Abstract
Rationale
Oxytocin (OT) and arginine-vasopressin (AVP) regulate social behavior in mammals. Zebrafish (Danio rerio) allows higher throughput and ease in studying human brain disorders.
Objectives
This study investigated in zebrafish the effect of non-mammalian homologs isotocin (IT) and vasotocin (AVT) in comparison with OT/AVP on social behavior and fear response to predator. The mechanism was studied using the most human selective OT and AVP receptor antagonists.
Methods
Zebrafish were injected i.m. with increasing doses (0.001–40 ng/kg) of the neuropeptides. DesGly-NH2-d(CH2)5-[d-Tyr2,Thr4]OVT) for OT receptor, SR 49059 for V1a subtype receptor, and SSR-149415 for V1b subtype receptor were injected i.m. 10 min before each agonist.
Results
All the peptides increased social preference and reduced fear to predator response in a dose-dependent manner interpolated by symmetrical parabolas. AVT/AVP were more potent to elicit anxiolytic than social effect while IT and OT were equally potent. All the antagonists dose-dependently inhibited both the effects induced by the neuropeptides. The ratio between the ED50 obtained for blocking the OT-induced effects on social preference and fear response to predator was very high only for desglyDTTyrOVT (160). SR49059 showed the highest ratio in blocking AVP-induced effects (807). The less selective antagonist appeared to be SSR149415.
Conclusions
For the first time, IT/AVT and OT/AVP were found to modulate in zebrafish, social behavior, unrelated to sex, and fear to predator response through at least two different receptors. Zebrafish is confirmed as a valid, reliable model to study deficit in social behavior characteristic of some psychiatric disorders.
Similar content being viewed by others
References
Al-Imari L, Gerlai R (2008) Sight of conspecifics as reward in associative learning in zebrafish (Danio rerio). Behav Brain Res 189:216–219
An KW, Kim NN, Choi CY (2008) Cloning and expression of aquaporin 1 and arginine vasotocin receptor mRNA from the black porgy, Acanthopagrus schlegeli: effect of freshwater acclimation. Fish Physiol Biochem 34:185–194
Anichtchik OV, Kaslin J, Peitsaro N, Scheinin M, Panula P (2004) Neurochemical and behavioral changes in zebrafish Danio rerio after systemic administration of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 88:443–453
Backström T, Pettersson A, Johansson V, Winberg S (2011) CRF and urotensin I effects on aggression and anxiety-like behavior in rainbow trout. J Exp Biol 214:907–914
Baker BI, Bird DJ, Buckingham JC (1996) In the trout, CRH and AVT synergize to stimulate ACTH release. Regul Pept 67:207–210
Barcellos LJG, Ritter F, Kreutz LC, Quevedo RM, Silva LB, Bedin AC et al (2007) Whole body cortisol increases after direct and visual contact with a predator in zebrafish, Danio rerio. Aquaculture 272:774–778
Barros TP, Alderton WK, Reynolds HM, Roach AG, Berghmans S (2008) Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery. Br J Pharmacol 154:1400–1413
Bass SL, Gerlai R (2008) Zebrafish (Danio rerio) responds differentially to stimulus fish: the effects of sympatric and allopatric predators and harmless fish. Behav Brain Res 186:107–117
Bencan Z, Sledge D, Levin ED (2009) Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety. Pharmacol Biochem Behav 94:75–80
Bielsky IF, Young LJ (2004) Oxytocin, vasopressin, and social recognition in mammals. Peptides 25:1565–1574
Black MP, Reavis RH, Grober MS (2004) Socially induced sex change regulates forebrain isotocin in Lythrypnus dalli. Neuroreport 15:185–189
