Psychopharmacology

, Volume 193, Issue 3, pp 423–436 | Cite as

Effect of quinpirole on timing behaviour in the free-operant psychophysical procedure: evidence for the involvement of D2 dopamine receptors

  • T. H. C. Cheung
  • G. Bezzina
  • C. L. Hampson
  • S. Body
  • K. C. F. Fone
  • C. M. Bradshaw
  • E. Szabadi
Original Investigation
First Online:
Received:
Accepted:

Abstract

Rationale

Operant timing behaviour is sensitive to dopaminergic manipulations. It has been proposed that this effect is mediated principally by D2-like dopamine receptors. However, we recently found that the effect of d-amphetamine on timing in the free-operant psychophysical procedure was mediated by D1-like dopamine receptors. It has not been established whether stimulation of D2-like receptors affects timing in this schedule.

Objective

To examine the effects of a D2-like receptor agonist quinpirole on second-range timing and the ability of dopamine receptor antagonists to reverse quinpirole’s effects.

Materials and methods

Rats responded on two levers (A and B) under a free-operant psychophysical schedule in which reinforcement was provided intermittently for responding on A during the first half, and B during the second half, of 50-s trials. Logistic functions were fitted to the relative response rates [percent responding on B (%B) vs time (t)] under each treatment; quantitative timing indices [T 50 (value of t when %B = 50) and Weber fraction] were compared among treatments.

Results

Quinpirole (0.04, 0.08 mg kg−1) reduced T 50. This effect was attenuated by D2-like receptor antagonists haloperidol (0.05, 0.1 mg kg−1), eticlopride (0.04, 0.08 mg kg−1) and sulpiride (30, 60 mg kg−1), but not by the D3 receptor-preferring antagonist nafadotride (0.5, 1 mg kg−1), the D4 receptor antagonist L-745870 (1, 3 mg kg−1) or the D1-like receptor antagonist SKF-83566 (0.015 mg kg−1).

Conclusions

Results suggest that quinpirole reduced T 50 via an action at D2 receptors. D1-like and D2-like receptors may mediate behaviourally similar but pharmacologically distinct effects on timing behaviour.

Keywords

Interval timing Free-operant psychophysical procedure Quinpirole D2 dopamine receptors Haloperidol Eticlopride Sulpiride Nafadotride L-745870 SKF-83566 
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Notes

Acknowledgements

This work was supported by the BBSRC. We are grateful to Ms. V. K. Bak for skilled technical help.

