Ghrelin and ghrelin receptor modulation of psychostimulant action

Abstract

Ghrelin (GHR) is an orexigenic gut peptide that modulates multiple homeostatic functions including gastric emptying, anxiety, stress, memory, feeding, and reinforcement. GHR is known to bind and activate growth-hormone secretagogue receptors (termed GHR-Rs). Of interest to our laboratory has been the assessment of the impact of GHR modulation of the locomotor activation and reward/reinforcement properties of psychostimulants such as cocaine and nicotine. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP) in rats, as does food restriction (FR) which elevates plasma ghrelin levels. Ghrelin enhancement of psychostimulant function may occur owing to a direct action on mesolimbic dopamine function or may reflect an indirect action of ghrelin on glucocorticoid pathways. Genomic or pharmacological ablation of GHR-Rs attenuates the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and blunts the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. Inactivation of ghrelin circuit function in rats by injection of a ghrelin receptor antagonist (e.g., JMV 2959) diminishes the development of nicotine-induced locomotor sensitization. These results suggest a key permissive role for GHR-R activity for the induction of locomotor sensitization to nicotine. Our finding that GHR-R null rats exhibit diminished patterns of responding for intracranial self-stimulation complements an emerging literature implicating central GHR circuits in drug reward/reinforcement. Finally, antagonism of GHR-Rs may represent a smoking cessation modality that not only blocks nicotine-induced reward but that also may limit weight gain after smoking cessation.

Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking

“…; Jerlhag & Engel ; Wellman et al . ; Wellman, Clifford & Rodriguez ), which further supports our hypothesis that ghrelin signaling system regulates reward in general.…”

Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling

“…These observations point out a role for the ghrelin signaling on HFD sensitization. Interestingly, GHSR-deficient mice also exhibit diminished behavioral activation and reinforcement responses to cocaine and nicotine (Abizaid et al, 2011;Jerlhag and Engel, 2011), and it has been proposed that ghrelin signaling could induce a form of central sensitization in which animals are more reactive to rewarding stimuli (Wellman et al, 2013). Indeed, it has been shown that GHSR-deficient mice display a reduced anticipatory locomotor response to scheduled meals (Blum et al, 2009).…”

Khat use and appetite: An overview and comparison of amphetamine, khat and cathinone

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