Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non-human primates

• Type of Material: Article
• Authors: K. S. Murnane, Emory University; M. L. Andersen, Emory University; K. C. Rice, National Institute of Health; Leonard Howell, Emory University
• Language: English
• Date: 2013-10-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 European Sleep Research Society.
• Final Published Version (URL): http://dx.doi.org/10.1111/jsr.12045
• Title of Journal or Parent Work: Journal of Sleep Research
• ISSN: 0962-1105
• Volume: 22
• Issue: 5
• Start Page: 581
• End Page: 588
• Grant/Funding Information: A portion of this work was supported by the Intramural Research Programs of National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism.; These studies were supported by USPHS grants (DA010344, DA012514, and RR000165).
• Keywords: Receptors, Dopamine; Arousal; Receptor, Serotonin, 5-HT2A; Telemetry; Central Nervous System Stimulants; Amphetamine; Caudate Nucleus; Dopamine; Piperidines; Animals; Circadian Rhythm; Wakefulness; Microdialysis; Sleep; Serotonin 5-HT2 Receptor Antagonists; Fluorobenzenes; Female; Dopamine Uptake Inhibitors; Macaca mulatta
• Research Categories: Biology, Neuroscience; Psychology, Psychobiology

Abstract

The objective of the present study was to further elucidate the mechanisms involved in the wake-promoting effects of psychomotor-stimulants. Many previous studies have tightly linked the effects of stimulants to dopamine neurotransmission, and some studies indicate that serotonin 2A receptors modulate these effects. However, the role of dopamine in arousal is controversial, most notably because dopamine neurons do not change firing rates across arousal states. In the present study, we examined the wake-promoting effects of the dopamine-releaser amphetamine using non-invasive telemetric monitoring. These effects were evaluated in rhesus monkeys as a laboratory animal model with high translational relevance for human disorders of sleep and arousal. To evaluate the role of dopamine in the wake-promoting effects of amphetamine, we used in vivo microdialysis targeting the caudate nucleus, as this approach provides clearly interpretable measures of presynaptic dopamine release. This is beneficial in the present context because some of the inconsistencies between previous studies examining the role of dopamine in arousal may be related to differences between postsynaptic dopamine receptors. We found that amphetamine significantly and dose-dependently increased arousal at doses that engendered higher extracellular dopamine levels. Moreover, antagonism of serotonin 2A receptors attenuated the effects of amphetamine on both wakefulness and dopamine overflow. These findings further elucidate the role of dopamine and serotonin 2A receptors in arousal, and they suggest that increased dopamine neurotransmission may be necessary for the wake-promoting effects of amphetamine, and possibly other stimulants.