Behavioral effects of neuropeptides in rodent models of depression and anxiety
Abstract
In recent years, studies have advocated neuropeptide systems as modulators for the behavioral states found in mood disorders such as depression and anxiety disorders. Neuropeptides have been tested in traditional animal models and screening procedures that have been validated by known antidepressants and anxiolytics. However, it has become clear that although these tests are very useful, neuropeptides have distinct behavioral effects and dose-dependent characteristics, and therefore, use of these tests with neuropeptides must be done with an understanding of their unique characteristics. This review will focus on the behavioral actions of neuropeptides and their synthetic analogs, particularly in studies utilizing various preclinical tests of depression and anxiety. Specifically, the following neuropeptide systems will be reviewed: corticotropin-releasing factor (CRF), urocortin (Ucn), teneurin C-terminal associated peptide (TCAP), neuropeptide Y (NPY), arginine vasopressin (AVP), oxytocin, the Tyr-MIF-1 family, cholecystokinin (CCK), galanin, and substance P. These neuropeptide systems each have a unique role in the regulation of stress-like behavior, and therefore provide intriguing therapeutic targets for mood disorder treatment.
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Preclinical studies demonstrated that exogenous intravenous and intranasal oxytocin can influence fear related responses in rodents and monkeys respectively, reducing hiding behaviour during an open field test and attentional bias towards threatening facial expressions.
“Preclinical studies demonstrated that exogenous intravenous and intranasal oxytocin can influence fear related responses in rodents and monkeys respectively, reducing hiding behaviour during an open field test and attentional bias towards threatening facial expressions (Parr et al., 2013;Rotzinger et al., 2010).”
From Meta-analytic review of the effects of a single dose of intranasal oxytocin on threat processing in humans (2018) · cites this paper as Rotzinger et al., 2010
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The Effects of Psychological Stress on Depression
Yang, L., Zhao, Y., Wang, Y., Liu, L., Zhang, X., Li, B., & Cui, R. (2015) · Current Neuropharmacology · doi:10.2174/1570159x1304150831150507 · Cited by 589 · see citing works
Breaking the loop: Oxytocin as a potential treatment for drug addiction
McGregor, I. S., & Bowen, M. T. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.12.001 · Cited by 268 · see citing works
Cochran, D. M., Fallon, D., Hill, M., & Frazier, J. A. (2013) · Harvard Review of Psychiatry · doi:10.1097/hrp.0b013e3182a75b7d · Cited by 267 · see citing works
Stress, Endocrine Physiology and Pathophysiology -- Endotext
DeGroot, L. J., Chrousos, G. P., Dungan, K., Grossman, A. B., Jm, H., Koch, C., Korbonits, M., McLachlan, R., New, M., Purnell, J. Q., et al. (2000) · Europe PMC (PubMed Central) · Cited by 260 · see citing works
Comparative Analyses of Zebrafish Anxiety-Like Behavior Using Conflict-Based Novelty Tests
Kysil, E. V., Мешалкина, Д. А., Frick, E. E., Echevarria, D. J., Rosemberg, D. B., Maximino, C., Lima, M. G., de Abreu, M. S., Giacomini, A. C. V. V., Barcellos, L. J. G., et al. (2017) · Zebrafish · doi:10.1089/zeb.2016.1415 · Cited by 257 · see citing works
The endocannabinoid system in anxiety, fear memory and habituation
Ruehle, S., Rey, A. A., Remmers, F., & Lutz, B. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111408958 · Cited by 236 · see citing works
Albers, H. E. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.07.001 · Cited by 200 · see citing works
The neuroendocrinology of primate maternal behavior
Wendy Saltzman, A., & Dario Maestripieri, A. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.09.017 · Cited by 150 · see citing works
Sequeira‐Cordero, A., Salas-Bastos, A., Fornaguera, J., & Brenes, J. C. (2019) · Scientific Reports · doi:10.1038/s41598-019-53624-1 · Cited by 140 · see citing works
Oxytocin׳s role in anxiety: A critical appraisal
MacDonald, K., & Feifel, D. (2014) · Brain Research · doi:10.1016/j.brainres.2014.01.025 · Cited by 139 · see citing works
