Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

5-HT2C receptor-mediated phosphoinositide turnover and the stimulus effects ofm-chlorophenylpiperazine

  • 33 Accesses

  • 38 Citations

Abstract

The present study was designed to investigate the hypothesis that agonist interactions at 5-HT2C receptors mediate the discriminative stimulus properties ofm-chlorophenylpiperazine (mCPP). Three structural classes of compounds have been described to stimulate increases in phosphoinositide (PI) hydrolysis at the 5-HT2C receptor site: phenylpiperazines, phenylalkylamines, and indolamines. Four representative phenylpiperazines, mCPP, TFMPP, MK-212 and quipazine, one phenylalkylamine, (-)DOM, and one indolamine, LSD, were employed in the present study. The efficacies of these compounds were defined (1) in vitro, with respect to their abilities to stimulate increases in PI hydrolysis in the choroid plexus, and (2) in vivo with respect to their abilities to substitute for the mCPP discriminative stimulus. In vitro intrinsic activity at the 5-HT2C site was expressed as a fraction of the maximal PI hydrolysis response elicited by serotonin (5-HT). MK-212 (fractional efficacy=1.1) and (-)DOM (0.77) were full agonists, while mCPP (0.72), LSD (0.27), quipazine (0.24), and TFMPP (0.22) were partial agonists with respect to the stimulation of PI hydrolysis at the 5-HT2C receptor. In vivo, each of the phenylpiperazines fully substituted for the mCPP stimulus, while (-)DOM (75%), and LSD (67%) elicited only partial substitution. While compounds with agonist activity at the 5-HT2C receptor in vitro substitute for the mCPP stimulus in vivo, no clear relationship exists between in vitro intrinsic activity at the 5-HT2C receptor with respect to the stimulation of PI turnover and maximal substitution for the mCPP stimulus in vivo. The present data suggest that mCPP elicits a compound stimulus which is mediated by agonist interactions at the 5-HT2C receptor and possibly additional interactions with 5-HT2A, 5-HT3, and/or 5-HT1B receptors.

This is a preview of subscription content, log in to check access.

References

  1. Balster RL (1990) Perception of drug effects. In: Berkeley MA, Stebbins WG (eds) Comparative perception, vol. 1, basic mechanisms. Wiley, N.Y., pp 127–154

  2. Berendsen HHG, Broekkamp CLE (1987) Drug-induced penile erections in rats: indications of serotonin1B receptor mediation. Eur J Pharmacol 135:279–287

  3. Berendsen HHG, Broekkamp CLE, van Delft AML (1991) Depletion of brain serotonin differentially affects behaviors induced by 5-HT1A, 5-HT1C and 5-HT2 receptor activation in rats. Behav Neural Biol 55:214

  4. Berridge MJ, Downes CP, Hanley MR (1982) Lithium amplifies agonist dependent phosphatidylinositol responses in brain and salivary glands. Biochem J 206:587–595

  5. Brady JV, Hienz, RD, Ator NA (1990) Stimulus functions of drugs and the assessment of abuse liability. Drug Res Dev 20:231–249

  6. Caccia S, Ballabio M, Samanin R, Zanini MG, Garattini S (1981) (-)mCPP, a central 5-hydroxytryptamine agonist, is a metabolite of trazadone. J Pharm Pharmacol 33:477–478

  7. Caccia S, Fung MH, Garattini S, Zanini MG (1982) Plasma concentrations of trazadone and 1-(3-chlorophenyl)piperazine in man after a single oral dose of trazadone. J Pharm Pharmacol 34:605–606

  8. Callahan PM, Cunningham KA (1994) Involvement of 5-HT2C receptors in mediating the discriminative stimulus properties ofm-chlorophenylpiperazine (mCPP). Eur J Pharmacol 257:27–38

  9. Carver JG, Grahame-Smith DG, Johnson ES, Madgwick Z (1993) The effects of 5-HT andm-chlorophenylpiperazine (mCPP) on the efflux of (3H)5-HT from human perfused platelets. Br J Clin Pharmacol 35:473–478

  10. Cohen ML, Fuller RW (1983) Antagonism of vascular serotonin receptors by m-chlorophenylpiperazine andm-trifluoromethylphenylpiperazine. Life Sci 32:711–718

  11. Colpaert FC (1990) Drug discrimination: methods of manipulation, measurement and analysis. In: Bozarch MA (ed) Methods of assessing the reinforcing properties of abused drugs. Springer, New York, pp 341–372

  12. Conn PJ, Sanders-Bush E (1985) Serotonin stimulated phosphoinositide turnover: mediation by the S2 binding site in rat cerebral cortex, but not subcortical regions. J Pharmacol Exp Ther 234:195–203

  13. Conn PJ, Sanders-Bush E (1986) Agonist-induced phosphoinositide hydrolysis in rat choroid plexus. J Neurochem 47:1754–1769

  14. Conn PJ, Sanders-Bush E (1987) Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic 5-HT1C and 5-HT2 receptors. J Pharmacol Exp Ther 242:552–557

  15. Dixon JF, Lee HL, Los GV, Hokin LE (1992) Lithium enhances accumulation of (3H)inositol radioactivity and mass of second messenger inositol 1,4,5-triphosphate in monkey cerebral cortex slices. J Neurochem 59:2332–2335

  16. Feig S, Lipton P (1990)N-Methyl-d-aspartate receptor activation and Ca2+ account for poor pyramidal cell structure in hippocampal slices J Neurochem 55:473–483

  17. Fiorella D, Rabin RA, Winter JC (1995a) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects ofm-chlorophenylpiperazine. Psychopharmacology 119:222–230

  18. Fiorella D, Palumbo PA, Rabin RA, Winter JC (1995b) The time dependent stimulus effects of (-)2,5-dimethoxy-4-methylamphetamine: implications for drug-induced stimulus control as a method for the study of hallucinogenic drugs. Psychopharmacology 119:239–245

  19. Fiorella D, Rabin RA, Winter JC (1995c) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs I: antagonist correlation analysis. Psychopharmacology 121:347–356

  20. Fiorella D, Rabin RA, Winter JC (1995d) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs II: reassessment of LSD false positives. Psychopharmacology 121:357–363

  21. Fiorella D, Helsley S, Lorrain DS, Palumbo PA, Rabin RA, Winter JC (1995e) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs III: the mechanistic basis for supersensitivity to the LSD stimulus following serotonin depletion. Psychopharmacology 121:364–372

  22. Friedman RL, Barrett RJ, Sanders-Bush E (1984) Discriminative stimulus properties of quipazine: mediation by serotonin2 binding sites. J Pharmacol Exp Ther 228:628–634

  23. Hoyer D (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Recept Res 8:59–81

  24. Hutson PH, Donohoe TP, Curzon G (1988) Infusion of 5-hydroxytryptamine agonists RU24969 and TFMPP into the paraventricular nucleus of the hypothalamus causes hypophagia. Psychopharmacology 95:550–552

  25. Kahn RS, Wetzler S (1991)m-Chlorophenylpiperazine as a probe of serotonin function. Biol Psychol 30:1139–1166

  26. Kennett GA, Curzon G (1988a) Evidence that mCPP may have behavioral effects mediated by central 5-HT1C receptors. Br J Pharmacol 94:137–147

  27. Kennet GA, Curzon G (1988b) Evidence that hypophagia induced by mCPP and TFMPP require 5-HT1C and 5-HT1B receptors: hypophagia induced by RU24969 requires only 5-HT1B receptors. Psychopharmacology 96:93–100

  28. Kennet GA, Curzon G (1991) Potencies of antagonists indicate that 5-HT1C receptors mediate 1–3 (chlorophenyl)piperazine induced hypophagia. Br J Pharmacol 103:2016–2020

  29. Kennet GA, 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 164:445–454

  30. Klodzinska A, Jaros T, Chojnacka-Wojcik E, Maj J (1989) Exploratory hypoactivity induced bym-trifluoromethylphenylpiperazine (TFMPP) andm-chlorophenylpiperazine (m-CPP) J Neural Transm 1:207–218

  31. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin reagent. J Biol Chem 193:265–275

  32. Lucki I (1992) 5-HT1 receptors and behavior. Neurosci Biobehav Rev 16:83–93

  33. Lucki I, Ward HR, Frazer A (1989) Effect of 1-(m-chlorophenyl) piperazine and 1-(m-trifluoromethylphenyl) piperazine on locomoter activity. J Pharmacol Exp Ther 249:155–164

  34. Murphy DL, Lesch KP, Aulakh CS, Pigott TA (1991) Serotonin-selective arylpiperazines with neuroendocrine, temperature, and cardiovascular effects in humans. Pharmacol Rev 43:527–552

  35. Pranzatelli MR (1990) Neonatal 5,7-DHT lesions upregulate (3H)mesulergine-labelled spinal 5-HT1C binding sites in the rat. Brain Res Bull 25:151–153

  36. Robertson DW, Bloomquist W, Wong DT, Cohen ML (1992) mCPP but not TFMPP is an antagonist at cardiac 5-HT3 receptors. Life Sci 60:599–605

  37. Sanders-Bush E, Conn PJ (1988) LSD and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to PI hydrolysis. J Pharmacol Exp Ther 246:924–928

  38. Simansky KJ, Schechter LE (1988) Properties of some 1-arylpiperazines as antagonists of stereotyped behaviors mediated by central serotonergic receptors in rodents. J Pharmacol Exp Ther 247:1073–1081

  39. Sokal RR, Rohlf FJ (1969) Single classification analysis of variance. In: Emerson R, Kennedy D, Park R et al. (eds) Biometry. WH Freeman and Company, San Francisco, Calif., pp 242–245

  40. Winter JC (1978) Drug-induced stimulus control. In: Blackman D, Sanger J (eds) Contemporary research in behavioral pharmacology. Plenum Press, N.Y., pp 341–372

  41. Winter JC (1994) The stimulus effects of serotonergic hallucinogens in animals. In: Lin GC, Glennon GC (eds) NIDA Monograph #146. USGPO, Washington D.C., pp 157–182

  42. Winter JC, Rabin RA (1993) Discriminative stimulus properties ofm-chlorophenylpiperazine. Pharmacol Biochem Behav 45:221–223

Download references

Author information

Correspondence to D. Fiorella.

Additional information

This study was supported in part by US Public Health Service grant DA 03385 (J.C.W., R.A.R.), by National Research Service Award MH 10567 (D.F.), and by a fellowship from Schering-Plough Research Institute (D.F.). Animals used in these studies were maintained in accordance with the “Guide for Care and Use of Laboratory Animals” of the Institute of Laboratory Animal Resources, National Research Council.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fiorella, D., Helsley, S., Rabin, R.A. et al. 5-HT2C receptor-mediated phosphoinositide turnover and the stimulus effects ofm-chlorophenylpiperazine. Psychopharmacology 122, 237–243 (1995). https://doi.org/10.1007/BF02246545

Download citation

Key words

  • m-Chlorophenylpiperazine (mCPP)
  • Drug-induced stimulus control
  • 5-HT2A
  • 5-HT2C