, Volume 105, Issue 4, pp 513–520 | Cite as

Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists

  • James T. Winslow
  • Thomas R. Insel
Original Investigations


A modulatory role for serotonin has been described for the development and expression of the ultransonic call of infant rat pups during brief maternal separations. In previous studies, serotonin reuptake inhibitors selectively reduced the rate of calling following acute administration to 9–11-day-old pups and a serotonin neurotoxin (MDMA) systematically disrupted the development of ultrasonic vocalizations but not other measures of motor development. In the current studies, we extended our investigations to include drugs with purported receptor subtype selectivities. Consistent with previous reports, acute administration of 5HT1A agonists buspirone and 8-OH-DPAT ((±)-8-hydroxy-2-(di-N-propylamino)tetralin) reduced the rate of calling at doses which did not affect motor activity or core body temperature. The rate reducing effects of buspirone persisted up to 1 but not 2 h after injection. Administration of purported 5HT1B receptor agonists, CGS12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline) and TFMPP (1-[3-fluoromethyl)phenyl]-piperazine) increased the rate of calling depending on the specificity of the drug for the 5HT1B receptor.d,l-Propranolol, a 5HT1 receptor antagonist, blocked the effects of both 8-OH-DPAT and TFMPP. m-CPP (1-(3-chlorophenyl)piperazine) and DOI ((±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), drugs with putative actions at 5HT1C and 5HT2 receptor sites both decreased calling but differed according to their effects on motor activity. Ritanserin, a 5HT2 and 5HT1C antagonist, produced a dose-related increase in call rate. A dose of ritanserin with no apparent intrinsic effects effectively antagonized DOI rate reducing effects but potentiated the rate reducing effects of m-CPP. These data extend previous studies demonstrating a role for serotonin in the expression of rat pup separation calls and further demonstrate that 5HT may increase or decrease calling depending on with receptor subtype is affected.