Blanchard RJ, Griebel G, Farrokhi C, Markham C, Yang M, Blanchard DC (2005) AVP V1b selective receptor antagonist SSR149415 blocks aggressive behaviors in hamsters. Pharmacol Biochem Behav 80:189–194
Braida D, Limonta V, Pegorini S, Zani A, Guerini-Rocco C, Gori E, Sala M (2007) Hallucinatory and rewarding effect of salvinorin A in zebrafish: kappa-opioid and CB1-cannabinoid receptor involvement. Psychopharmacology (Berl) 190:441–448
Breder CM Jr, Halpern F (1946) Innate and acquired behavior affecting the aggregation of fishes. Physiol Zool 19:154–190
Bretaud S, Lee S, Guo S (2004) Sensitivity of zebrafish to environmental toxins implicated in Parkinson's disease. Neurotoxicol Teratol 26:857–864
Buske C, Gerlai R (2010) Shoaling develops with age in Zebrafish (Danio rerio). Prog Neuropsychopharmacol Biol Psychiatry. doi:10.1016/j.pnpbp.2010.09.003
Caldwell HK, Stephens SL, Young WS 3rd (2009) Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice. Mol Psychiatry 14:190–196
Chini B, Manning M, Guillon G (2008) Affinity and efficacy of selective agonists and antagonists for vasopressin and oxytocin receptors: an “easy guide” to receptor pharmacology. Prog Brain Res 170:513–517
Chini B, Mouillac B, Ala Y, Balestre MN, Trumpp-Kallmeyer S, Hoflack J, Elands J, Hibert M, Manning M, Jard S et al (1995) Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor. EMBO J 14:2176–2182
Conklin DJ, Smith MP, Olson KR (1999) Pharmacological characterization of arginine vasotocin vascular smooth muscle receptors in the trout (Oncorhynchus mykiss) in vitro. Gen Comp Endocrinol 114:36–46
Derick S, Cheng LL, Voirol MJ, Stoev S, Giacomini M, Wo NC, Szeto HH, Ben Mimoun M, Andres M et al (2002) [1-Deamino-4-cyclohexylalanine] arginine vasopressin: a potent and specific agonist for vasopressin V1b receptors. Endocrinology 143:4655–4664
Domenici P, Lefrançois C, Shingles A (2007) Hypoxia and the antipredator behaviours of fishes. Philos Trans R Soc Lond B Biol Sci 362:2105–2121
Domenici P (2010) Context-dependent variability in the components of fish escape response: integrating locomotor performance and behavior. J Exp Zool A Ecol Genet Physiol 313:59–79
Donaldson ZR, Young LJ (2008) Oxytocin, vasopressin, and the neurogenetics of sociality. Science 322:900–904
Dooley K, Zon LI (2000) Zebrafish: a model system for the study of human disease. Curr Opin Genet Dev 10:252–256
Egashira N, Tanoue A, Matsuda T, Koushi E, Harada S, Takano Y, Tsujimoto G, Mishima K, Iwasaki K, Fujiwara M (2007) Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice. Behav Brain Res 178:123–127
Engeszer RE, Barbiano LA, Ryan MJ, Parichy DM (2007) Timing and plasticity of shoaling behaviour in the zebrafish, Danio rerio. Anim Behav 74:1269–1275
Engeszer RE, Ryan MJ, Parichy DM (2004) Learned social preference in zebrafish. Curr Biol 14:881–884
Engeszer RE, Wang G, Ryan MJ, Parichy DM (2008) Sex-specific perceptual spaces for a vertebrate basal social aggregative behavior. Proc Natl Acad Sci USA 105:929–933
Ermisch A, Rühle HJ, Landgraf R, Hess J (1985) Blood–brain barrier and peptides. J Cereb Blood Flow Metab 5:350–357
Ferguson JN, Aldag JM, Insel TR, Young LJ (2001) Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 21:8278–8285
Filby AL, Paull GC, Hickmore TF, Tyler CR (2010) Unreavelling the neurophysiological basis of aggression in a fish model. BMC Genomics 11:498
Foran CM, Bass AH (1999) Preoptic GnRH and AVT: axes for sexual plasticity in teleost fish. Gen Comp Endocrinol 116:141–152
