Abstract
Rationale
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.
Objectives
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.
Similar content being viewed by others
References
Bannon AW, Seda J, Carmouche M, Francis JM, Norman MH, Karbon B, Mccaleb ML (2000) Behavioral characterization of neuropeptide Y knockout mice. Brain Res 868:79–87
Bodnoff SR, Suranyi-Cadotte B, Aitken DH, Quirion R, Meaney MJ (1988) The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology (Berl) 95:298–302
Boyce-Rustay JM, Holmes A (2006) Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31:2405–2414
Broqua P, Wettstein JG, Rocher MN, Gauthier-Martin B, Junien JL (1995) Behavioral effects of neuropeptide receptor agonists in the elevated plus-maze and fear-potentiated startle procedure. Behav Pharmacol 6:215–222
Cabrele C, Beck-Sickinger AG (2000) Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family. J Pept Sci 6:97–122
Cameron HA, McKay RD (2001) Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol 435:406–417
Carvajal C, Dumont Y, Herzog H, Quirion R (2006) Emotional behavior in aged neuropeptide Y (NPY) Y2 knockout mice. J Mol Neurosci 28:239–245
Crawley JN (1981) Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines. Pharmacol Biochem Behav 15:695–699
Crawley J (2007) What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice, 2nd edn. Wiley, Hoboken, NJ
Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790
David DJ, Klemenhagen KC, Holick KA, Saxe MD, Mendez I, Santarelli L, Craig DA, Zhong H, Swanson CJ, Hegde LG, Ping XI, Dong D, Marzabadi MR, Gerald CP, Hen R (2007) Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphen yl]-2-methylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis. J Pharmacol Exp Ther 321:237–248
Dayer AG, Ford AA, Cleaver KM, Yassaee M, Cameron HA (2003) Short-term and long-term survival of new neurons in the rat dentate gyrus. J Comp Neurol 460:563–572
De Quidt ME, Emson PC (1986a) Distribution of neuropeptide Y-like immunoreactivity in the rat central nervous system—I. Radioimmunoassay and chromatographic characterisation. Neuroscience 18:527–543
De Quidt ME, Emson PC (1986b) Distribution of neuropeptide Y-like immunoreactivity in the rat central nervous system—II. Immunohistochemical analysis. Neuroscience 18:545–618
Dulawa SC, Holick KA, Gundersen B, Hen R (2004) Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology 29:1321–1330
Duman RS (2004) Depression: a case of neuronal life and death? Biol Psychiatry 56:140–145
El Bahh B, Balosso S, Hamilton T, Herzog H, Beck-Sickinger AG, Sperk G, Gehlert DR, Vezzani A, Colmers WF (2005) The anti-epileptic actions of neuropeptide Y in the hippocampus are mediated by Y and not Y receptors. Euro J Neurosci 22:1417–1430
Gerald C, Walker MW, Criscione L, Gustafson EL, Batzlhartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM, Linemeyer DL, Schaffhauser AO, Whitebread S, Hofbauer KG, Taber RI, Branchek TA, Weinshank RL (1996) A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 382:168–171
Hayes DM, Knapp DJ, Breese GR, Thiele TE (2005) Comparison of basal neuropeptide Y and corticotropin releasing factor levels between the high ethanol drinking C57BL/6J and low ethanol drinking DBA/2J inbred mouse strains. Alcohol Clin Exp Res 29:721–729
Hefner K, Cameron HA, Karlsson RM, Holmes A (2007) Short-term and long-term effects of postnatal exposure to an adult male in C57BL/6J mice. Behav Brain Res 182:344–348
Heilig M (1995) Antisense inhibition of neuropeptide Y (NPY)-Y1 receptor expression blocks the anxiolytic like action of NPY in amygdala and paradoxically increases feeding. Regul Pept 59:201–205
Heilig M (2004) The NPY system in stress, anxiety and depression. Neuropeptides 38:213–224
Heilig M, Söderpalm B, Engel JA, Widerlöv E (1989) Centrally administered neuropeptide Y (NPY) produces anxiolytic-like effects in animal anxiety models. Psychopharmacology (Berl) 98:524–529
