, Volume 100, Issue 3, pp 308–315 | Cite as

Reinforcing effects of peripherally administered substance P and its C-terminal sequence pGlu6-SP6-11 in the rat

  • M. -S. Oitzl
  • R. U. Hasenöhrl
  • J. P. Huston
Original Investigations


Reinforcing effects of intraperitoneally (IP) administered substance P (SP1-11), its amino-terminal fragment SP1-7 (SPN) and an analog of the carboxy terminus (pGlu6-SP6-11: SPC) were studied in rats. Two conditioned place preference paradigms were used. After three pairings of the drug with a certain environment the effect of the treatment was evaluated in the drug-free state during a test trial. The reinforcing effects of SP (37 nmol) and the equimolar dose of SPC were expressed by a significant increase in the amount of time the animals spent in the treatment environment. Other doses of SP (3.7 and 185 nmol) and SPC (7.4 and 185 nmol) and none of the doses of SPN (37, 185, 370 nmol) influenced the place preference behavior of the rats. The reinforcing effects of SP parallel the known facilitating effects of peripherally administered SP on memory. The amino acids that encode the reinforcing effects of SP may lie within the C-terminal sequence of the SP molecule.

Key words

Substance P Reinforcement SP fragments Structure-activity Conditioned place preference Rat 


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  1. Banks WA, Kastin AJ (1985) Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res Bull 15:287–292Google Scholar
  2. Bardo MT, Miller JS, Neisewander JL (1984) Conditioned place preference with morphine: the effect of extinction training on the reinforcing CR. Pharmacol Biochem Behav 21:545–549Google Scholar
  3. Blumberg S, Teichberg VI (1982) The role of the N-terminal sequence in the biological activities of substance P. In: Costa E, Trabucchi M (eds) Regulatory peptides: from molecular biology to function. Raven Press, New York, pp 445–452Google Scholar
  4. Bozarth MA (1987) Methods of assessing the reinforcing properties of abused drugs. Springer, New YorkGoogle Scholar
  5. Bradbury MW (1989) Transport across the blood-brain barrier. In: Neuwelt EA (ed) Implications of the blood-brain barrier and its manipulation, vol 1. Plenum Press, New York, pp 119–136Google Scholar
  6. Bury RW, Mashford ML (1976) Biological activity of C-terminal partial sequences of substance P. J Med Chem 19:854–856Google Scholar
  7. Costa M (1988) Tachykinins in the sensory and peripheral nervous system. Regul Peptides 22:3–5Google Scholar
  8. Couture R, Fournier A, Magnan J, St-Pierre S, Regoli D (1979) Structure activity studies on substance P. Can J Physiol Pharmacol 57:1427–1436Google Scholar
  9. De Wied D, Jolles J (1982) Neuropeptides derived from proopiomelanocortin: behavioral, physiological and neurochemical effects. Physiol Rev 62:976–1059Google Scholar
  10. Edvinsson L, Rosendal-Helgesen R, Uddman R (1983) Substance P: localization, concentration and release in cerebral arteries, choroid plexus and dura mater. Cell Tissue Res 234:1–7Google Scholar
  11. Elliott PJ (1988) Place aversion induced by the substance P analogue, dimethyl-C7, is not state dependent: implication of substance P in aversion. Exp Brain Res 73:354–356Google Scholar
  12. Gaffori O, Stewart JM, De Wied D (1984) Influence of substance P and fragments on passive avoidance behavior. Experientia 40:89–91Google Scholar
  13. Gold PE (1986) The use of avoidance training in studies of modulation of memory storage. Behav Neural Biol 46:87–98Google Scholar
  14. Hall ME, Stewart JM (1983) Substance P and behavior: opposite effects of N-terminal and C-terminal fragments. Peptides 4:763–768Google Scholar
  15. Hall ME, Stewart JM (1984) Modulation of isolation-induced fighting by N- and C-terminal analogs of substance P: evidence for multiple recognition sites. Peptides 5:85–89Google Scholar
  16. Hall ME, Miley FB, Stewart JM (1987a) Modulation of blood pressure by substance P: opposite effects of N- and C-terminal fragments on anesthesized rats. Life Sci 40:1909–1914Google Scholar
  17. Hall ME, Grantham P, Limoli J, Stewart JM (1987b) Effects of substance P and neurokinin A (substance K) on motor behavior: unique effect of substance P attributable to its amino-terminal sequence. Brain Res 420:82–94Google Scholar
  18. Hasenöhrl RU, Oitzl M-S, Huston JP (1989) Conditioned place preference in the corral: a procedure for measuring reinforcing properties of drugs. J Neurosci Meth 30:141–146Google Scholar
  19. Holzhäuer-Oitzl M-S, Boucke K, Huston JP (1987) Reinforcing properties of substance P in the lateral hypothalamus revealed by conditioned place preference. Pharmacol Biochem Behav 28:511–515Google Scholar
  20. Holzhäuer-Oitzl M-S, Hasenöhrl R, Huston JP (1988) Reinforcing properties of substance P in the region of the nucleus basalis magnocellularis in rats. Neuropharmacology 27:749–756Google Scholar
  21. Huston JP, Oitzl M-S (1989) The relationship between reinforcement and memory: parallels in the rewarding and mnemonic effects of the neuropeptide substance P. Neurosci Biobehav Rev 13:171–180Google Scholar
