Review
The role of the central ghrelin system in reward from food and chemical drugs

https://doi.org/10.1016/j.mce.2011.02.017Get rights and content

Abstract

Here we review recent advances that identify a role for the central ghrelin signalling system in reward from both natural rewards (such as food) and artificial rewards (that include alcohol and drugs of abuse). Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called “cholinergic–dopaminergic reward link”. This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the “cholinergic–dopaminergic” reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour (“wanting” or “incentive motivation”). Further, direct injection of ghrelin into the brain ventricles or into the VTA increases the consumption of rewarding foods as well as alcohol in mice and rats. Studies in rodents show beneficial effects of ghrelin receptor (GHS-R1A) antagonists to suppress the intake of palatable food, to reduce preference for caloric foods, to suppress food reward and motivated behaviour for food. They have also been shown to reduce alcohol consumption, suppress reward induced by alcohol, cocaine and amphetamine. Furthermore, variations in the GHS-R1A and pro-ghrelin genes have been associated with high alcohol consumption, smoking and increased weight gain in alcohol dependent individuals as well as with bulimia nervosa and obesity. Thus, the central ghrelin signalling system interfaces neurobiological circuits involved in reward from food as well as chemical drugs; agents that directly or indirectly suppress this system emerge as potential candidate drugs for suppressing problematic over-eating that leads to obesity as well as for the treatment of substance use disorder.

Section snippets

The central ghrelin signalling system

The “central ghrelin signalling system” is recognised as an important CNS target for the control of food intake (Wren et al., 2000) and energy balance (Lall et al., 2001, Tschöp et al., 2000). Here we review the emerging concept that this system operates at the interface between neurobiological circuits involved in appetite and reward, increasing the incentive motivational value of both natural rewards (such as food) and artificial rewards (such as drugs of abuse).

We have coined the term

The physiological role of ghrelin: from hunger to reward-seeking

Soon after the discovery of ghrelin, the first endogenous ligand for GHS-R1A (Kojima et al., 1999), it became clear that this receptor is also a potentially interesting target for controlling food intake and obesity. In rodents, acute injection of ghrelin, peripherally or centrally, induces a rapid orexigenic response (Asakawa et al., 2001, Wren et al., 2000). It was also found that chronic stimulation of this receptor by ghrelin (Tschöp et al., 2000) or by synthetic growth hormone

The central ghrelin signalling system integrates with a key reward pathway

The mesolimbic dopamine pathway (Fig. 1) from the VTA to the N.Acc, that has a rather well-established role in incentive motivation (i.e. wanting) (Berridge and Robinson, 2003), is clearly an important component of the central ghrelin-responsive network. Ghrelin receptors are present in the VTA (Guan et al., 1997, Zigman et al., 2006), including a sub-population of dopamine cells in this region (Abizaid et al., 2006). Both central and intra-VTA administration of ghrelin induces an increase in

The central ghrelin signalling system is required for reward from drugs of abuse, including alcohol

Alcohol dependence, one of the major causes of death, is a chronic relapsing disease and is also a major cost for the society. Available treatments include medical, psychosocial as well as social interventions, which may help to increase time to relapse and to reduce the intake of alcohol. Alcohol dependence is a heterogeneous disorder where several signalling systems play important roles. By understanding the complex mechanisms underlying this disease new treatment strategies may be developed.

The central ghrelin signalling system is required for reward from food

In normal physiology, it seems likely that ghrelin does indeed operate as a circulating hunger hormone, conferring information to the brain about energy deficit and then interacting with key brain circuits to manifest a coordinated feeding response. This is achieved, in part, through activation of the aforementioned hypothalamic and brainstem circuits involved in energy homeostasis. Specifically, it has been shown that ghrelin increases food intake via activation of homeostatic feeding circuits

Conclusions

The exact circuitry and mechanisms through which ghrelin modulates the intake and seeking of rewards remains to be further elucidated, but likely involves actions at the level of the cholinergic–dopaminergic reward system. GHS-R1A is expressed pre- and post-synaptically in the VTA (Abizaid et al., 2006) as well as on cholinergic neurons in the LDTg (Dickson et al., 2010). Ghrelin injection into these discrete brain regions increases accumbal dopamine (Jerlhag et al., 2007) increases alcohol

Acknowledgments

Supported by the EU (FP7-HEALTH-2009-241592, FP7-KBBE-2009-3-245009; FP7-KBBE-2010-266408), Swedish Medical Research Council (K2007-54X-20328–013, K2006-21X-04247-33-3, 2009-S266, and 2009-2782), ALF/LUA grants from the Sahlgrenska Hospital Göteborg (SU7601, 7136, 7341, ALFGBG-138741, -148251), the Alcohol Research Council of the Swedish Alcohol Retailing Monopoly, The Swedish brain foundation, the foundations of Wilhelm and Martina Lundgren, Knut and Alice Wallenberg, The Adlerbert Research,

References (125)

  • E. Disse et al.

    Peripheral ghrelin enhances sweet taste food consumption and preference, regardless of its caloric content

    Physiology & Behavior

    (2010)
  • W. Dyr et al.

