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Biol Psychiatry. 2017 Dec 1;82(11):828-838. doi: 10.1016/j.biopsych.2016.12.028. Epub 2017 Jan 10.

Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling.

Author information

1
Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
2
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.
3
Department of Biological Sciences, Human and Evolutionary Biology Section, Los Angeles, California.
4
Neurobiology Section, University of Southern California, Los Angeles, California.
5
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania.
6
Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address: hayesmr@mail.med.upenn.edu.

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.

KEYWORDS:

Calcitonin; Food intake; IAPP; Motivated behavior; Obesity; Reward

PMID:
28237459
PMCID:
PMC5503810
DOI:
10.1016/j.biopsych.2016.12.028
[Indexed for MEDLINE]
Free PMC Article

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