Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system

Recently, we demonstrated that the central ghrelin signalling system, involving the ghrelin receptor (GHS‐R1A), is important for alcohol reinforcement. Ghrelin targets a key mesolimbic circuit involved in natural as well as drug‐induced reinforcement, that includes a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present study was to determine whether it is possible to suppress ghrelin's effects on this mesolimbic dopaminergic pathway can be suppressed, by interrupting afferent inputs to the VTA dopaminergic cells, as shown previously for cholinergic afferents. Thus, the effects of pharmacological suppression of glutamatergic, orexin A and opioid neurotransmitter systems on ghrelin‐induced activation of the mesolimbic dopamine system were investigated. We found in the present study that ghrelin‐induced locomotor stimulation was attenuated by VTA administration of the N‐methyl‐D‐aspartic acid receptor antagonist (AP5) but not by VTA administration of an orexin A receptor antagonist (SB334867) or by peripheral administration of an opioid receptor antagonist (naltrexone). Intra‐VTA administration of AP5 also suppressed the ghrelin‐induced dopamine release in the nucleus accumbens. Finally the effects of peripheral ghrelin on locomotor stimulation and accumbal dopamine release were blocked by intra‐VTA administration of a GHS‐R1A antagonist (BIM28163), indicating that GHS‐R1A signalling within the VTA is required for the ghrelin‐induced activation of the mesolimbic dopamine system. Given the clinical knowledge that hyperghrelinemia is associated with addictive behaviours (such as compulsive overeating and alcohol use disorder) our finding highlights a potential therapeutic strategy involving glutamatergic control of ghrelin action at the level of the mesolimbic dopamine system.

[1]  R. Wise,et al.  A psychomotor stimulant theory of addiction. , 1987, Psychological review.

[2]  C. Lawrence,et al.  Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. , 2002, Endocrinology.

[3]  I. Robinson,et al.  Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons , 1993, Neuroscience.

[4]  H. Fibiger,et al.  Feeding-evoked dopamine release in the nucleus accumbens: regulation by glutamatergic mechanisms , 1997, Neuroscience.

[5]  T. Horvath,et al.  Novel analogs of ghrelin: physiological and clinical implications. , 2004, European journal of endocrinology.

[6]  Gary Aston-Jones,et al.  Orexin/hypocretin signaling at the orexin 1 receptor regulates cue‐elicited cocaine‐seeking , 2009, The European journal of neuroscience.

[7]  L. Leila,et al.  theoretical and clinical implications , 1992 .

[8]  M. Kenneally,et al.  Where Is the Novel , 1989 .

[9]  D. Feldman,et al.  Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity , 2008, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[10]  J. Kornhuber,et al.  Ghrelin levels are increased in alcoholism. , 2005, Alcoholism, clinical and experimental research.

[11]  G. Di Chiara,et al.  Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. , 1986, The Journal of pharmacology and experimental therapeutics.

[12]  T. Sakurai,et al.  Ghrelin-induced food intake is mediated via the orexin pathway. , 2003, Endocrinology.

[13]  Roy G. Smith,et al.  Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. , 2006, Molecular endocrinology.

[14]  S. M. Robinson,et al.  Extent and Direction of Ghrelin Transport Across the Blood-Brain Barrier Is Determined by Its Unique Primary Structure , 2002, Journal of Pharmacology and Experimental Therapeutics.

[15]  M. Nakazato,et al.  A role for ghrelin in the central regulation of feeding , 2001, Nature.

[16]  T. Svensson,et al.  Putative role of presynaptic α7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area , 2000, Synapse.

[17]  P. Kalivas,et al.  GABA and enkephalin projection from the nucleus accumbens and ventral pallidum to the ventral tegmental area , 1993, Neuroscience.

[18]  J. Watkins,et al.  Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord , 1982, Brain Research.

[19]  B. Wisse,et al.  A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. , 2001, Diabetes.

[20]  T. Bartness,et al.  Peripheral ghrelin injections stimulate food intake, foraging, and food hoarding in Siberian hamsters. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[21]  S. Dickson,et al.  Systemic Administration of Ghrelin Induces Fos and Egr‐1 Proteins in the Hypothalamic Arcuate Nucleus of Fasted and Fed Rats , 2000, Journal of neuroendocrinology.