  22. Huston JP, Stäubli U (1978) Retrograde amnesia produced by post-trial injection of substance P into the substantia nigra. Brain Res 159:468–472Google Scholar
  23. Huston JP, Stäubli U (1979) Post-trial injection of substance P into lateral hypothalamus and amygdala, respectively, facilitates and impairs learning. Behav Neural Biol 27:244–248Google Scholar
  24. Huston JP, Stäubli U (1981) Substance P and its effects on learning and memory. In: Martinez JL, Jensen RA, Messing RB, Rigter H, McGaugh JL (eds) Endogenous peptides and learning and memory processes. Academic Press, New York, pp 521–540Google Scholar
  25. Huston JP, Mueller CC, Mondadori C (1977) Memory facilitation by post-trial hypothalamic stimulation and other reinforcers: a central theory of reinforcement. Biobehav Rev 1:143–150Google Scholar
  26. Iversen LL, Watson SP, Sandberg BE, Hunter J, Maggio J (1985) Biochemical pharmacology of substance P. In: Tsukada Y (ed) Perspectives on neuroscience. Springer, New York, pp 3–17Google Scholar
  27. Kafetzopoulos E, Holzhäuer M-S, Huston JP (1986) Substance P injected into the region of the nucleus basalis magnocellularis facilitates performance of an inhibitory avoidance task. Psychopharmacology 90:281–283Google Scholar
  28. Kastin AJ, Olson RD, Schally AV, Coy DH (1979) CNS effects of peripherally administered brain peptides. Life Sci 25:401–414Google Scholar
  29. Koob FG (1987) Neuropeptides and memory. In: Iversen S, Iversen L, Snyder S (eds) Handbook of psychopharmacology, vol 19. Plenum Press, New York, pp 531–573Google Scholar
  30. Lembeck F (1988) The 1988 Ulf von Euler Lecture. Acta Physiol Scand 133:435–454Google Scholar
  31. Ljungdahl A, Hökfelt T, Nilsson G (1978) Distribution of substance P-like immunoreactivity in the central nervous system of the rat. — I. Cell bodies and nerve terminals. Neuroscience 3:861–894Google Scholar
  32. Mazurek N, Pecht I, Teichberg VI, Blumberg S (1981) The role of the N-terminal tetrapeptide in the histamine releasing action of substance P. Neuropharmacology 20:1025–1027Google Scholar
  33. Nagel JA, Huston JP (1988) Enhanced inhibitory avoidance learning produced by post-trial injections of substance P into the basal forebrain. Behav Neural Biol 49:374–385Google Scholar
  34. Nicoll RA, Schenker C, Leeman SE (1980) Substance P as a transmitter candidate. Ann Rev Neurosci 3:227–268Google Scholar
  35. Pelleymounter MA, Fisher Q, Schlesinger K, Hall M, Dearmey P, Stewart J (1986) The effect of substance P and its fragments on passive avoidance retention and brain monoamine activity. Behav Brain Res 21:119–127Google Scholar
  36. Pelleymounter MA, Schlesinger K, Wehner J, Hall ME, Stewart JM (1988) Nigral 5-HT and substance P-induced enhancement of passive avoidance retention. Behav Brain Res 29:159–172Google Scholar
  37. Pernow B (1983) Substance P. Pharmacol Rev 35:85–141Google Scholar
  38. Reid M, Herrera-Marschitz M, Hökfelt T, Terenius L, Ungerstedt U (1988) Differential modulation of striatal dopamine release by intranigral injection ofγ-aminobutric acid (GABA), dynorphin A and substance P. Eur J Pharmacol 147:411–420Google Scholar
  39. Sandberg BEB (1985) Structure-activity relationships for substance P: a review. In: Jordan CC, Oehme P (eds) Substance P: metabolism and biological action. Taylor & Francis, London, pp 65–81Google Scholar
  40. Schlesinger K, Lipsitz DU, Peck PL, Pelleymounter MA, Stewart JM, Chase TN (1983a) Substance P enhancement of passive and active avoidance conditioning in mice. Pharmacol Biochem Behav 19:655–666Google Scholar
  41. Schlesinger K, Lipsitz DU, Peck PL, Pelleymounter MA (1983b) Substance P reversal of electroconvulsive shock and cyclohexamide-induced retrograde amnesia. Behav Neural Biol 39:30–39Google Scholar
  42. Schlesinger K, Pelleymounter MA, Van der Kamp J, Bader DL, Stewart JM, Chase TN (1986) Substance P facilitation of memory: effects in an appetitively motivated learning task. Behav Neural Biol 45:230–239Google Scholar
  43. Spruijt BM, Gispen WH (1984) Behavioral sequences as an easy quantifiable parameter in experimental studies. Physiol Behav 32:707–710Google Scholar
  44. Stäubli U, Huston JP (1985) Central action of substance P: possible role in reward. Behav Neural Biol 43:100–108Google Scholar
  45. Stein L, Belluzzi JD (1979) Brain endorphins: possible role in reward and memory formation. Fed Proc 38:2468–2472Google Scholar
  46. Stern P, Hadzovic J (1973) Pharmacological analysis of central actions of synthetic substance P. Arch Int Pharmacodyn 202:259–262Google Scholar
  47. Tomaz C, Huston JP (1986) Facilitation of conditioned inhibitory avoidance by post-trial peripheral injection of substance P. Pharmacol Biochem Behav 25:469–472Google Scholar
  48. Wetzel W, Matthies H (1982) Effect of substance P on the retention of a brightness discrimination task in rats. Acta Biol Med Germ 41:647–652Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • M. -S. Oitzl
    • 1
  • R. U. Hasenöhrl
    • 1
  • J. P. Huston
    • 1
  1. 1.Institute of Physiological PsychologyUniversity of DüsseldorfDüsseldorfGermany

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