References

  1. Al-Zahrani SS, Ho MY, Velazquez Martinez DN, Lopez Cabrera M, Bradshaw CM, Szabadi E (1996) Effect of destruction of the 5-hydroxytryptaminergic pathways on behavioural timing and “switching” in a free-operant psychophysical procedure. Psychopharmacology 127:346–352PubMedCrossRefGoogle Scholar
  2. Areola OO, Jadhav AL (2001) Low-level lead exposure modulates effects of quinpirole and eticlopride on response rates in a fixed-interval schedule. Pharmacol Biochem Behav 69:151–156PubMedCrossRefGoogle Scholar
  3. Audinot V, Newman-Tancredi A, Gobert A, Rivet JM, Brocco M, Lejeune F, Gluck L, Desposte I, Bervoets K, Dekeyne A, Millan MJ (1998) A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194. J Pharmacol Exp Ther 287:187–197PubMedGoogle Scholar
  4. Bayley PJ, Bentley GD, Dawson GR (1998) The effects of selected antidepressant drugs on timing behaviour in rats. Psychopharmacology 136:114–122PubMedCrossRefGoogle Scholar
  5. Bizo LA, White KG (1994a) The behavioral theory of timing: reinforcer rate determines pacemaker rate. J Exp Anal Behav 61:19–33PubMedCrossRefGoogle Scholar
  6. Bizo LA, White KG (1994b) Pacemaker rate and the behavioral theory of timing. J Exp Psychol Anim Behav Processes 20:308–321CrossRefGoogle Scholar
  7. Body S, Kheramin S, Mobini S, Ho M-Y, Velazquez-Martinez DN, Bradshaw CM, Szabadi E (2002) Antagonism by WAY-100635 of the effects of 8-OH-DPAT on performance on a free-operant timing schedule in intact and 5-HT-depleted rats. Behav Pharmacol 13:514–603Google Scholar
  8. Body S, Kheramin S, Ho M-Y, Miranda F, Bradshaw CM, Szabadi E (2003) Effects of a 5-HT2 receptor agonist, DOI (2,5-dimethoxy-4-iodoamphetamine), and antagonist, ketanserin, on the performance of rats on a free-operant timing schedule. Behav Pharmacol 14:599–607PubMedCrossRefGoogle Scholar
  9. Body S, Kheramin S, Ho M-Y, Miranda F, Bradshaw CM, Szabadi E (2004) Effects of fenfluramine on free-operant timing behaviour: evidence for involvement of 5-HT2A receptors. Psychopharmacology 176:154–165PubMedCrossRefGoogle Scholar
  10. Body S, Asgari K, Cheung THC, Bezzina G, Fone KFC, Glennon JC, Bradshaw CM, Szabadi E (2006a) Evidence that the effect of 5-HT2 receptor stimulation on temporal differentiation is not mediated by receptors in the dorsal striatum. Behav Processes 71:258–267PubMedCrossRefGoogle Scholar
  11. Body S, Cheung THC, Bezzina G, Asgari K, Fone KCF, Glennon JC, Bradshaw CM, Szabadi E (2006b) Effects of d-amphetamine and DOI (2,5-dimethoxy-4-iodoamphetamine) on timing behaviour: interaction between D1 and 5-HT2A receptors. Psychopharmacology 189:331–343PubMedCrossRefGoogle Scholar
  12. Bowman BP, Vaughan SR, Walker QD, Davis SL, Little PJ, Scheffler NM, Thomas BF, Kuhn CM (1999) Effects of sex and gonadectomy on cocaine metabolism in the rat. J Pharmacol Exp Ther 290:1316–1323PubMedGoogle Scholar
  13. Buhusi CV, Meck WH (2002) Differential effects of methamphetamine and haloperidol on the control of an internal clock. Behav Neurosci 116:291–297PubMedCrossRefGoogle Scholar
  14. Catania AC (1970) Reinforcement schedules and psychophysical judgments: a study of some temporal properties of behavior. In: Schoenfeld WN (ed) The theory of reinforcement schedules. Appleton, New YorkGoogle Scholar
  15. Catania AC, Reynolds GS (1968) A quantitative analysis of the responding maintained by interval schedules of reinforcement. J Exp Anal Behav 11(Suppl):327–383CrossRefGoogle Scholar
  16. Cheung THC, Bezzina G, Asgari K, Body S, Fone KFC, Bradshaw CM, Szabadi E (2006) Evidence for a role of D1 dopamine receptors in d-amphetamine’s effect on timing behaviour in the free-operant psychophysical procedure. Psychopharmacology 185:378–388PubMedCrossRefGoogle Scholar
  17. Chiang TJ, Al-Ruwaitea ASA, Ho MY, Bradshaw CM, Szabadi E (1998) The influence of ‘switching’ on the psychometric function in the free-operant psychophysical procedure. Behav Processes 44:197–209CrossRefGoogle Scholar
  18. Chiang TJ, Al-Ruwaitea AS, Ho MY, Bradshaw CM, Szabadi E (1999) Effect of central 5-hydroxytryptamine depletion on performance in the free-operant psychophysical procedure: facilitation of switching, but no effect on temporal differentiation of responding. Psychopharmacology 143:166–173PubMedCrossRefGoogle Scholar