Gerlai R (2010) Zebrafish antipredatory responses: a future for translational research? Behav Brain Res 207:223–231
Gerlai R, Fernandes Y, Pereira T (2009) Zebrafish (Danio rerio) responds to the animated image of a predator: towards the development of an automated aversive task. Behav Brain Res 201:318–324
Giacomini NJ, Rose B, Kobayashi K, Guo S (2006) Antipsychotics produce locomotor impairment in larval zebrafish. Neurotoxicol Teratol 28:245–250
Gilchriest BJ, Tipping DR, Levy A, Baker BI (1998) Diurnal changes in the expression of genes encoding for arginine vasotocin and pituitary pro-opiomelanocortin in the rainbow trout (Oncorhynchus mykiss): correlation with changes in plasma hormones. J Neuroendocrinol 10:937–943
Gonçalves-de-Freitas E, Mariguela TC (2006) Social isolation and aggressiveness in the Amazonian juvenile fish Astronotus ocellatus. Braz J Biol 66:233–238
Goodson JL, Bass AH (2000) Forebrain peptides modulate sexually polymorphic vocal circuitry. Nature 403:769–772
Goodson JL, Bass AH (2001) Social behavior functions and related anatomical characteristics of vasotocin/vasopressin systems in vertebrates. Brain Res Brain Res Rev 35:246–265
Goodson JL, Schrock SE, Klatt JD, Kabelik D, Kingsbury MA (2009) Mesotocin and nonapeptide receptors promote estrildid flocking behavior. Science 325:862–866
Griebel G, Simiand J, Serradeil-Le Gal C, Wagnon J, Pascal M, Scatton B, Maffrand JP, Soubrie P (2002) Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders. Proc Natl Acad Sci USA 99:6370–6375
Griffiths SW, Brockmark S, Höjesjö J, Johnsson J (2004) Coping with divided attention: the advantage of familiarity. Proc Biol Sci 271:695–699
Hausmann H, Meyerhof W, Zwiers H, Lederis K, Richter D (1995) Teleost isotocin receptor: structure, functional expression, mRNA distribution and phylogeny. FEBS Lett 370:227–230
Hoyle CHV (1999) Neuropeptide families and their receptors: evolutionary perspectives. Brain Res 848:1–25
Insel TR, Winslow JT, Wang Z, Young LJ (1998) Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation. Adv Exp Med Biol 449:215–224
Jeong JY, Kwon HB, Ahn JC, Kang D, Kwon SH, Park JA, Kim KW (2008) Functional and developmental analysis of the blood–brain barrier in zebrafish. Brain Res Bull 75:619–628
Jesuthasan SJ, Mathuru AS (2008) The alarm response in zebrafish: innate fear in a vertebrate genetic model. J Neurogenet 22:211–228
Klenerova V, Krejci I, Sida P, Hlinak Z, Hynie S (2009) Modulary effects of oxytocin and carbetocin on stress-induced changes in rat behavior in the open-field. J Physiol Pharmacol 60:57–62
Landgraf R, Frank E, Aldag JM, Neumann ID, Sharer CA, Ren X, Terwilliger EF, Niwa M, Wigger A, Young LJ (2003) Viral vector-mediated gene transfer of the vole V1a vasopressin receptor in the rat septum: improved social discrimination and active social behaviour. Eur J Neurosci 18:403–411
Larson ET, O'Malley DM, Melloni RH Jr (2006) Aggression and vasotocin are associated with dominant-subordinate relationships in zebrafish. Behav Brain Res 167:94–102
Lee HJ, Macbeth AH, Pagani JH, Young WS 3rd (2009) Oxytocin: the great facilitator of life. Prog Neurobiol 88:127–151
Ledesma JM, McRobert SP (2008) Shoaling in juvenile guppies: the effects of body size and shoal size. Behav Process 77:384–388
Lema SC (2010) Identification of multiple vasotocin receptor cDNAs in teleost fish: sequences, phylogenetic analysis, sites of expression, and regulation in the hypothalamus and gill in response to hyperosmotic challenge. Mol Cell Endocrinol 321:215–230
