The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice.
BACKGROUND
Neuropeptide Y (NPY) is implicated in the pathophysiology of affective illness. Multiple receptor subtypes (Y1R, Y2R, and Y5R) have been suggested to contribute to NPY's effects on rodent anxiety and depression-related behaviors.


OBJECTIVE
To further elucidate the role of Y1R in (1) NPY's anxiolytic-like effects and (2) fluoxetine's antidepressant-like and neurogenesis-inducing effects.


METHODS
Mice lacking Y1R were assessed for spontaneous anxiety-like behavior (open field, elevated plus-maze, and light/dark exploration test) and Pavlovian fear conditioning, and for the anxiolytic-like effects of intracerebroventricularly (icv)-administrated NPY (elevated plus-maze). Next, Y1R -/- were assessed for the antidepressant-like effects of acute fluoxetine in the forced swim test and chronic fluoxetine in the novelty-induced hypophagia test, as well as for chronic fluoxetine-induced hippocampal neurogenesis.


RESULTS
Y1R -/- exhibited largely normal baseline behavior as compared to +/+ littermate controls. Intraventricular administration of NPY in Y1R -/- mice failed to produce the normal anxiolytic-like effect in the elevated plus-maze test seen in +/+ mice. Y1R mutant mice showed higher immobility in the forced swim test and longer latencies in the novelty-induced hypophagia test. In addition, Y1R -/- mice responded normally to the acute and chronic effects of fluoxetine treatment in the forced swim test and the novelty-induced hypophagia test, respectively, as well as increased neuronal precursor cell proliferation in the hippocampus.


CONCLUSIONS
These data demonstrate that Y1R is necessary for the anxiolytic-like effects of icv NPY, but not for the antidepressant-like or neurogenesis-inducing effects of fluoxetine. The present study supports targeting Y1R as a novel therapeutic target for anxiety disorders.
Karlsson
Rose-Marie
RM
Laboratory of Clinical and Translational Studies, NIH, National Institute of Alcohol Abuse and Alcoholism, NIH, 10 Center Drive, 1-15330, Bethesda, MD 20892-1375, USA. karlssonr@mail.nih.gov
Choe
Jessica S
JS
Cameron
Heather A
HA
Thorsell
Annika
A
Crawley
Jacqueline N
JN
Holmes
Andrew
A
Heilig
Markus
M
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001007:Anxiety / Q000503:physiopathology*; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000503:physiopathology*; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009478:Neuropeptide Y / Q000494:pharmacology / Q000502:physiology*; D017476:Receptors, Neuropeptide Y / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
D018687:Antidepressive Agents, Second-Generation; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D005473:Fluoxetine