Banasr, M., Lepack, A., Fee, C., Duric, V., Maldonado-Aviles, J., DiLeone, R., Sibille, E., Duman, R. S., & Sanacora, G. (2017) · Chronic Stress · doi:10.1177/2470547017720459 · Cited by 135 · see citing works
Exploring the role of neuropeptides in depression and anxiety
Rana, T., Behl, T., Sehgal, A., Singh, S., Sharma, N., Abdeen, A., Ibrahim, S. F., Mani, V., Iqbal, M. S., Bhatia, S., et al. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110478 · Cited by 126 · see citing works
Sciolino, N. R., & Holmes, P. V. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.06.005 · Cited by 116 · see citing works
Huang, H.-J., Zhu, X.-C., Han, Q.-Q., Wang, Y.-L., Yue, N., Wang, J., Yu, R., Li, B., Wu, G.-C., Liu, Q., et al. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.02.040 · Cited by 114 · see citing works
Sabihi, S., Durosko, N. E., Dong, S. M., & Leuner, B. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.03.009 · Cited by 106 · see citing works
Holt-Lunstad, J., Birmingham, W., & Light, K. C. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.03.007 · Cited by 103 · see citing works
High plasma nesfatin-1 level in patients with major depressive disorder
Arı, M., Öztürk, O. H., Bez, Y., Oktar, S., & Erduran, D. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.12.004 · Cited by 105 · see citing works
Sabihi, S., Dong, S. M., Durosko, N. E., & Leuner, B. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00258 · Cited by 101 · see citing works
Balmus, I. M., Ciobica, A., Antioch, I., Dobrin, R., & Timofte, D. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/3975101 · Cited by 103 · see citing works
“Of course, the animal models are not the perfect representation of the complex human diseases, especially considering the fact that psychiatric concepts such as self-esteem, recurrent thoughts of death [162], or fear of losing control [163] are not reproducible in this case.”
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Neuropeptidergic Signaling Partitions Arousal Behaviors in Zebrafish
Woods, I. G., Schoppik, D., Shi, V. J., Zimmerman, S., Coleman, H. A., Greenwood, J. S. F., Soucy, E. R., & Schier, A. F. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3529-13.2014 · Cited by 97 · see citing works
Effects of early life social stress on maternal behavior and neuroendocrinology
Murgatroyd, C., & Nephew, B. C. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.05.020 · Cited by 100 · see citing works
Hansson, C., Haage, D., Taube, M., Egecioglu, E., Salomé, N., & Dickson, S. L. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.02.002 · Cited by 100 · see citing works
Shi, H., Zhu, W., Liu, J., Luo, Y., Si, J., Wang, S., Xue, Y.-X., Ding, Z., Shi, J., & Lü, L. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.131 · Cited by 96 · see citing works
Curley, J. P., Jensen, C. L., Franks, B., & Champagne, F. A. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.01.013 · Cited by 90 · see citing works
Phylogenetic Analysis of the Teneurins: Conserved Features and Premetazoan Ancestry
Tucker, R. P., Beckmann, J., Leachman, N. T., Schöler, J., & Chiquet‐Ehrismann, R. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msr271 · Cited by 91 · see citing works
Role of Orexin in the Pathophysiology of Depression: Potential for Pharmacological Intervention
Nollet, M., & Leman, S. (2013) · CNS Drugs · doi:10.1007/s40263-013-0064-z · Cited by 89 · see citing works
Ayers, L. W., Missig, G., Schulkin, J. A., & Rosen, J. B. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.138 · Cited by 87 · see citing works
The Role of Clock in Ethanol-Related Behaviors
Ozburn, A. R., Falcón, E., Mukherjee, S., Gillman, A. G., Arey, R. N., Spencer, S. M., & McClung, C. A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.138 · Cited by 86 · see citing works
The mechanism of electroacupuncture for depression on basic research: a systematic review
Han, X., Gao, Y., Yin, X., Zhang, Z., Lao, L., Chen, Q., & Xu, S. (2021) · Chinese Medicine · doi:10.1186/s13020-020-00421-y · Cited by 87 · see citing works
Sabihi, S., Dong, S. M., Maurer, S., Goodpaster, C. M., & Leuner, B. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.06.024 · Cited by 84 · see citing works