  19. Chiang TJ, Al-Ruwaitea AS, Mobini S, Ho MY, Bradshaw CM, Szabadi E (2000a) The effect of d-amphetamine on performance on two operant timing schedules. Psychopharmacology 150:170–184PubMedCrossRefGoogle Scholar
  20. Chiang TJ, Al-Ruwaitea AS, Mobini S, Ho MY, Bradshaw CM, Szabadi E (2000b) Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on performance on two operant timing schedules. Psychopharmacology 151:379–391PubMedCrossRefGoogle Scholar
  21. Cook CD, Beardsley PM (2003) The modulatory actions of dopamine D2/3 agonists and antagonists on the locomotor-activating effects of morphine and caffeine in mice. Pharmacol Biochem Behav 75:363–371PubMedCrossRefGoogle Scholar
  22. Deng Y-P, Lei W-L, Reiner A (2006) Differential perikaryal localization in rats of D1 and D2 dopamine receptors on striatal projection neuron types identified by retrograde labeling. J Chem Neuroanat 32:101–116PubMedCrossRefGoogle Scholar
  23. Depoortere R, Perrault G, Sanger DJ (1996) Behavioural effects in the rat of the putative dopamine D-3 receptor agonist 7-OH-DPAT: comparison with quinpirole and apomorphine. Psychopharmacology 124:231–240PubMedCrossRefGoogle Scholar
  24. Eckerman DA, Segbefia D, Manning S, Breese GS (1987) Effects of methylphenidate and d-amphetamine on timing in the rat. Pharmacol Biochem Behav 27:513–515PubMedCrossRefGoogle Scholar
  25. Enguehard-Gueiffier C, Hubner H, El Hakmaoui A, Allouchi H, Gmeiner P, Argiolas A, Melis MR, Gueiffier A (2006) 2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective d-4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D-4 partial agonist. J Med Chem 49:3938–3947PubMedCrossRefGoogle Scholar
  26. Flietstra RJ, Levant B (1998) Comparison of D2 and D3 dopamine receptor affinity of dopaminergic compounds in rat brain. Life Sci 62:1825–1831PubMedCrossRefGoogle Scholar
  27. Fowler SC, Lion JR (1998) Haloperidol, raclopride, and eticlopride induce microcatalepsy during operant performance in rats, but clozapine and SCH 23390 do not. Psychopharmacology 140:81–90PubMedCrossRefGoogle Scholar
  28. Frederick DL, Allen JD (1996) Effects of selective dopamine D1- and D2-agonists and antagonists on timing performance in rats. Pharmacol Biochem Behav 53:759–764PubMedCrossRefGoogle Scholar
  29. Gerfen CR (2004) Basal ganglia. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier, San DiegoGoogle Scholar
  30. Gerfen CR, Engber TM, Mahon LC, Susel Z, Chase TN, Monsna FJ, Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432PubMedCrossRefGoogle Scholar
  31. Gerfen CR, Miyachi S, Paletzki R, Brown P (2002) D1 receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase. J Neurosci 22:5042–5054PubMedGoogle Scholar
  32. Gibbon J, Malapani C, Dale CL, Gallistel C (1997) Toward a neurobiology of temporal cognition: advances and challenges. Curr Opin Neurobiol 7:170–184PubMedCrossRefGoogle Scholar
  33. Haleem DJ, Shireen E, Haleem MA (2004) Somatodendritic and postsynaptic serotonin-1A receptors in the attenuation of haloperidol-induced catalepsy. Prog Neuropsychopharmacol Biol Psychiatry 28:1323–1329PubMedCrossRefGoogle Scholar
  34. Hinton SC, Meck WH (1997) How time flies: functional and neural mechanisms of interval timing. In: Bradshaw CM, Szabadi E (eds) Time and behaviour: psychological and neurobehavioural analyses. Elsevier, AmsterdamGoogle Scholar
  35. Ho MY, Velazquez-Martinez DN, Bradshaw CM, Szabadi E (2002) 5-Hydroxytryptamine and interval timing behaviour. Pharmacol Biochem Behav 71:773–785PubMedCrossRefGoogle Scholar
  36. Hu M, Crombag HS, Robinson TE, Becker JB (2004) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology 29:81–85PubMedCrossRefGoogle Scholar
  37. Jackson DM, Westlind-Danielsson A (1994) Dopamine receptors: molecular biology, biochemistry and behavioural aspects. Pharmacol Ther 64:291–370PubMedCrossRefGoogle Scholar
  38. Killeen PR, Fetterman JG (1988) A behavioral theory of timing. Psychol Rev 95:274–295PubMedCrossRefGoogle Scholar
  39. Killeen PR, Fetterman JG, Bizo LA (1997) Time’s causes. In: Bradshaw CM, Szabadi E (eds) Time and behaviour: psychological and neurobehavioural analyses. Elsevier, AmsterdamGoogle Scholar
