Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role

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, the authors demonstrate that elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli. The 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). 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. Furthermore, JMV2959 pretreatment also inhibits brain stimulation reward and cocaine-potentiated brain stimulation reward maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice. 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 suggest that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and may provide a viable target for mitigating cocaine use disorder.