Oxytocin Reduces Background Anxiety in a Fear-Potentiated Startle Paradigm
Missig, G., Ayers, L. W., Schulkin, J., & Rosen, J. B. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.155 · Cited by 79 · see citing works
Hypothalamus and Post-Traumatic Stress Disorder: A Review
Raise‐Abdullahi, P., Meamar, M., Vafaei, A. A., Alizadeh, M., Dadkhah, M., Shafia, S., Ghalandari-Shamami, M., Naderian, R., Samaei, A., & Rashidy‐Pour, A. (2023) · Brain Sciences · doi:10.3390/brainsci13071010 · Cited by 80 · see citing works
Role of 5-HT3 Receptors in the Antidepressant Response
Betry, C., Etiévant, A., Oosterhof, C. A., Ebert, B., Sánchez, C., & Haddjeri, N. (2011) · Pharmaceuticals · doi:10.3390/ph4040603 · Cited by 76 · see citing works
Smith, C. M., Walker, A. W., Hosken, I. T., Chua, B. E., Zhang, C., Haidar, M., & Gundlach, A. L. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00046 · Cited by 68 · see citing works
Sánchez-Vidaña, D. I., Chan, N.-M. J., Chan, A. H. L., Hui, K. K. Y., Lee, S. Y., Chan, H.-Y., Law, Y. S., Sze, M. Y., Tsui, W.-C. S., Fung, T. K. H., et al. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.07.005 · Cited by 70 · see citing works
Morales‐Medina, J. C., Dumont, Y., Benoit, C.-É., Bastianetto, S., Flores, G., Fournier, A., & Quirion, R. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.06.030 · Cited by 68 · see citing works
May oxytocin be a trait marker for bipolar disorder?
Turan, T., Uysal, C., Asdemir, A., & Kılıç, E. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.07.017 · Cited by 66 · see citing works
Behavioral effect of neuropeptides related to feeding regulation in fish
Matsuda, K., Kang, K. S., Sakashita, A., Yahashi, S., & Vaudry, H. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05884.x · Cited by 65 · see citing works
Davidson, S., Lear, M., Shanley, L. J., Hing, B. W. Q., Baizan-Edge, A., Herwig, A., Quinn, J. P., Breen, G. D., McGuffin, P., Starkey, A. J., et al. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.93 · Cited by 65 · see citing works
Lach, G., & de Lima, T. C. M. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.04.005 · Cited by 64 · see citing works
Kumar, J. R., Rajkumar, R., Jayakody, T., Marwari, S., Hóng, J., Ma, S., Gundlach, A. L., Lai, M. K. P., & Dawe, G. S. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13564 · Cited by 62 · see citing works
Neurobiological consequences of juvenile stress: A GABAergic perspective on risk and resilience
Albrecht, A., Müller, I., Ardi, Z., Çalışkan, G., Gruber, D., Ivens, S., Segal, M., Behr, J., Heinemann, U., Stork, O., et al. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.005 · Cited by 63 · see citing works
Shi, D.-D., Zhang, Y.-D., Ren, Y.-Y., Peng, S.-Y., Yuan, T.-F., & Wang, Z. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01293-w · Cited by 63 · see citing works
Hofmann, T., Elbelt, U., Ahnis, A., Rose, M., Klapp, B. F., & Stengel, A. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.06.014 · Cited by 63 · see citing works
MOLECULAR EVOLUTION OF GPCRS: CRH/CRH receptors
Lovejoy, D. A., Chang, B. S. W., Lovejoy, N. R., & del Castillo, J. (2014) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0238 · Cited by 63 · see citing works
Self-citationArey, R. N., Enwright, J. F., Spencer, S. M., Falcon, E., Ozburn, A. R., Ghose, S., Tamminga, C., & McClung, C. A. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.12 · Cited by 62 · see citing works
On the Teneurin track: a new synaptic organization molecule emerges
Mosca, T. J. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00204 · Cited by 60 · see citing works
Del Boca, C., Lutz, P. E., Le Merrer, J., Koebel, P., & Kieffer, B. L. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.05.022 · Cited by 59 · see citing works
Ida, T., Takahashi, T., Tominaga, H., Sato, T., Kume, K., Ozaki, M., Hiraguchi, T., Maeda, T., Shiotani, H., Terajima, S., et al. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.06.081 · Cited by 58 · see citing works
Decreased plasma nesfatin-1 levels in patients with generalized anxiety disorder
Gunay, H., Tutuncu, R., Aydın, S., Dağ, E., & Abaslı, D. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.04.007 · Cited by 58 · see citing works
Anxiety and Depression: What Do We Know of Neuropeptides?
