title: Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling.
abstract: BACKGROUND
  The pancreatic- and brain-derived hormone amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating amylin's effects are not fully characterized. We postulated that amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural processing hub for reward and homeostatic feeding signals.
  
  
  METHODS
  We used immunohistochemical and quantitative polymerase chain reaction analyses to examine expression of the amylin receptor complex in rat LDTg tissue. Behavioral experiments were performed to examine the mechanisms underlying the hypophagic effects of amylin receptor activation in the LDTg.
  
  
  RESULTS
  Immunohistochemical and quantitative polymerase chain reaction analyses show expression of the amylin receptor complex in the LDTg. Activation of LDTg amylin receptors by the agonist salmon calcitonin dose-dependently reduces body weight, food intake, and motivated feeding behaviors. Acute pharmacological studies and longer-term adeno-associated viral knockdown experiments indicate that LDTg amylin receptor signaling is physiologically and potentially preclinically relevant for energy balance control. Finally, immunohistochemical data indicate that LDTg amylin receptors are expressed on gamma-aminobutyric acidergic neurons, and behavioral results suggest that local gamma-aminobutyric acid receptor signaling mediates the hypophagia after LDTg amylin receptor activation.
  
  
  CONCLUSIONS
  These findings identify the LDTg as a novel nucleus with therapeutic potential in mediating amylin's effects on energy balance through gamma-aminobutyric acid receptor signaling.
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: David J
authors.initials: DJ
authors.lastname: Reiner
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Mietlicki-Baase
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Olivos
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: McGrath
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Zimmer
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Kieran
authors.initials: K
authors.lastname: Koch-Laskowski
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Joanna
authors.initials: J
authors.lastname: Krawczyk
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Turner
authors.affiliation: Department of Biological Sciences, Human and Evolutionary Biology Section, Los Angeles, California.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Noble
authors.affiliation: Neurobiology Section, University of Southern California, Los Angeles, California.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Hahn
authors.affiliation: Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Heath D
authors.initials: HD
authors.lastname: Schmidt
authors.affiliation: Department of Biological Sciences, Human and Evolutionary Biology Section, Los Angeles, California.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kanoski
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address: hayesmr@mail.med.upenn.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hayes
mesh_terms: D065091:Amylin Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002116:Calcitonin / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D018682:GABA Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology*; D008297:Male; D009042:Motivation / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058261:Receptor Activity-Modifying Proteins / Q000235:genetics / Q000378:metabolism; D058287:Receptors, Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D065091:Amylin Receptor Agonists; D018682:GABA Agents; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D058261:Receptor Activity-Modifying Proteins; D058287:Receptors, Islet Amyloid Polypeptide; C087166:AC 187; D005680:gamma-Aminobutyric Acid; C028815:salmon calcitonin; D002116:Calcitonin; D010751:Phosphopyruvate Hydratase
keywords: Calcitonin; Food intake; IAPP; Motivated behavior; Obesity; Reward