NPY y 1 receptors differentially modulate gaba a and nmda receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons

Andrei I. Molosh, Tammy J. Sajdyk, William A. Truitt, Weiguo Zhu, Gerry S. Oxford, Anantha Shekhar

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y 1 receptor (Y 1 R) isoform. Activation of Y 1 Rs results in G-protein-mediated reduction of cAMP levels, which results in reduced excitability of amygdala projection neurons. Understanding the mechanisms linking decreased cAMP levels to reduced excitability in amygdala neurons is important for identifying novel anxiolytic targets. We studied the intracellular mechanisms of activation of Y 1 Rs on synaptic transmission in the BLA. Activating Y 1 Rs by Leu 31,Pro 34 -NPY (L-P NPY) reduced the amplitude of evoked NMDA-mediated excitatory postsynaptic currents (eEPSCs), without affecting AMPA-mediated eEPSCs, but conversely increased the amplitude of GABA A-mediated evoked inhibitory postsynaptic currents (eIPSCs). Both effects were abolished by the Y 1 R antagonist, PD160170. Intracellular GDP-β-S, or pre-treatment with either forskolin or 8Br-cAMP, eliminated the effects of L-P NPY on both NMDA-and GABA A-mediated currents. Thus, both the NMDA and GABA A effects of Y 1 R activation in the BLA are G-protein-mediated and cAMP-dependent. Pipette inclusion of protein kinase A (PKA) catalytic subunit blocked the effect of L-P NPY on GABA A-mediated eIPSCs, but not on NMDA-mediated eEPSCs. Conversely, activating the exchange protein activated by cAMP (Epac) with 8CPT-2Me-cAMP blocked the effect of L-P NPY on NMDA-mediated eEPSCs, but not on GABA A-mediated eIPSCs. Thus, NPY regulates amygdala excitability via two signal-transduction events, with reduced PKA activity enhancing GABA A-mediated eIPSCs and Epac deactivation reducing NMDA-mediated eEPSCs. This multipathway regulation of NMDA-and GABA A-mediated currents may be important for NPY plasticity and stress resilience in the amygdala.

Original languageEnglish (US)
Pages (from-to)1352-1364
Number of pages13
JournalNeuropsychopharmacology
Volume38
Issue number7
DOIs
StatePublished - Jun 2013

Keywords

  • anxiety
  • Epac
  • neuromodulation
  • neuropeptide Y
  • PKA
  • stress

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Medicine(all)

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