Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors

Featured Paper of the Month – June 2022

Published in Neuropsychopharmacology by Zhi-Bing You, Ph.D. and Eliot Gardner, Ph.D., et al. of the NIDA IRP Neuropsychopharmacology Section.

Summary

Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of anti-addiction, anti-craving, and anti-relapse medications for cocaine addiction remains largely unsuccessful. To aid this medication development, more knowledge is needed about the brain circuits and mechanisms that underlie addiction. In the present article, the authors show that: (1) elevation of the brain hormone ghrelin by cocaine plays a critical role in cocaine-taking and in cocaine-seeking behaviors; (2) acquisition of cocaine-taking behavior is associated with enhancement of the stimulatory effects of cocaine and of cocaine-associated environmental cues on brain ghrelin; (3) cocaine-taking behavior is associated with an increase in genetic coding for ghrelin receptors in the reward, craving, and relapse circuits of the brain; (4) blockade of ghrelin signaling in the brain inhibits relapse to cocaine-seeking behavior; and (5) blockade of the effects of noradrenaline receptors outside the brain on ghrelin inside the brain inhibits cocaine-taking and relapse to cocaine addiction. These findings show that ghrelin plays an important role in brain mechanisms underlying cocaine addiction. Therefore, targeting the body’s ghrelin system may be a useful strategy for developing anti-cocaine-addiction medications.

Publication Information

You, Zhi-Bing; Galaj, Ewa; Alén, Francisco; Wang, Bin; Bi, Guo-Hua; Moore, Allamar R; Buck, Tristram; Crissman, Madeline; Pari, Sruti; Xi, Zheng-Xiong; Leggio, Lorenzo; Wise, Roy A; Gardner, Eliot L

Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors Journal Article

In: Neuropsychopharmacology, 2021, ISSN: 1740-634X.

Abstract | Links

@article{pmid34923576,

title = {Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral β1 receptors},

author = {Zhi-Bing You and Ewa Galaj and Francisco Alén and Bin Wang and Guo-Hua Bi and Allamar R Moore and Tristram Buck and Madeline Crissman and Sruti Pari and Zheng-Xiong Xi and Lorenzo Leggio and Roy A Wise and Eliot L Gardner},

url = {https://pubmed.ncbi.nlm.nih.gov/34923576/},

doi = {10.1038/s41386-021-01249-2},

issn = {1740-634X},

year  = {2021},

date = {2021-12-01},

urldate = {2021-12-01},

journal = {Neuropsychopharmacology},

abstract = {Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic β1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.},

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pubstate = {published},

tppubtype = {article}

}