  40. Kraemer PJ, Randall CK, Dose JM, Brown RW (1997) Impact of d-amphetamine on temporal estimation in pigeons tested with a production procedure. Pharmacol Biochem Behav 58:323–327PubMedCrossRefGoogle Scholar
  41. Kuhn CM, Walker QD, Li ST (2001) Sex, steroids, and stimulant sensitivity. Ann N Y Acad Sci 937:188–201PubMedCrossRefGoogle Scholar
  42. Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB (1999) Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 20:612–627PubMedCrossRefGoogle Scholar
  43. Leriche L, Schwartz JC, Sokoloff P (2003) The dopamine D3 receptor mediates locomotor hyperactivity induced by NMDA receptor blockade. Neuropsychopharmacology 45:174–181CrossRefGoogle Scholar
  44. Levant B (1997) The D3 dopamine receptor: neurobiology and potential clinical relevance. Pharmacol Rev 49:231–252PubMedGoogle Scholar
  45. Levant B (2002) Novel drug interactions at D2 dopamine receptors: modulation of [3H]quinpirole binding by monoamine oxidase inhibitors. Life Sci 71:2691–2700PubMedCrossRefGoogle Scholar
  46. Levant B, Vansell NR (1997) In vivo occupancy of D2 dopamine receptors by nafadotride. Neuropsychopharmacology 17:67–71PubMedCrossRefGoogle Scholar
  47. Levant B, Grigoriadis DE, Desouza EB (1992) Characterization of [3H] quinpirole binding to D2-like dopamine-receptors in rat-brain. J Pharmacol Exp Ther 262:929–935PubMedGoogle Scholar
  48. Levant B, Moehlenkamp JD, Morgan KA, Leonard NL, Cheng CC (1996) Modulation of [3H]quinpirole binding in brain by monoamine oxidase inhibitors: evidence for a potential novel binding site. J Pharmacol Exp Ther 278:145–153PubMedGoogle Scholar
  49. Levesque M, Parent A (2005) The striatofugal fiber system in primates: a reevaluation of its organization based on single-axon tracing studies. Proc Natl Acad Sci USA 102:11888–11893PubMedCrossRefGoogle Scholar
  50. MacDonald CJ, Meck WH (2005) Differential effects of clozapine and haloperidol on interval timing in the supraseconds range. Psychopharmacology 182:232–244PubMedCrossRefGoogle Scholar
  51. Machado A, Guilhardi P (2000) Shifts in the psychometric function and their implications for models of timing. J Exp Anal Behav 74:25–54PubMedCrossRefGoogle Scholar
  52. Maricq AV, Roberts S, Church RM (1981) Methamphetamine and time estimation. J Exp Psychol Anim Behav Processes 7:18–30CrossRefGoogle Scholar
  53. Matell MS, Meck WH (2004) Cortico-striatal circuits and interval timing: coincidence detection of oscillatory processes. Cogn Brain Res 21:139–170CrossRefGoogle Scholar
  54. Matell MS, King GR, Meck WH (2004) Differential modulation of clock speed by the administration of intermittent versus continuous cocaine. Behav Neurosci 118:150–156PubMedCrossRefGoogle Scholar
  55. Meck WH (1986) Affinity for the dopamine D2 receptor predicts neuroleptic potency in decreasing the speed of an internal clock. Pharmacol Biochem Behav 25:1185–1189PubMedCrossRefGoogle Scholar
  56. Meck WH (1996) Neuropharmacology of timing and time perception. Cogn Brain Res 3:227–242CrossRefGoogle Scholar
  57. Meck WH, Benson AM (2002) Dissecting the brain’s internal clock: how frontal–striatal circuitry keeps time and shifts attention. Brain Cogn 48:195–211PubMedCrossRefGoogle Scholar
  58. Melis MR, Succu S, Sanna F, Melis T, Mascia MS, Enguehard-Gueiffier C, Hubner H, Gmeiner P, Gueiffier A, Argiolas A (2006) PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain. Eur J Neurosci 24:2021–2030PubMedCrossRefGoogle Scholar
  59. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 303:791–804PubMedCrossRefGoogle Scholar
  60. Moreland RB, Moreland RB, Nakane M, Donnelly-Roberts DL, Miller LN, Chang RJ, Uchic ME, Terranova MA, Gubbins EJ, Helfrich RJ, Namovic MT, El-Kouhen OF, Masters JN, Brioni JD (2004) Comparative pharmacology of human dopamine D2-like receptor stable cell lines coupled to calcium flux through Gαqo5. Biochem Pharmacol 68:761–772PubMedCrossRefGoogle Scholar
  61. Niznik HB, Van Tol HHM (1992) Dopamine receptor genes—new tools for molecular psychiatry. J Psychiatry Neurosci 17:158–180PubMedGoogle Scholar
  62. Parent A, Levesque M, Parent M (2001) A re-evaluation of the current model of the basal ganglia. Parkinsonism Relat Disord 7:193–198PubMedCrossRefGoogle Scholar
