Advertisement

Psychopharmacology

, Volume 97, Issue 3, pp 319–325 | Cite as

Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine

  • J. E. Barrett
  • S. M. Hoffmann
  • S. N. Olmstead
  • M. J. Foust
  • C. Harrod
  • B. A. Weissman
Original Investigations

Abstract

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)1A receptor, were compared with compounds believed to function as agonists at the 5-HT1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock (“conflict” procedure). Under the multiple schedule, spiroxatrine (0.3–1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01–1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [3H]8-OH-DPAT binding to pigeon cerebral membranes with IC50 values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.

Key words

Spiroxatrine 8-OH-DPAT Serotonin 5-HT1A Buspirone Pigeon 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Asarch KB, Shih J (1987) Solubilization of serotonin 1A and serotonin 1B binding sites from bovine brain. J Neurochem 48:1494–1501.Google Scholar
  2. Barrett JE, Olmstead SN (1988) Spiroxatrine as a discriminative stimulus: effects depend on pharmacological history. Drug Dev Res (in press)Google Scholar
  3. Barrett JE, Witkin JM (1988) Buspirone in animal models of anxiety. In: Tunnicliff G, Eison AS, Taylor DP (eds) Buspirone: mechanisms and clinical aspects. Academic Press, New York (in press)Google Scholar
  4. Barrett JE, Witkin JM, Mansbach RS, Skolnick P, Weissman BA (1987) Behavioral studies with anxiolytic drugs. III. Antipunishment actions of buspirone in the pigeon do not involve benzodiazepine receptor mechanisms. J Pharmacol Exp Ther 238:1009–1013.Google Scholar
  5. Barrett JE, Fleck-Kandath C, Mansbach RS (1988a) Effects of buspirone differ from those of gepirone and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on unpunished responding of pigeons. Pharmacol Biochem Behav 30:723–727.Google Scholar
  6. Barrett JE, Olmstead SN, Lei Z, Harrod C, Hoffmann SM, Glover K, Nader MA, Weissman BA (1988b) Behavioral, neurochemical and discriminative stimulus effects of spiroxatrine, a putative 5-HT1A antagonist. In: Archer T, Beven P, Cool A (eds) Behavioural pharmacology of 5-HT. Lawrence Erlbaum, Hillsdale, New Jersey (in press)Google Scholar
  7. Costall B, Naylor RJ (1976) Dissociation of stereotyped biting responses and oro-bucco-lingual dyskinesias. Eur J Pharmacol 36:423–429.Google Scholar
  8. Costall B, Naylor RJ (1978) Dopamine antagonistic effects of a series of analogues of oxiperomide and spiroxatrine measured behaviorally in the rodent. J Pharm Pharmacol 30:693–698.Google Scholar
  9. Costall B, Naylor RJ, Pinder RM (1976) Mechanisms of dyskinesia induction by 1-(3,4-dihydroxyphenyl) piperazine in the rat. Neuropharmacology 15:203–210.Google Scholar
  10. Cunningham KA, Callahan PM, Appel JB (1987) Discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT): implications for understanding the actions of novel anxiolytics. Eur J Pharmacol 138:29–36.Google Scholar
  11. DeVivo M, Maayani S (1986) Characterization of the 5-hydroxytryptamine1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. J Pharmacol Exp Ther 238:248–253.Google Scholar
  12. Eison MS, Eison AS (1984) Buspirone as a midbrain modulator: anxiolysis unrelated to traditional benzodiazepine mechanisms. Drug Dev Res 4:109–119.Google Scholar
  13. Engel JA, Hjorth S, Svesson K, Carlsson A, Liljiquist S (1984) Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Eur J Pharmacol 105:365–368.Google Scholar
  14. Herrick-Davis K, Titeler M (1988) [3H]Spiroxatrine: a 5-HT1A radioligand with agonist binding properties. J Neurochem 50:528–533.Google Scholar
  15. Leysen J, Tollenaere JP, Koch MHJ, Laduron P (1977) Differentiation of opiate and neuroleptic receptor binding in rat brain. Eur J Pharmacol 43:253–267.Google Scholar
  16. Mansbach RS, Barrett JE (1987) Discriminative stimulus properties of buspirone in the pigeon. J Pharmacol Exp Ther 240:364–369.Google Scholar