Key words

Attachment behavior Vocalization Infant rats Serotonin Development Anxiety 


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  1. Benjamin D, Lal H, Meyerson LR (1990) The effects of 5HT1B characterizing agents in the mouse elevated plus-maze. Life Sci 47:195–203CrossRefPubMedGoogle Scholar
  2. Berendsen HH, Broekkamp CL (1987) Drug-induced penile erections in rats: indications of serotonin receptor mediation. Eur J Pharmacol 135:279–287CrossRefPubMedGoogle Scholar
  3. Broekemp C, Jenk F (1989) The relationship between various animal models of anxiety, fear-related psychiatric syndromes and response to serotonergic drugs. In: Bevan P, Cools A, Archer T (eds) Behavioural pharmacology of 5H-T. Lawrence Erlbaum, Hillsdale, NJ, pp 321–337Google Scholar
  4. Burkholder JH, Hill JL, Vaughn WJ, Casio HE (1982) A broad-band digitizing rat detector: simultaneous recording from all sound frequencies in the range of rat ultrasonic vocalizations. Behav Res Meth Instr 14:511–518Google Scholar
  5. Ceulemans DLS, Hoppenbrouwers M, Gelders YG, Reyntjens AJM (1985) The influence of ritanserin, a serotonin antagonist, in anxiety disorders. A double-blind placebo-controlled study versus lorazepam. Pharmacopsychiatry 18:303–305PubMedGoogle Scholar
  6. Curzon G, Kennett GA (1990) mCPP: a tool for studying behavioural responses associated with 5-HT1C receptors. TIPS 11:181–182PubMedGoogle Scholar
  7. Engel G, Gother M, Hoyer D, Schlicker E, Hillenbrand K (1986) Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites. Arch Pharmacol 332:1–7CrossRefGoogle Scholar
  8. Enters EK, Spears LP (1988) Ontogenetic transitions in the psychopharmacological response to serotonergic manipulations. Psychopharmacology 96:161–168CrossRefPubMedGoogle Scholar
  9. Erikkson E, Humble M (1990) Serotonin in psychiatric pathophysiology: a review of data from experimental and clinical research. In: Pohl R, Gershon S (eds) The biological basis of psychiatric treatment. Progress in basic and clinical pharmacology. Karger, Basel, pp 66–119Google Scholar
  10. Gardner CR (1985) Inhibition of ultrasonic distress vocalizations in rat pups by chlordiazepoxide and diazepam. Drug Dev Res 5:185–193CrossRefGoogle Scholar
  11. Gardner CR, Buddhram P (1987) Effects of agents which interact with central benzodiazepine binding sites on stress. Eur J Pharmacol 134:275–283CrossRefPubMedGoogle Scholar
  12. Goodwin GM, De Souza RJ, Green AR, Heal DJ (1987) The pharmacology of the behavioral and hypothermic responses of rats to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Psychopharmacology 91:506–511CrossRefPubMedGoogle Scholar
  13. Hamik A, Peroutka SJ (1989) 1-(m-Chlorophenyl)piperazine (mCPP interactions with neurotransmitter receptors in the human brain. Biol Psychiatry 25:569–575CrossRefPubMedGoogle Scholar
  14. Hamon M, Lanfumey L, El Mestikawy S, Boni C, Miquel M-C, Bolanos F, Schecter L, Gozlan H (1990) The main features of central 5-HT receptors. Neuropsychopharmacology 3:349–360PubMedGoogle Scholar
  15. Hård E, Engel J (1988) Effects of 8-OH-DPAT on ultrasonic vocalization and audiogenic immobility reaction in pre-weaning rats. Neuropharmacology 27:981–986CrossRefPubMedGoogle Scholar
  16. Hård E, Engel J, Lindh A-S (1988) Effect of clonidine on ultrasonic vocalization in preweaning rats. J Neural Transm 73:217–237CrossRefPubMedGoogle Scholar
  17. Hartig PR, Hoffman BJ, Kaufman MJ, Hirata F (1990) The 5-HT1C receptor. In: Whitaker-Azmitia PM, Peroutka SJ (eds) The neuropharmacology of serotonin. The New York Academy of Sciences, New York, pp 149–167Google Scholar
  18. Hofer MA, Shair HN (1987) Isolation distress in two-week-old rats: influence of home cage, social companions, and prior experience with littermates. Dev Psychobiol 20:465–476CrossRefPubMedGoogle Scholar
  19. Hofer MA, Shair HN, Murowchick E (1989) Isolation distress and maternal comfort responses of two-week-old rat pups reared in social isolation. Dev Psychobiol 22:553–556CrossRefPubMedGoogle Scholar
  20. Hutson PH, Kennett GA, Donohoe TP, Dourish CT, Curzon G (1989) Opposite effects of 5HT1A and 5HT1B/1C agonists on food intake. In: Bevan I, Cools AR, Archer T (eds) Behavioral pharmacology of 5-HT. Lawrence Erlbaum, Hillsdale, NJ, pp 283–287Google Scholar
  21. Insel T, Winslow J (1990) Neurobiology of obsessive-compulsive disorder: a possible role for serotonin. J Clin Psychiatry 51:1–9Google Scholar
  22. Insel TR, Winslow JT (1991) Rat pup ultrasonic vocalizations: an ethologically relevant behavior responsive to anxiolytics. In: Olivier B, Mos J (eds) New animal models of psychiatric illness (in press)Google Scholar
  23. Insel TR, Hill JL, Mayor RB (1986) Rat pup ultrasonic isolation calls: possible mediation by the benzodiazepine receptor complex. Pharmacol Biochem Behav 24:1263–1267CrossRefPubMedGoogle Scholar