Levin ED, Bencan Z, Cerutti DT (2007) Anxiolytic effects of nicotine in zebrafish. Physiol Behav 90:54–58
Levin ED, Chen E (2004) Nicotinic involvement in memory function in zebrafish. Neurotoxicol Teratol 26:731–735
Levin ED, Limpuangthip J, Rachakonda T, Peterson M (2006) Timing of nicotine effects on learning in zebrafish. Psychopharmacology (Berl) 184:547–552
Mahlmann S, Meyerhof W, Hausmann H, Heierhorst J, Schönrock C, Zwiers H, Lederis K, Richter D (1994) Structure, function, and phylogeny of [Arg8] vasotocin receptors from teleost fish and toad. Proc Natl Acad Sci USA 91:1342–1345
Manning M, Miteva K, Pancheva S, Stoev S, Wo NC, Chan WY (1995) Design and synthesis of highly selective in vitro and in vivo uterine receptor antagonists of oxytocin: comparisons with Atosiban. Int J Peptide Protein Res 46:244–252
Manning M, Stoev S, Chini B, Durroux T, Mouillac B, Guillon G (2008) Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Prog Brain Res 170:473–512
Maximino C, Marques de Brito T, Dias CA, Gouveia A Jr, Morato S (2010) Scototaxis as anxiety-like behavior in fish. Nat Protoc 5:209–216
McLennan DA, Ryan MJ (1997) Responses to conspecific and heterospecific olfactory cues in the swordtail Xiphophorus cortezi. Anim Behav 54:1077–1088
Morrell LJ, James R (2008) Mechanisms for aggregation in animals: rule success depends on ecological variables. Behav Ecol 19:193–201
Miller NY, Gerlai R (2011) Shoaling in zebrafish: what we don't know. Rev Neurosci 22:17–25
Oldfield RG, Hofmann HA (2011) Neuropeptide regulation of social behavior in a monogamous cichlid fish. Physiol Behav 102:296–303
Peichel CL (2004) Social behavior: how do fish find their shoal mate? Curr Biol 14:R503–R504
Perrott MN, Sainsbury RJ, Balment RJ (1993) Peptide hormone-stimulated second messenger production in the teleostean nephron. Gen Comp Endocrinol 89:387–395
Pickford GE, Strecker EL (1977) The spawning reflex response of the killifish, Fundulus heteroclitus: isotocin is relatively inactive in comparison with arginine vasotocin. Gen Comp Endocrinol 32:132–137
Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B, Schechter LE, Rizzo S, Rahman Z, Rosenzweig-Lipson S (2006) Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications. Psychopharmacology 185:218–225
Rosenthal GG, Ryan MJ (2005) Assortative preferences for stripes in danios. Anim Behav 70:1063–1066
Ross HE, Freeman SM, Spiegel LL, Ren X, Terwilliger EF, Young LJ (2009) Variation in oxytocin receptor density in the nucleus accumbens has differential effects on affiliative behaviors in monogamous and polygamous voles. J Neurosci 29:1312–1318
Sackerman J, Donegan JJ, Cunningham CS, Nguyen NN, Lawless K, Long A, Benno RH, Gould GG (2010) Zebrafish behavior in novel environments: effects of acute exposure to anxiolytic compounds and choice of Danio rerio line. Int J Comp Psychol 23:43–61
Sala M, Braida D, Lentini D, Busnelli M, Bulgheroni E, Capurro V, Finardi A, Donzelli A, Pattini L, Rubino TB et al (2011) Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry 69:875–882
Semsar K, Godwin J (2004) Multiple mechanisms of phenotype development in the bluehead wrasse. Horm Behav 45:345–353
Serradeil-Le Gal C, Raufaste D, Derick S, Blankenstein J, Allen J, Pouzet B, Pascal M, Wagnon J, Ventura MA (2007) Biological characterization of rodent and human vasopressin V1b receptors using SSR-149415, a nonpeptide V1b receptor ligand. Am J Physiol Regul Integr Comp Physiol 293:R938–R949