  17. Mansbach RS, Harrod C, Hoffmann SM, Nader MA, Lei Z, Witkin JM, Barrett JE (1988) Behavioral studies with anxiolytic drugs. V. Behavioral and in vivo neurochemical analyses in pigeons of drugs that increase punished responding. J Pharmacol Exp Ther 246:114–120.Google Scholar
  18. McCloskey TC, Paul BK, Commissaris RL (1987) Buspirone effects in an animal conflict procedure: comparison with diazepam and phenobarbital. Pharmacol Biochem Behav 27:171–175.Google Scholar
  19. Middlemiss DN, Fozard JR (1983) 8-Hydroxy-2-(di-n-propylamino)tetralin discriminates between subtypes of the 5HT1 recognition site. Eur J Pharmacol 90:151–153.Google Scholar
  20. Nelson DL, Taylor EW (1986) Spiroxatrine: a selective serotonin1A receptor antagonist. Eur J Pharmacol 124:207–208.Google Scholar
  21. Nelson DL, Monroe PJ, Lambert G, Yamamura HI (1987) [3H]Spiroxatrine labels a serotonin 1A-like site in the rat hippocampus. Life Sci 41:1567–1576.Google Scholar
  22. Niemegeers CJE, Verbruggen FJ, Van Nueten JM, Janssen PAJ (1964) Spiroxamide (R 5188): a new compound producing morphine-like and chlorpromazine-like effects in animals. Int J Neuropharmacol 2:349–354.Google Scholar
  23. Peroutka SJ (1985) Selective interaction of novel anxiolytics with 5-hydroxytryptamine1A receptors. Biol Psychiatry 20:971–979.Google Scholar
  24. Pich EM, Samanin R (1986) Disinhibitory effects of buspirone and low doses of sulpiride and haloperidol in two experimental anxiety models in rats: possible role of dopamine. Psychopharmacology 89:125–130.Google Scholar
  25. Riblet LA, Taylor DP, Eison MS, Stanton HC (1982) Pharmacology and neurochemistry of buspirone. J Clin Psychiatry 43:11–16.Google Scholar
  26. Sanger DJ, Joly D, Zivkovic B (1985) Behavioral effects of nonbenzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide. J Pharmacol Exp Ther 232:831–837.Google Scholar
  27. Sepinwall J (1985) Behavioral effects of antianxiety agents: possible mechanisms of action. In: Seiden LS, Balster RL (eds) Behavioral pharmacology: the current status. Liss, New York, pp 181–203.Google Scholar
  28. Skolnick P, Weissman BA, Youdim MBH (1985) Monoaminergic involvement in the pharmacological actions of buspirone. Br J Pharmacol 86:637–644.Google Scholar
  29. Taylor DP, Riblet LA, Stanton HC, Eison AS, Eison MS, Temple DL Jr (1982) Dopamine and antianxiety activity. Pharmacol Biochem Behav 17:25–35.Google Scholar
  30. Taylor DP, Eison MS, Riblet LA, Vandermaelen CP (1985) Pharmacological and clinical effects of buspirone. Pharmacol Biochem Behav 23:687–694.Google Scholar
  31. Tricklebank MD, Neill J, Kidd EJ, Fozard JR (1987) Mediation of the discriminative stimulative properties of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) by the putative 5-HT1A receptor. Eur J Pharmacol 133:47–56.Google Scholar
  32. Weissman BA, Barrett JE, Brady LS, Witkin JM, Mendelson WB, Paul SM, Skolnick P (1984) Behavioral and neurochemical studies on the anticonflict actions of buspirone. Drug Dev Res 4:83–93.Google Scholar
  33. Witkin JM, Barrett JE (1986) Interaction of buspirone and dopaminergic agents on punished behavior of pigeons. Pharmacol Biochem Behav 24:751–756.Google Scholar
  34. Witkin JM, Mansbach RS, Barrett JE, Bolger GT, Skolnick P, Weissman BA (1987) Behavioral studies with anxiolytic drugs. IV. Serotonergic involvement in effects of buspirone on punished behavior of pigeons. J Pharmacol Exp Ther 243:970–977.Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • J. E. Barrett
    • 1
  • S. M. Hoffmann
    • 1
  • S. N. Olmstead
    • 1
  • M. J. Foust
    • 1
  • C. Harrod
    • 1
  • B. A. Weissman
    • 2
  1. 1.Department of PsychiatryUniformed Services University of the Health SciencesBethesdaUSA
  2. 2.Department of PharmacologyIsrael Institute for Biological ResearchNess ZionaIsrael

Personalised recommendations