Heilig M, Zachrisson O, Thorsell A, Ehnvall A, Mottagui-Tabar S, Sjogren M, Asberg M, Ekman R, Wahlestedt C, Agren H (2004) Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism. J Psychiatr Res 38:113–121
Hokfelt T, Millhorn D, Seroogy K, Tsuruo Y, Ceccatelli S, Lindh B, Meister B, Melander T, Schalling M, Bartfai T (1987) Coexistence of peptides with classical neurotransmitters. Experientia 43:768–780
Holick KA, Lee DC, Hen R, Dulawa SC (2007) Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology, Epub ahead of print
Holmes A, Yang RJ, Murphy DL, Crawley JN (2002) Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology 27:914–923
Holmes A, Heilig M, Rupniak NMJ, Steckler T, Griebel G (2003a) Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci 24:580–588
Holmes A, Kinney JW, Wrenn CC, Li Q, Yang RJ, Ma L, Vishwanath J, Saavedra MC, Innerfield CE, Jacoby AS, Shine J, Iismaa TP, Crawley JN (2003b) Galanin GAL-R1 receptor null mutant mice display increased anxiety-like behavior specific to the elevated plus-maze. Neuropsychopharmacology 28:1031–1044
Holmes A, le Guisquet AM, Vogel E, Millstein RA, Leman S, Belzung C (2005) Early life genetic, epigenetic and environmental factors shaping emotionality in rodents. Neurosci Biobehav Rev 29:1335–1346
Howell OW, Scharfman HE, Herzog H, Sundstrom LE, Beck-Sickinger A, Gray WP (2003) Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells. J Neurochem 86:646–659
Howell OW, Doyle K, Goodman JH, Scharfman HE, Herzog H, Pringle A, Beck-Sickinger AG, Gray WP (2005) Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus. J Neurochem 93:560–570
Howell OW, Silva S, Scharfman HE, Sosunov AA, Zaben M, Shatya A, McKhann G, Herzog H, Laskowski A, Gray WP (2007) Neuropeptide Y is important for basal and seizure-induced precursor cell proliferation in the hippocampus. Neurobiol Dis 26:174–188
Ishida H, Shirayama Y, Iwata M, Katayama S, Yamamoto A, Kawahara R, Nakagome K (2007) Infusion of neuropeptide Y into CA3 region of hippocampus produces antidepressant-like effect via Y1 receptor. Hippocampus 17:271–280
Karl T, Lin S, Schwarzer C, Sainsbury A, Couzens M, Wittmann W, Boey D, von HS, Herzog H (2004) Y1 receptors regulate aggressive behavior by modulating serotonin pathways. Proc Natl Acad Sci USA 101:12742–12747
Karl T, Burne TH, Herzog H (2006) Effect of Y1 receptor deficiency on motor activity, exploration, and anxiety. Behav Brain Res 167:87–93
Karlsson RM, Holmes A (2006) Galanin as a modulator of anxiety and depression and a therapeutic target for affective disease. Amino Acids 31:231–239
Karlsson RM, Holmes A, Heilig M, Crawley JN (2005) Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57BL/6J mice. Pharmacol Biochem Behav 80:427–436
Kask A, Rago L, Harro J (1996) Anxiogenic-like effect of the neuropeptide Y Y-1 receptor antagonist BIBP3226—antagonism with diazepam. Euro J Pharmacol 317:R3–R4
Kask A, Rago L, Harro J (1998) Anxiolytic-like effect of neuropeptide Y (NPY) and NPY13-36 microinjected into vicinity of locus coeruleus in rats. Brain Res 788:345–348
Kask A, Vasar E, Heidmets LT, Allikmets L, Wikberg JE (2001) Neuropeptide Y Y(5) receptor antagonist CGP71683A: the effects on food intake and anxiety-related behavior in the rat. Eur J Pharmacol 414:215–224
Kask A, Harro J, von Horsten S, Redrobe JP, Dumont Y, Quirion R (2002) The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y. Neurosci Biobehav Rev 26:259–283
Kempermann G, Kuhn HG, Gage FH (1997) Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc Natl Acad Sci USA 94:10409–10414
Kim JJ, Fanselow MS (1992) Modality-specific retrograde amnesia of fear. Science 256:675–677
Meshi D, Drew MR, Saxe M, Ansorge MS, David D, Santarelli L, Malapani C, Moore H, Hen R (2006) Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat Neurosci 9:729–731
Naveilhan P, Canals JM, Valjakka A, Vartiainen J, Arenas E, Ernfors P (2001a) Neuropeptide Y alters sedation through a hypothalamic Y1-mediated mechanism. Eur J Neurosci 13:2241–2246