Kupcová, I., Danišovič, Ľ., Grgac, I., & Harsányi, Š. (2022) · Behavioral Sciences · doi:10.3390/bs12080262 · Cited by 57 · see citing works
Doosti, M.-H., Bakhtiari, A., Zare, P., Amani, M., Zolbanin, N. M., Babri, S., & Salari, A. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.12.003 · Cited by 56 · see citing works
Relaxin-3-Deficient Mice Showed Slight Alteration in Anxiety-Related Behavior
Watanabe, Y., Tsujimura, A., Takao, K., Nishi, K., Ito, Y., Yasuhara, Y., Nakatomi, Y., Yokoyama, C., Fukui, K., Miyakawa, T., et al. (2011) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2011.00050 · Cited by 56 · see citing works
Massey, S. H., Backes, K. A., & Schuette, S. (2016) · Depression and Anxiety · doi:10.1002/da.22467 · Cited by 53 · see citing works
Kang, K. S., Yahashi, S., & Matsuda, K. (2011) · Peptides · doi:10.1016/j.peptides.2011.05.006 · Cited by 47 · see citing works
Leppanen, J., Ng, K. W., Kim, Y.-R., Tchanturia, K., & Treasure, J. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.08.041 · Cited by 45 · see citing works
Jlalia, I., Lensen, N., Chaume, G., Dzhambazova, E. B., Astasidi, L., Tafradjiiska-Hadjiolova, R. K., Bocheva, A. I., & Brigaud, T. (2013) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2012.12.041 · Cited by 45 · see citing works
The role of orexin in post-stroke inflammation, cognitive decline, and depression
Song, J., Kim, E., Kim, C. H., Song, H., & Lee, J. E. (2015) · Molecular Brain · doi:10.1186/s13041-015-0106-1 · Cited by 46 · see citing works
Oxytocin and Anxiety Disorders: Translational and Therapeutic Aspects
Naja, W., & Aoun, M. P. (2017) · Current Psychiatry Reports · doi:10.1007/s11920-017-0819-1 · Cited by 40 · see citing works
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Interleukin-15 affects serotonin system and exerts antidepressive effects through IL15Rα receptor
Wu, X., Hsuchou, H., Kastin, A. J., He, Y., Khan, R. S., Stone, K. P., Cash, M. S., & Pan, W. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.07.017 · Cited by 41 · see citing works
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Chand, D. S., Casatti, C. A., de Lannoy, L., Song, L., Kollara, A., Baršytė-Lovejoy, D., Brown, T. J., & Lovejoy, D. A. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.09.006 · Cited by 40 · see citing works
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Oxytocin Signaling Pathway: From Cell Biology to Clinical Implications
Iovino, M., Messana, T., Tortora, A., Giusti, C., Lisco, G., Giagulli, V. A., Guastamacchia, E., Pergola, G. D., & Triggiani, V. (2020) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530320666200520093730 · Cited by 39 · see citing works
Kyeremanteng, C., MacKay, J. C., James, J. S., Kent, P., Cayer, C., Anisman, H., & Merali, Z. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.05.012 · Cited by 37 · see citing works
Substance P receptor antagonist in lateral habenula improves rat depression-like behavior
Yang, L.-M., Yu, L., Jin, H., & Zhao, H. (2013) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.10.007 · Cited by 36 · see citing works
The Role of the PACAP Signaling System in Depression
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The Role of Neuropeptide Y in the Nucleus Accumbens
Tanaka, M., Yamada, S., & Watanabe, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147287 · Cited by 35 · see citing works
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Anticonvulsant neuropeptides as drug leads for neurological diseases
