Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y.
Dysregulation of the central noradrenergic system is a core feature of post-traumatic stress disorder (PTSD). Here, we examined molecular changes in locus coeruleus (LC) triggered by single-prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal neuropeptide Y (NPY). Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of the SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated corticotropin-releasing hormone (CRH) in central nucleus of amygdala. Following testing for anxiety on elevated plus maze (EPM), there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressors, perhaps mediated by the up-regulation influence of amygdalar CRH input and down-regulation of Y2R presynaptic inhibition in LC. Results also demonstrate the therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments. Single-prolonged stress (SPS)-triggered long-term changes in the locus coeruleus/norepinephrine (LC/NE) system with increased tyrosine hydroxylase (TH) protein and CRH receptor 1(CRHR1) mRNA and lower neuropeptide Y receptor 2 (Y2R) mRNA levels as well as elevated corticotropin-releasing hormone (CRH) in the central nucleus of amygdala (CeA) that were prevented by early intervention with intranasal neuropeptide Y (NPY). SPS treatment led to increased sensitivity of LC to mild stress of elevated plus maze (EPM), with elevated mRNA for NE biosynthetic enzymes in subset of animals.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.
Esther L
EL
Sabban
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.|On a long-term leave from Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.
Marcela
M
Laukova
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.
Lishay G
LG
Alaluf
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.|Visiting student from Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Emelie
E
Olsson
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.
Lidia I
LI
Serova
D000281:Administration, Intranasal / Q000379:methods*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008125:Locus Coeruleus / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009478:Neuropeptide Y / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D012149:Restraint, Physical / Q000009:adverse effects; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D009478:Neuropeptide Y; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D017476:Receptors, Neuropeptide Y; D003346:Corticotropin-Releasing Hormone; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase
corticotropin-releasing hormone; glucocorticoid receptor; locus coeruleus; neuropeptide Y; post-traumatic stress disorder; tyrosine hydroxylase