Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats

Abstract

Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating.

Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

“…However, this needs to be further elucidated. The findings that the cholinergic–dopaminergic reward link is activated by pharmacological‐induced hyperghrelinemia (Jerlhag, 2008; Jerlhag et al., 2012) and that elevated ghrelin levels associated with craving (Addolorato et al., 2006; Koopmann et al., 2012; Leggio et al., 2012), may imply that high plasma levels of ghrelin may be needed for reward interactions. Supportively, animal studies show that hyperghrelinemia is associated with cocaine seeking and that peripheral ghrelin administration augments the cocaine‐induced conditioned place preference and locomotor stimulation (Clifford et al., 2012; Davis et al., 2007; Tessari et al., 2007; Wellman et al., 2005, 2012).…”

Peptide YY and ghrelin predict craving and risk for relapse in abstinent smokers

“…Ghrelin also declines following two months of successful abstinence from nicotine (Lee, Joe et al 2006) but some have shown that ghrelin is not associated nicotine craving and withdrawal symptoms (Mutschler et al, 2012). In addition, ghrelin interacts with the nicotinic acetylcholine receptor to stimulate dopamine release in the brain, particularly in areas related to drug reward and emotional functioning (Jerlhag, Janson, Waters, & Engel, 2012; Palotai et al, 2013a, 2013b). An early genetic study has identified ghrelin genes and personality trait relationships that may have implications for trait differences between alcoholics and non-alcoholics (Landgren et al, 2011).…”

Effects of Long Acting Methylphenidate on Ghrelin Levels in Male Children with Attention Deficit Hyperactivity Disorder: An Open Label Trial

“…Ghrelin increases dopamine receptor D5 and acetylcholine receptor nAChRβ2 gene expression in the VTA and decreases expression of dopamine receptor genes D1, D3 and D5 and acetylcholine receptor gene nAChRα3 in the nucleus accumbens 28 . Ghrelin increases ventral tegmental acetylcholine and increases dopamine release in the nucleus accumbens 57 . It is claimed that glutamate is required for ghrelin to stimulate the mesolimbic dopamine system rather than orexin or opioid signaling 58 .…”

“…Methylphenidate also has a positive dopaminergic effect 1,2 . Dysfunction in the cholinergic-dopaminergic reward system due to hyperghrelinemia is associated with addictive behaviors like compulsive overeating, alcohol use disorder and binge eating whether or not related to bulimia 29,57 .Ghrelin promotes the rewarding, hedonic aspects of eating independent from eating associated with body weight homeostasis 54 . Ghrelin activity is associated with activity or the hippocampus and nucleus accumbens (NA).…”