Robertson, C. R., Flynn, S. P., White, H. S., & Bulaj, G. W. (2011) · Natural Product Reports · doi:10.1039/c0np00048e · Cited by 33 · see citing works
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Urocortin 2 modulates aspects of social behaviour in mice
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Effects of environmental manipulations in genetically targeted animal models of affective disorders
Renoir, T., Pang, T. Y., & Hannan, A. J. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.04.003 · Cited by 31 · see citing works
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The octadecaneuropeptide exerts an anxiogenic-like action in goldfish
Matsuda, K., Wada, K., Azuma, M., Leprince, J., Tonon, M., Sakashita, A., Maruyama, K., Uchiyama, M., & Vaudry, H. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.02.058 · Cited by 29 · see citing works
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On the Role of Cholecystokinin (CCK) in Fear and Anxiety: A Review and Research Proposal
Crespi, F. (2019) · Journal of Human Psychology · doi:10.14302/issn.2644-1101.jhp-19-2766 · Cited by 26 · see citing works
Circadian Modulation of Anxiety: A Role for Somatostatin in the Amygdala
Albrecht, A., Thiere, M., Bergado-Acosta, J. R., Poranzke, J., Müller, B., & Stork, O. (2013) · PLoS ONE · doi:10.1371/journal.pone.0084668 · Cited by 26 · see citing works
The Neurokinin-1 Receptor in Addictive Processes
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The Effects of Ghrelin on Energy Balance and Psychomotor Activity in a Goldfish Model: An Overview
Kang, K. S., Yahashi, S., & Matsuda, K. (2011) · International Journal of Peptides · doi:10.1155/2011/171034 · Cited by 26 · see citing works
Plasma Nesfatin-1 Level May Be Associated with Disease Severity in Patients with Panic Disorder
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The Role of Endogenous Oxytocin in Anxiolysis: Structural and Functional Correlates
Lancaster, K., Goldbeck, L., Pournajafi‐Nazarloo, H., Connelly, J. J., Carter, C. S., & Morris, J. P. (2017) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2017.10.003 · Cited by 23 · see citing works
Lancaster, K., Goldbeck, L., Puglia, M. H., Morris, J. P., & Connelly, J. J. (2018) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsy086 · Cited by 23 · see citing works
- Authors
- Rotzinger, S., Lovejoy, D. A., & Tan, L. A.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Tan, Laura A.
- Venue
- Peptides
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 31
- Issue
- 4
- Pages
- 736-756
- ISSN
- 0196-9781 (ISSN-L)
- OpenAlex
- W2087834131
- Cited by
- 211
- References
- 245
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 10 · 2021: 6 · 2020: 6 · 2019: 8 · 2018: 9 · 2017: 14 · 2016: 10 · 2015: 12 · 2014: 21 · 2013: 24 · 2012: 27
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Peptides (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (FRN 72027622)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- neuropeptides, depression, anxiety, mood disorders, corticotropin-releasing factor, urocortin, neuropeptide Y, vasopressin, oxytocin, cholecystokinin, galanin, substance P, antidepressant screening, rodent models, therapeutic target
- MeSH terms
- Animals, Anxiety, Arginine Vasopressin, Behavior, Animal, Cholecystokinin, Corticotropin-Releasing Hormone, Depression, Disease Models, Animal, Humans, MSH Release-Inhibiting Hormone, Neuropeptide Y, Neuropeptides, Neuropsychological Tests, Oxytocin, Social Behavior, Galanin, Urocortins
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