Naveilhan P, Hassani H, Lucas G, Blakeman KH, Hao JX, Xu XJ, Wiesenfeld-Hallin Z, Thoren P, Ernfors P (2001b) Reduced antinociception and plasma extravasation in mice lacking a neuropeptide Y receptor. Nature 409:513–517
Parker RM, Herzog H (1999) Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur J Neurosci 11:1431–1448
Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, London
Pedrazzini T, Seydoux J, Kunstner P, Aubert JF, Grouzmann E, Beermann F, Brunner HR (1998) Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor (see comments). Nat Med 4:722–726
Porsolt RD, Bertin A, Jalfre M (1978) “Behavioural despair” in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol 51:291–294
Rasmusson AM, Hauger RL, Morgan CA, Bremner JD, Charney DS, Southwick SM (2000) Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD. Biol Psychiatry 47:526–539
Redrobe JP, Dumont Y, Fournier A, Quirion R (2002a) The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test. Neuropsychopharmacology 26:615–624
Redrobe JP, Dumont Y, Quirion R (2002b) Neuropeptide Y (NPY) and depression: from animal studies to the human condition. Life Sci 71:2921–2937
Redrobe JP, Dumont Y, Herzog H, Quirion R (2003) Neuropeptide Y (NPY) Y2 receptors mediate behaviour in two animal models of anxiety: evidence from Y2 receptor knockout mice. Behav Brain Res 141:251–255
Redrobe JP, Dumont Y, Fournier A, Baker GB, Quirion R (2005) Role of serotonin (5-HT) in the antidepressant-like properties of neuropeptide Y (NPY) in the mouse forced swim test. Peptides 26:1394–1400
Sajdyk TJ, Vandergriff MG, Gehlert DR (1999) Amygdalar neuropeptide Y Y-1 receptors mediate the anxiolytic-like actions of neuropeptide Y in the social interaction test. Eur J Pharmacol 368:143–147
Sajdyk TJ, Schober DA, Gehlert DR (2002) Neuropeptide Y receptor subtypes in the basolateral nucleus of the amygdala modulate anxiogenic responses in rats. Neuropharmacology 43:1165–1172
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809
Sorensen G, Lindberg C, Wortwein G, Bolwig TG, Woldbye DP (2004) Differential roles for neuropeptide Y Y1 and Y5 receptors in anxiety and sedation. J Neurosci Res 77:723–729
Thorsell A, Michalkiewicz M, Dumont Y, Quirion R, Caberlotto L, Rimondini R, Mathe AA, Heilig M (2000) Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression. Proc Natl Acad Sci USA 97:12852–12857
Thorsell A, Karlsson RM, Heilig M (2006) NPY in alcoholism and psychiatric disorders. In: Zukowska Z, Feuerslein GZ (eds) NPY family of peptides in tneurobiology, cardiovascular and metabolic disorders: from genes to therapeutics. Birkhauser Verlag, Switzerland, pp 183–192
Tschenett A, Singewald N, Carli M, Balducci C, Salchner P, Vezzani A, Herzog H, Sperk G (2003) Reduced anxiety and improved stress coping ability in mice lacking NPY-Y2 receptors. Eur J Neurosci 18:143–148
Wahlestedt C, Pich EM, Koob GF, Yee F, Heilig M (1993) Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides. Science 259:528–531
Wan CP, Lau BH (1995) Neuropeptide Y receptor subtypes. Life Sci 56:1055–1064
Acknowledgements
We thank Dr. Patrik Ernfors at the Karolinska Institute for providing the mutant mice for breeding, Dr. Judith Davis and Monique Melige for assistance with breeding, and Michael Feyder and Jaynann Juhasz for technical assistance. Research supported by the Intramural Research Programs of the National Institute of Alcoholism and Alcohol Abuse Research Program, National Institute of Mental Health (NH002784, NH02177), the NIH/Karolinska Graduate Partnership Program and the Swedish Medical Research Council.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Karlsson, RM., Choe, J.S., Cameron, H.A. et al. 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. Psychopharmacology 195, 547–557 (2008). https://doi.org/10.1007/s00213-007-0945-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-007-0945-2