with arousal in response to stimulation of the VTA but not to substantia nigra stimulation.
“These results suggest that the results of our methylphenidate studies were produced by increased dopamine release from the VTA,” says Solt, an assistant professor of Anæsthesia at Harvard Medical School. “Now we need to investigate the specific role of dopamine neurons and whether activating those cells could help prevent or treat postoperative problems.”
Co-authors of the Anesthesiology paper are Christa Van Dort, PhD, Jessica Chemali, Norman Taylor, MD, PhD, Jonathan Kenny, and senior author Emery N. Brown, MD, PhD, all of the MGH Department of Anesthesia, Critical Care and Pain Medicine. The study was supported by National Institutes of Health grants TR01-GM104948, DP1-OD003646, and K08-GM094394.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $785 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.
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