The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning

  • Neuropsychopharmacology. 2017 Dec;42(13):2527-2536. doi: 10.1038/npp.2017.79.
Erin N Bobeck  1 ,  Ivone Gomes  1 ,  Darlene Pena  2 ,  Kirstie A Cummings  3 ,  Roger L Clem  3 ,  Mihaly Mezei  1 ,  Lakshmi A Devi  1
Affiliations
  • 1. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
  • 3. Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
PMID: 28425495 DOI: 10.1038/npp.2017.79
Abstract

Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and Other mood disorders. Since GPR171, a recently deorphanized receptor for the abundant neuropeptide BigLEN, is expressed in the BLA, we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits, MS0021570_1, was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells, (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons, and (iii) feeding induced by DREADD-mediated activation of BigLEN containing AgRP neurons in the arcuate nucleus. The role of GPR171 in anxiety-like behavior or fear conditioning was evaluated following systemic or intra-BLA administration of MS0021570_1, as well as following lentiviral-mediated knockdown of GPR171 in the BLA. We find that systemic administration of MS0021570_1 attenuates anxiety-like behavior while intra-BLA administration or knockdown of GPR171 in the BLA reduces anxiety-like behavior and fear conditioning. These results indicate that the BigLEN-GPR171 system plays an important role in these behaviors and could be a novel target to develop therapeutics to treat psychiatric disorders.

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