Re-exposure and environmental enrichment reveal NPY-Y1 as a possible target for post-traumatic stress disorder.
Exposure-based cognitive behavioral therapy in post-traumatic stress disorder (PTSD) patients relieves symptoms caused by fear association as well as symptoms that are not the result of associative learning. We used the inescapable foot shock model (IFS), an animal model for PTSD, to study the possible involvement of glutamate receptors, the corticotropin-releasing factor (CRF) system, and the neuropeptide Y (NPY) system in the reduction of stress sensitization following repeated re-exposure to the conditioning context. Starting one week after the IFS procedure, the rats were repeatedly re-exposed to the shock environment. Stress sensitivity was measured in a modified open field test (sudden silence was used as a stressor). Selected mRNAs (GluN1, -2A-C, GluA1-4, GluK1-5, CRF, CRF-R1, NPY, NPY-Y1) were quantified in the amygdala. Repeated re-exposure (RE) to the IFS context reduced both trauma-associated anxiety (to the IFS context) and the enhanced stress sensitivity (in the open field). Changes in glutamate receptor subunits (GluN1, GluN2A-B, GluA1, GluA4, GluK3, GluK4) were detected in the amygdala that were normalized by RE. However, infusion of the AMPA/kainate antagonist NBQX in the BLA (basolateral amygdala) did not improve the anxious behavior. RE normalized IFS-induced increases in CRF-R1 mRNA and increased NPY-Y1 mRNA expression in the amygdala. Previously, and repeated here, we showed that environmental enrichment (EE) enhances recovery from IFS. EE led to similar changes in CRF-R1 and NPY-Y1 expression as RE did. Importantly, administration of [Leu31, Pro34]-NPY (Y1 agonist) in the BLA normalized the enhanced sensitivity to stress after IFS. Our data suggest that the NPY-Y1 receptor in the amygdala may serve as a therapeutic target for the treatment of PTSD.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. h.hendriksen@uu.nl
Hendrikus
H
Hendriksen
Diewertje I
DI
Bink
Eileen G
EG
Daniels
Rahul
R
Pandit
Carole
C
Piriou
Roderick
R
Slieker
Koen G C
KG
Westphal
Berend
B
Olivier
Ronald S
RS
Oosting
D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000523:psychology; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D018377:Neurotransmitter Agents / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012960:Socioenvironmental Therapy; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology / Q000628:therapy*; D000099052:CRF Receptor, Type 1
D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D043562:Receptors, G-Protein-Coupled; D018092:Kainic Acid Receptors; D018013:Receptors, Neuropeptide; D000099052:CRF Receptor, Type 1; C066211:Npy1r protein, rat; C062259:neuropeptide Y, Leu(31)-Pro(34)-