NPY Y1 receptors differentially modulate GABAA and NMDA receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons.
Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y1 receptor (Y1R) isoform. Activation of Y1Rs 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 Y1Rs on synaptic transmission in the BLA. Activating Y1Rs 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 GABAA-mediated evoked inhibitory postsynaptic currents (eIPSCs). Both effects were abolished by the Y1R 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 GABAA-mediated currents. Thus, both the NMDA and GABAA effects of Y1R 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 GABAA-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 GABAA-mediated eIPSCs. Thus, NPY regulates amygdala excitability via two signal-transduction events, with reduced PKA activity enhancing GABAA-mediated eIPSCs and Epac deactivation reducing NMDA-mediated eEPSCs. This multipathway regulation of NMDA- and GABAA-mediated currents may be important for NPY plasticity and stress resilience in the amygdala.
Department of Psychiatry, Institute of Psychiatric Research, Indiana University, Indianapolis, IN, USA.
Andrei I
AI
Molosh
Tammy J
TJ
Sajdyk
William A
WA
Truitt
Weiguo
W
Zhu
Gerry S
GS
Oxford
Anantha
A
Shekhar
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000187:drug effects; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D000634:Aminoquinolines; D014151:Anti-Anxiety Agents; D020662:Guanine Nucleotide Exchange Factors; D009478:Neuropeptide Y; C066211:Npy1r protein, rat; C585848:PD160170; C526973:Rapgef3 protein, rat; D018091:Receptors, AMPA; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D018013:Receptors, Neuropeptide; D013450:Sulfones; D013873:Thionucleotides; D006153:Guanosine Diphosphate; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C023427:guanosine 5'-O-(2-thiodiphosphate); D000242:Cyclic AMP; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits