Psychopharmacology

, Volume 107, Issue 4, pp 474–479 | Cite as

Flesinoxan shows antidepressant activity in a DRL 72-s screen

  • A. van Hest
  • M. van Drimmelen
  • B. Olivier
Original Investigations

Abstract

Schedules which selectively reinforce low rates of responding (DRL, differential reinforcement of low rate) distinguish between antidepressants and other types of drugs. In a DRL schedule a subject is required to pause for a specified minimum period of time between two consecutive responses in order to obtain a reinforcer. The dependent variables are rate of responding and rate of reinforcement. Response patterns of rats treated with clinically effective antidepressant drugs such as imipramine (2.0–32.0 mg/kg) or fluvoxamine (4.0–32.0 mg/kg) are characterized by a decrease in response rate and an increase in reinforcement rate. Treatment with the 5-HT1A agonist flesinoxan (0.1–3.0 mg/kg) also dose-dependently decreased response rates while at the same time increasing reinforcement rates. Chlordiazepoxide (2.5–20.0 mg/kg) and diazepam (0.25–2.0 mg/kg) had no effects in the present experiment.d-Amphetamine increased response rates at low doses (0.5–2.0 mg/kg), and decreased it at the higher doses (4.0 mg/kg), but reinforcement rates were unaltered. Overall analysis of the effects of haloperidol (0.02–0.32 mg/kg) showed decreased responding and increased reinforcement rates. Post hoc analysis, however, clearly differentiated between haloperidol's profile and that of the antidepressants. As such, the results of the present experiment show that flesinoxan might possess antidepressant activity in humans.

Key words

Flesinoxan 5HT1A agonist Serotonin Antidepressants Differential-reinforcement-of-low-rate (DRL) 72-s Rat 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Amsterdam JD, Berwish N, Potter L, Rickels K (1987) Open trial of gepirone in the treatment of major depressive disorder. Curr Ther Res Clin Exp 41:185–193Google Scholar
  2. Barrett JE, Glesson S, Nader MA, Hoffmann SM (1989) Anticonflict effects of the 5-HT1A compound flesinoxan. J Psychopharmacol 3:64–69Google Scholar
  3. Britton KT, Koob GF (1989) Effects of corticotropin releasing factor, desipramine and haloperidol on a DRL schedule of reinforcement. Pharmacol Biochem Behav 32:967–970Google Scholar
  4. Cervo L, Grinaschi G, Samanin R (1988) 8-Hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin1A receptor agonist, reduces the immobility of rats in the forced swimming test by acting on the nucleus raphe dorsalis. Eur J Pharmacol 158:53–59Google Scholar
  5. Chojnacka-Wójcik E, Tatarczynska E, Golembiowska K, Przegalinski E (1991) Involvement of 5-HT1A receptors in the antidepressant-like activity of gepirone in the forced swimming test in rats. Neuropharmacology 30:711–718Google Scholar
  6. Cott JM, Kurtz NM, Robinson DS, Copp JE (1988) A 5-HT1A ligand with both antidepressant and anxiolytic activity. Psychopharmacol Bull 24:164–167Google Scholar
  7. Dews PB, Wenger GR (1977) Rate-dependency of the behavioural effects of amphetamine. In: Thompson T, Dews PB (eds) Advances in behavioural pharmacology, vol 1. Academic Press, New York, pp 167–227Google Scholar
  8. Goodwin GM (1989) The effects of antidepressant treatments and lithium upon 5-HT1A receptor function. Prog Neuropsychopharmacol Biol Psychiatry 13:445–451Google Scholar
  9. Howard JL, Pollard GT (1984) Effects of imipramine, bupropion, chlorpromazine, and clozapine on differential-reinforcement-of-low-rate (DRL) > 72-sec and > 36-sec schedules in rat. Drug Dev Res 4:607–616Google Scholar
  10. Kennett GA, Curzon G (1989) Mechanism of action of 8-OH-DPAT on a rat model for human depression. In: Bevan P, Cools A, Archer T (eds) Behavioural pharmacology of 5-HT. Lawrence Erlbaum, London 225–229Google Scholar
  11. Kennett GA, Dourish CT, Curzon G (1987) Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression. Eur J Pharmacol 134:265–274Google Scholar
  12. Li AA, Marek GJ, Hand TH, Seiden LS (1990) Antidepressant-like effects of trazodone on a behavioural screen mediated by trazodone, not the metabolite m-chlorophenylpiperazine. Eur J Pharmacol 177:137–144Google Scholar
  13. Marek GJ, Seiden LS (1988) Selective inhibition of MAO-A, not MAO-B, results in antidepressant-like effects on DRL 72-s behaviour. Psychopharmacology 96:153–160Google Scholar
  14. Marek GJ, Li AA, Seiden LS (1989a) Selective 5-hydroxytryptamine2 antagonists have antidepressant-like effects on differential-reinforcement-of-low-rate 72-second schedule. J Pharmacol Exp Ther 250[1]:52–59Google Scholar
  15. Marek GJ, Li AA, Seiden LS (1989b) Evidence for involvement of 5-hydroxytryptamine1 receptors in antidepressant-like drug effects on differential-reinforcement-of-low-rate 72-second behaviour. J Pharmacol Exp Ther 250[1]:60–71Google Scholar
  16. McGuire PS, Seiden LS (1980a) The effects of tricyclic antidepressants on performance under a differential-reinforcement-of-low-rate schedule in rats. J Pharmacol Exp Ther 214:635–641Google Scholar
  17. McGuire PS, Seiden LS (1980b) Differential effects of imipramine in rats as a function of DRL schedule value. Pharmacol Biochem Behav 13:691–694Google Scholar
  18. O'Donnell JM, Seiden LS (1982) Effects of monoamine oxidase inhibitors on performance during differential reinforcement of low response rate. Psychopharmacology 78:214–218Google Scholar
  19. O'Donnell JM, Seiden LS (1983) Differential-reinforcement-of-low-rate 72-sec schedule: selective effects of antidepressant drugs. J Pharmacol Exp Ther 224:80–88Google Scholar
  20. Pearl RG, Seiden LS (1976) The existence of tolerance to and cross-tolerance between d-amphetamine and methylphenidate for their effects on milk consumption and on differential-reinforcement-of-low-rate performance in the rat. J Pharmacol Exp Ther 198:635–647Google Scholar
  21. Pollard GT, Howard JL (1986) Similar effects of antidepressant and non-antidepressant drugs on behaviour under an interresponse-time > 72-s schedule. Psychopharmacology 89:253–258Google Scholar
  22. Porsolt RD (1981) Behavioural despair. In: Enna SJ, Malick JB, Richelson E (eds) Antidepressants: neurochemical, behavioural and clinical perspectives. Raven Press, New York, pp 121–139Google Scholar
  23. Schipper J, Tulp M, Sybesma H, Krijzer F, Mos J, van der Heyden J, Olivier B (1990) Preclinical evaluation of flesinoxan as a potential anxiolytic and antidepressant drug. Eur J Pharmacol 183:2059–2060Google Scholar
  24. Schipper J, Tulp M, Berkelmans HS, Krijzer F, van der Heyden J, Olivier B (1991a) Flesinoxan: antidepressant activity in animal models. Soc Neurosci Abstr 17:1357Google Scholar
  25. Schipper J, Tulp M, Berkelmans HS, Mos J, van der Heyden J, Olivier B (1991b) Preclinical pharmacology of lesinoxan: a potential anxiolytic and antidepressant drug. Hum Psychopharmacol Clin Exp 6:S53-S63Google Scholar
  26. Schoeffter P, Hoyer D (1988) Centrally acting hypotensive agents with affinity for 5-HT1A binding sites inhibit forskolin-stimulated adenylate cyclase activity in calf hippocampus. Br J Pharmacol 95:975–985Google Scholar
  27. Schweizer EE, Amsterdam J, Rickels L, Kaplan M, Droba M (1986) Open trial of buspirone in the treatment of major depressive disorder. Psychopharmacol Bull 22:183–185Google Scholar
  28. Seiden LS, Dahms JL, Shaughnessy RA (1985) Behavioural screen for antidepressants: the effects of drugs and electroconvulsive shock on performance under a differential-reinforcement-of-low-rate schedule. Psychopharmacology 86:55–60Google Scholar
  29. Sulser F (1983) Noradrenergic receptor regulation and the action of antidepressants. In: Depression and antidepressants — recent events. Excerpta Medica, Amsterdam, pp 24–36Google Scholar
  30. Tatham TA, Zurn KR (1989) The MED-PC experimental apparatus programming system. Behav Res Methods Instrum Comp 21[2]:294–302Google Scholar
  31. Ybema CE, Slangen JL, Olivier B, Mos J, (1990) Discriminative stimulus properties of flesinoxan. Pharmacol Biochem Behav 35:781–784Google Scholar
  32. Ybema CE, van den Broek I, Slangen JL, Olivier B, Mos J (1991) Further study on the discriminative stimulus properties of flesinoxan. In: Olivier B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhauser, Basel, Switzerland, pp 387–395Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • A. van Hest
    • 1
  • M. van Drimmelen
    • 1
  • B. Olivier
    • 1
  1. 1.Department of PharmacologySOLVAY-DUPHAR b.v.WeespThe Netherlands

Personalised recommendations