Serradeil-Le Gal C, Raufaste D, Marty E, Garcia C, Maffrand JP, Le Fur G (1994) Binding of [3H] SR 49059, a potent nonpeptide vasopressin V1a antagonist, to rat and human liver membranes. Biochem Biophys Res Commun 199:353–360
Serradeil-Le Gal C, Wagnon J, Valette G, Garcia G, Pascal M et al (2002) Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. Prog Brain Res 139:197–210
Sneckser JL, McRobert SP, Murphy CE, Clotfelter ED (2006) Aggregation behaviour in wildtype and transgenic zebrafish. Ethology 112:181–187
Sneckser JL, Ruhl N, Bauer K, McRobert SP (2010) The influence of sex and phenotype on shoaling decisions in zebra fish. Int J Comp Psychol 23:70–81
Speedie N, Gerlai R (2008) Alarm substance induced behavioral responses in zebrafish (Danio rerio). Behav Brain Res 188:168–177
Stemmelin J, Lukovic L, Salome N, Griebel G (2005) Evidence that the lateral septum is involved in the antidepressant-like effects of the vasopressin V1b receptor antagonist, SSR149415. Neuropsychopharmacology 30:35–42
Streisinger G (2000) The zebrafish book. Oregon Press, Eugene, Oregon
Swain HA, Sigstad C, Scalzo FM (2004) Effects of dizocilpine (MK-801) on circling behavior, swimming activity, and place preference in zebrafish (Danio rerio). Neurotoxicol Teratol 26:725–729
Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T, Yanagisawa T, Kimura T, Matzuk MM, Young LJ, Nishimori K (2005) Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci USA 102:16096–16101
Terrillon S, Cheng LL, Stoev S, Mouillac B, Barberis C, Manning M, Durroux T (2002) Synthesis and characterization of fluorescent antagonists and agonists for human oxytocin and vasopressin V(1)(a) receptors. J Med Chem 45:2579–2588
Thibonnier M, Preston JA, Dulin N, Wilkins PL, Berti-Mattera LN, Mattera R (1997) The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways. Endocrinology 138:4109–4122
Thompson, Walton (2004) Peptide effects on social behavior: effects of vasotocin and isotocin on social approach behavior in male goldfish (Carassius auratus). Behav Neurosci 118:620–626
Toyoda F, Yamamoto K, Ito Y, Tanaka S, Yamashita M, Kikuyama S (2003) Involvement of arginine vasotocin in reproductive events in the male newt Cynops pyrrhogaster. Horm Behav 44:346–353
Warne JM (2001) Cloning and characterization of an arginine vasotocin receptor from the euryhaline flounder Platichthys flesus. Gen Comp Endocrinol 122:312–319
Wersinger SR, Ginns EI, O'Carroll AM, Lolait SJ, Young WS 3rd (2002) Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol Psychiatry 7:975–984
Williams JR, Insel TR, Harbaugh CR, Carter CS (1994) Oxytocin administered centrally facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster). J Neuroendocrinol 6:247–250
Yoshida M, Takayanagi Y, Inoue K, Kimura T, Young LJ, Onaka T, Nishimori K (2009) Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J Neurosci 29:2259–2271
Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nat Rev Drug Discov 4:35–44
Acknowledgements
This work was supported by the CARIPLO Foundation Grant 2008 N. 2314. Regione Lombardia (Ter-DisMental, ID 16983-Rif.SAL50 to B.C.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Braida, D., Donzelli, A., Martucci, R. et al. Neurohypophyseal hormones manipulation modulate social and anxiety-related behavior in zebrafish. Psychopharmacology 220, 319–330 (2012). https://doi.org/10.1007/s00213-011-2482-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-011-2482-2