  24. Insel TR, Miller LP, Gelhard RE, Hill JL (1988) Rat pup ultrasonic isolation cells and the benzodiazepine receptor. In: Newman JD (ed) The physiological control of mammalian vocalization. Plenum Press, New York, pp 331–342Google Scholar
  25. Kehoe P (1988) Ontogeny of adrenergic and opioid effects on separation vocalizations in rats. In: Newman J (ed) The physiological control of mammalian vocalization. Plenum Press, New York, pp 301–320Google Scholar
  26. Kehoe P, Blass EM (1986) Opioid-mediation of separation distress in 10-day-old rats: reversal of stress with maternal stimuli. Dev Psychobiol 19:385–398CrossRefPubMedGoogle Scholar
  27. Kennett G, Whitton P, Shah K, Curzon G (1989) Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. Eur J Pharmacol 164:445–454CrossRefPubMedGoogle Scholar
  28. Middlemiss DN, Hutson PH (1990) The 5-HT1B receptors. In: Whitaker-Azmitia PM, Peroutka SJ (eds) The neuropharmacology of serotonin. The New York Academy of Sciences, New York, pp 132–149Google Scholar
  29. Morin D, Hennequin S, Monteau R, Hilaire G (1990) Serotonergic influences on central respiratory activity: an in vitro study in the newborn rat. Brain Res 535:281–287CrossRefPubMedGoogle Scholar
  30. Mos J, Olivier B (1989) Ultrasonic vocalizations by rat pups as an animal model for anxiolytic activity: effects of serotonergic drugs. In: Archer T, Bevan PAC (eds) Behavioural pharmacology of 5-HT. Lawrence Erlbaum, Hillsdale, NJ, pp 361–366Google Scholar
  31. Neale RF, Fallon SL, Boyar WC, Wasley JWF, Martin LL, Stone GA, Glaeser BS, Sinton CM, Williams M (1987) Biochemical and pharmacological characterization of CGS12066B, a selective serotonin-1B agonist. Eur J Pharmacol 136:1–9CrossRefPubMedGoogle Scholar
  32. Noirot E (1966) Ultra-sounds in young rodents. I. Changes with age in albino mice. Anim Behav 14:459–462PubMedGoogle Scholar
  33. Noirot E (1972) Ultrasounds and maternal behavior in small rodents. Dev Psychobiology 5:5–21Google Scholar
  34. Renyi L, Lewander T (1989) 5-HT1A and 5-HT1B agonists produce opposite effects on the ejaculatory response induced by amphetamine in rats. In: Bevan I, Cools AR, Archer T (eds) Behavioral pharmacology of 5-HT. Lawrence Erlbaum, Hillsdale, NJ, pp 79–83Google Scholar
  35. Shannon M, Battaglia G, Glennon RA, Titeler M (1984) 5HT1 and 5HT2 binding properties of derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA). Eur J Pharmacol 102:23–29CrossRefPubMedGoogle Scholar
  36. Smotherman WP, Bell RW, Starzec I, Ellias J, Zachman TA (1974) Maternal responses to infant vocalizations and olfactory cues in rats and mice. Behav Biol 12:55–66CrossRefPubMedGoogle Scholar
  37. Soubrie P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Sci 9:319–364Google Scholar
  38. Taylor DP (1987) Buspirone, a new approach to the treatment of anxiety. FASEB 2:2445–2552Google Scholar
  39. Titeler M, Lyon RA, Davis KH, Glennon RA (1987) Selectivity of serotonergic drugs for multiple brain serotonin receptor: the role of3H-DOB, a 5-HT2 agonist radioligand. Biochem Pharmacol 36:3265–3271CrossRefPubMedGoogle Scholar
  40. Titeler M, Lyon RA, Glennon RA (1988) Radioligand binding evidence implicates the brain 5-HT2 receptor as the site-of-action for LSD and phenylisoproylamine hallucinogens. Psychopharmacology 94:213–216CrossRefPubMedGoogle Scholar
  41. Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New YorkGoogle Scholar
  42. Winslow JT, Insel TR (1990a) Serotonergic and catecholaminergic reuptake inhibitors have opposite effects on the ultrasonic isolation call of rat pups. Neuropsychopharmacology 3:51–59PubMedGoogle Scholar
  43. Winslow JT, Insel TR (1990b) Serotonergic modulation of rat pup ultrasonic vocal development: studies with MDMA. J Pharmacol Exp Ther 254:212–220PubMedGoogle Scholar
  44. Winslow JT, Insel TR (1991) Endogenous opioid's: do they mediate the rat pup's response to social isolation? Behav Neurosci 105:31–41CrossRefGoogle Scholar
  45. Winslow JT, Insel TR, Trullas R, Skolnick P (1990) Rat pup isolation calls are reduced by functional antagonists of the NMDA receptor complex. Eur J Pharmacol 190:11–21CrossRefPubMedGoogle Scholar
  46. Wozniak KM, Aulakh CS, Hill JL, Murphy DL (1988) The effect of 8-OH-DPAT on temperature in the rat and its modification by chronic antidepressant treatments. Pharmacol Biochem Behav 301:451–456CrossRefGoogle Scholar
  47. Wozniak KM, Aulakh CS, Hill JL, Murphy DL (1989) Hyperthermia induced by m-CPP in the rat and its modification by anti-depressant treatments. Psychopharmacology 97:269–274CrossRefPubMedGoogle Scholar
  48. Zohar J, Muellar EA, Insel TR, Zohar-Kadouch RC, Murphy DL (1987) Serotonergic responsivity in obsessive-compulsive disorder: comparison of patients and healthy controls. Arch Gen Psychiatry 44:946–951PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • James T. Winslow
    • 1
  • Thomas R. Insel
    • 1
  1. 1.Laboratory of Clinical ScienceNational Institute of Mental Health, NIHACPoolesvilleUSA

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