  63. Patel S, Freedman S, Chapman KL, Emms F, Fletcher AE, Knowles M, Marwood R, McAllister G, Myers J, Patel S, Curtis N, Kulagowski JJ, Leeson PD, Ridgill M, Graham M, Matheson S, Rathbone D, Watt AP, Bristow LJ, Rupniak NMJ, Baskin E, Lynch JJ, Ragan CI (1997) Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. J Pharmacol Exp Ther 283:636–647PubMedGoogle Scholar
  64. Pugsley TA, Shih YH, Whetzel SZ, Zoski K, Van Leeuwen D, Akunne H, Mackenzie R, Heffner TG, Wustrow D, Wise LD (2002) The discovery of PD 89211 and related compounds: selective dopamine D4 receptor antagonists. Prog Neuropsychopharmacol Biol Psychiatry 26:219–226PubMedCrossRefGoogle Scholar
  65. Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY, Boyfield I, Branch CL, Cilia J, Coldwell MC, Hadley MS, Hunter AJ, Jeffrey P, Jewitt F, Johnson CN, Jones DNC, Medhurst AD, Middlemiss DN, Nash DJ, Riley GJ, Routledge C, Stemp G, Thewlis KM, Trail B, Vong AKK, Hagan JJ (2000) Pharmacological actions of a novel, high-affinity, and selective human dopamine D3 receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 294:1154–1165PubMedGoogle Scholar
  66. Roberts S (1981) Isolation of an internal clock. J Exp Psychol Anim Behav Processes 7:242–268CrossRefGoogle Scholar
  67. Salamone JD, Cousins MS, Maio C, Champion M, Turski T, Kovach J (1996) Different behavioral effects of haloperidol, clozapine and thioridazine in a concurrent lever pressing and feeding procedure. Psychopharmacology 125:105–112PubMedCrossRefGoogle Scholar
  68. Saulsgiver KA, McClure EA, Wynne CDL (2006) Effects of d-amphetamine on the behavior of pigeons exposed to the peak procedure. Behav Processes 71:268–285PubMedCrossRefGoogle Scholar
  69. Sautel F, Griffon N, Sokoloff P, Schwartz JC, Launay C, Simon P, Costentin J, Schoenfelder A, Garrido F, Mann A, Wermuth CG (1995) Nafadotride, a potent preferential dopamine D3 receptor antagonist, activates locomotion in rodents. J Pharmacol Exp Ther 275:1239–1246PubMedGoogle Scholar
  70. Schindler CW, Carmona GN (2002) Effects of dopamine agonists and antagonists on locomotor activity in male and female rats. Pharmacol Biochem Behav 72:857–863PubMedCrossRefGoogle Scholar
  71. Schotte A, Janssen PFM, Gommeren W, Luyten WHML, VanGompel P, Lesage AS, DeLoore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124:57–73PubMedCrossRefGoogle Scholar
  72. Seeman P, Van Tol HHM (1994) Dopamine receptor pharmacology. Trends Pharmacol Sci 15:264–270PubMedCrossRefGoogle Scholar
  73. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151PubMedCrossRefGoogle Scholar
  74. Strange PG (2001) Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol Rev 153:119–133Google Scholar
  75. Stubbs DA (1976) Scaling of stimulus duration by pigeons. J Exp Anal Behav 26:15–25PubMedCrossRefGoogle Scholar
  76. Stubbs DA (1980) Temporal discrimination and a free-operant psychophysical procedure. J Exp Anal Behav 33:167–185PubMedCrossRefGoogle Scholar
  77. Tang L, Todd RL, Heller A, O’Malley KL (1994) Pharmacological functional characterization of D2, D3 and D4 dopamine receptors in fibroblast and dopaminergic cell lines. J Pharmacol Exp Ther 268:495–502PubMedGoogle Scholar
  78. Van Tol HHM, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik NB, Olivier C (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614PubMedCrossRefGoogle Scholar
  79. Wanibuchi F, Usuda S (1990) Synergistic effects between D1 and D2 dopamine antagonists on catalepsy in rats. Psychopharmacology 102:339–342PubMedCrossRefGoogle Scholar
  80. Willner P, Sampson D, Phillips G, Muscat R (1990) A matching law analysis of the effects of dopamine receptor antagonists. Psychopharmacology 101:560–567PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • T. H. C. Cheung
    • 1
  • G. Bezzina
    • 1
  • C. L. Hampson
    • 1
  • S. Body
    • 1
  • K. C. F. Fone
    • 2
  • C. M. Bradshaw
    • 1
  • E. Szabadi
    • 1
  1. 1.Psychopharmacology Section, Division of PsychiatryUniversity of NottinghamNottinghamUK
  2. 2.School of Biomedical SciencesUniversity of NottinghamNottinghamUK

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