[22]  S. Dickson,et al.  PRECLINICAL STUDY: Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens , 2007, Addiction biology.

[23]  P. Wellman,et al.  Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin , 2007, Regulatory Peptides.

[24]  S. Melotto,et al.  PRECLINICAL STUDY: Correlation between serum ghrelin levels and cocaine‐seeking behaviour triggered by cocaine‐associated conditioned stimuli in rats , 2007, Addiction biology.

[25]  Dickson,et al.  Growth Hormone Secretagogue Activation of the Arcuate Nucleus and Brainstem Occurs Via a Non‐Noradrenergic Pathway , 2000, Journal of neuroendocrinology.

[26]  D. Moechars,et al.  Requirement of central ghrelin signaling for alcohol reward , 2009, Proceedings of the National Academy of Sciences.

[27]  M. Nakazato,et al.  Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. , 2000, Endocrinology.

[28]  Roy G. Smith,et al.  Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. , 1997, Brain research. Molecular brain research.

[29]  A. Herz.  Endogenous opioid systems and alcohol addiction , 1997, Psychopharmacology.

[30]  A. Levine,et al.  Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens , 2005, Peptides.

[31]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[32]  E. Jerlhag,et al.  PRECLINICAL STUDY: Systemic administration of ghrelin induces conditioned place preference and stimulates accumbal dopamine , 2008, Addiction biology.

[33]  R. Wise.  Brain Reward Circuitry Insights from Unsensed Incentives , 2002, Neuron.

[34]  Helen Young,et al.  Society for the study of addiction. , 1999, Addiction biology.

[35]  S. Bloom,et al.  The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. , 2000, Endocrinology.

[36]  W. Banks,et al.  Ghrelin controls hippocampal spine synapse density and memory performance , 2006, Nature Neuroscience.

[37]  S. Melotto,et al.  Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens , 2009, Neurochemistry International.

[38]  Alain Dagher,et al.  Ghrelin modulates brain activity in areas that control appetitive behavior. , 2008, Cell metabolism.

[39]  B. Peterson,et al.  Increased fasting plasma ghrelin levels during alcohol abstinence. , 2005, Alcohol and alcoholism.

[40]  Xiao-Bing Gao,et al.  Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. , 2006, The Journal of clinical investigation.

[41]  C. Fahlke,et al.  Biochemical and behavioral evidence for an interaction between ethanol and calcium channel antagonists , 2005, Journal of Neural Transmission.

[42]  G. Aston-Jones,et al.  Activation of Ventral Tegmental Area Cells by the Bed Nucleus of the Stria Terminalis: A Novel Excitatory Amino Acid Input to Midbrain Dopamine Neurons , 2002, The Journal of Neuroscience.

[43]  T. Svensson,et al.  N-methyl-d-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens , 1997, Neuroscience.

[44]  S. Dickson,et al.  Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens , 2008, European Neuropsychopharmacology.

[45]  S. Geisler,et al.  Afferents of the ventral tegmental area in the rat‐anatomical substratum for integrative functions , 2005, The Journal of comparative neurology.

[46]  M. Tschöp,et al.  Ghrelin induces adiposity in rodents , 2000, Nature.

[47]  P. Wellman,et al.  Augmentation of cocaine hyperactivity in rats by systemic ghrelin , 2005, Regulatory Peptides.

[48]  D. R. Sparta,et al.  Alcoholism and obesity: overlapping neuropeptide pathways? , 2003, Neuropeptides.

[49]  A. Nishi,et al.  Peripherally administered ghrelin induces bimodal effects on the mesolimbic dopamine system depending on food-consumptive states , 2009, Neuroscience.

[50]  S. Dickson,et al.  PRECLINICAL STUDY: Ghrelin stimulates locomotor activity and accumbal dopamine‐overflow via central cholinergic systems in mice: implications for its involvement in brain reward , 2006, Addiction biology.

[51]  B. Hoebel,et al.  Microdialysis Studies of Brain Norepinephrine, Serotonin, and Dopamine Release During Ingestive Behavior Theoretical and Clinical Implications a , 1989, Annals of the New York Academy of Sciences.