    Effects of D1 and D2 dopamine receptor agents on ethanol-consumption in the high-alcohol-drinking (Had) line of rats

    Alcohol

    (1993)
  • M. El-Ghundi et al.

    Disruption of dopamine D-1 receptor gene expression attenuates alcohol-seeking behavior

    European Journal of Pharmacology

    (1998)
  • C.R. Erdie-Lalena et al.

    Ghrelin levels in young children with Prader-Willi syndrome

    Journal of Pediatrics

    (2006)
  • P.S. Grigson

    Like drugs for chocolate: separate rewards modulated by common mechanisms?

    Physiology & Behavior

    (2002)
  • X.M. Guan et al.

    Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues

    Molecular Brain Research

    (1997)
  • L. Hernandez et al.

    Feeding and hypothalamic stimulation increase dopamine turnover in the accumbens

    Physiology & Behavior

    (1988)
  • B. Holst et al.

    Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation Trends in Pharmacological

    Sciences

    (2004)
  • E. Jerlhag et al.

    Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens

    European Neuropsychopharmacolology

    (2008)
  • S. Lall et al.

    Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues

    Biochemical and Biophysical Research Communications

    (2001)
  • A. Larsson et al.

    Neurochemical and behavioral studies on ethanol and nicotine interactions

    Neuroscience and Biobehavioral Reviews

    (2004)
  • A. Lindqvist et al.

    Overeating of palatable food is associated with blunted leptin and ghrelin responses

    Regulatory Peptides

    (2005)
  • S. Malik et al.

    Ghrelin modulates brain activity in areas that control appetitive behavior

    Cell Metabolism

    (2008)
  • S.A. McKee et al.

    Varenicline reduces alcohol self-administration in heavy-drinking smokers

    Biological Psychiatry

    (2009)
  • J. Mokrosinski et al.

    Modulation of the constitutive activity of the ghrelin receptor by use of pharmacological tools and mutagenesis

    Methods in Enzymology

    (2010)
  • A.M. Naleid et al.

    Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens

    Peptides

    (2005)
  • P.K. Olszewski et al.

    Hypothalamic paraventricular injections of ghrelin: effect on feeding and c-Fos immunoreactivity

    Peptides

    (2003)
  • P.K. Olszewski et al.

    Neural basis of orexigenic effects of ghrelin acting within lateral hypothalamus

    Peptides

    (2003)
  • M. Perello et al.

    Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner

    Biological Psychiatry

    (2010)
  • D. Quarta et al.

    Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens

    Neurochemistry International

    (2009)
  • P.V. Rada et al.

    Acetylcholine release in ventral tegmental area by hypothalamic self-stimulation, eating, and drinking

    Pharmacology Biochemistry and Behavior

    (2000)
  • T.E. Robinson et al.

    The neural basis of drug craving – an incentive-sensitization theory of addiction

    Brain Research Reviews

    (1993)
  • N. Salomé et al.

    Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats

    European Journal of Pharmacology

    (2009)
  • A. Abizaid et al.

    Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

    Journal of Clinical Investigation

    (2006)
  • G. Addolorato et al.

    Relationship between ghrelin levels, nutritional status and craving in current alcoholics

    Alcoholism – Clinical and Experimental Research

    (2006)
  • T. Ando et al.

    Possible role of preproghrelin gene polymorphisms in susceptibility to bulimia nervosa

    American Journal of Medical Genetics Part B – Neuropsychiatric Genetics

    (2006)
  • A. Asakawa et al.

    Antagonism of ghrelin receptor reduces food intake and body weight gain in mice

    Gut

    (2003)
  • A. Badaoui et al.

    Alcohol dependence is associated with reduced plasma and fundic ghrelin levels

    European Journal of Clinical Investigation

    (2008)
  • A. Baessler et al.

    Genetic linkage and association of the growth hormone secretagogue receptor (Ghrelin receptor) gene in human obesity

    Diabetes

    (2005)
  • C.Y. Bowers et al.

    On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone

    Endocrinology

    (1984)
  • D.I. Briggs et al.

    Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons

    Endocrinology

    (2010)
  • C.M. Bulik

    Family histories of bulimic women with and without comorbid alcohol abuse or dependence

    American Journal of Psychiatry

    (1991)
  • J. Calissendorff et al.

    Inhibitory effect of alcohol on ghrelin secretion in normal man

    European Journal of Endocrinology

    (2005)
  • M.E. Carroll et al.

    Food-deprivation increases oral and intravenous drug intake in rats

    Science

    (1979)
  • R.D. Cone et al.

    The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis

    International Journal of Obesity and Related Metabolic Disorders

    (2001)
  • D.E. Cummings et al.

    Elevated plasma ghrelin levels in Prader-Willi syndrome Nature

    Medicine

    (2002)
  • D.E. Cummings et al.

    Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues

    American Journal of Physiology – Endocrinology and Metabolism

    (2004)
  • D.E. Cummings et al.

    A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

    Diabetes

    (2001)
  • S.L. Dickson et al.

    Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6

    Endocrinology

    (1997)
  • C. Dornonville de la Cour et al.

    Ghrelin treatment reverses the reduction in weight gain and body fat in gastrectomised mice

    Gut

    (2005)
  • Cited by (0)

    View full text