, Volume 175, Issue 2, pp 206–214 | Cite as

Effects of orbital prefrontal cortex dopamine depletion on inter-temporal choice: a quantitative analysis

  • S. Kheramin
  • S. Body
  • M.-Y. Ho
  • D. N. Velázquez-Martinez
  • C. M. Bradshaw
  • E. Szabadi
  • J. F. W. Deakin
  • I. M. Anderson
Original Investigation



Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size and delay) has been proposed as a model of “impulsive choice” in animals. We recently found that destruction of the OPFC disrupted inter-temporal choice in rats. It is not known whether the dopaminergic projection to the OPFC contributes to the regulation of inter-temporal choice.


A quantitative method was used to compare inter-temporal choice in rats whose OPFC had been depleted of dopamine with that of sham-lesioned control rats.


Under halothane anaesthesia, rats received injections of 6-hydroxydopamine into the OPFC (2 μg μl−1, 0.5 μl, two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 μl of the sucrose solution after a delay dA; a press on B resulted in delivery of 100 μl of the same solution after a delay dB. dB was increased progressively across successive blocks of six trials in each session, while dA was manipulated systematically across phases of the experiment. The indifference delay, dB(50) (value of dB corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of dB(50) versus dA were derived, and the parameters of the function compared between the groups. Concentrations of monoamines in the OPFC were determined by high-performance liquid chromatography at the end of the experiment.


In both groups, dB(50) increased linearly with dA (r2>0.9 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. When delays of 4 or 8 s were imposed on the smaller reinforcer, the lesioned rats showed greater tolerance of delay to the larger reinforcer (i.e. they exhibited longer values of dB(50)) than the sham-lesioned rats. Dopamine, noradrenaline and 5-hydroxytryptamine levels in the OPFC of the lesioned group were 20, 75 and 98% of those of the sham-lesioned group.


The results indicate that dopaminergic afferents to the OPFC contribute to the regulation of inter-temporal choice behaviour due to their role in determining organisms’ sensitivity both to reinforcer size and to delay of reinforcement.


Orbital prefrontal cortex Dopamine 6-Hydroxydopamine Inter-temporal choice Delay discounting 



This work was supported by a grant from the Wellcome Trust to C.M.B. and E.S. (University of Nottingham) and J.F.W.D. and I.M.A. (University of Manchester). D.N.V.-M. was supported by grants from CONACYT (#25090-H) and Universidad Nacional Autónoma de México DGAPA (#229981). We are grateful to Mrs. Victoria Bak and Mr. R.W. Langley for skilled technical help.


  1. Ainslie GW (1975) Specious reward: a behavioral theory of impulsiveness and impulse control. Psychol Bull 82:463–492PubMedGoogle Scholar
  2. Cardinal RN, Robbins TW, Everitt BJ (2000) The effects of d-amphetamine, chlordiazepoxide, α-flupenthixol and behavioural manipulations on choice of signalled and unsignalled delay of reinforcement in rats. Psychopharmacology 152:362–375PubMedGoogle Scholar
  3. Cardinal RN, Pennicott DR, Lakmali Sugathapala C, Robbins TW, Everitt BJ (2001) Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 292:2499–2501CrossRefPubMedGoogle Scholar
  4. Dietrich A, Allen J (1998) Functional dissociation of the prefrontal cortex and hippocampus in timing behaviour. Behav Neurosci 112:1043–1047CrossRefPubMedGoogle Scholar
  5. Dietrich A, Frederick DL, Allen J (1997) The effect of total and subtotal prefrontal cortex lesions on the timing ability of the rat. Psychobiology 25:191–201Google Scholar
  6. Evenden JL (1999a) Impulsivity: a discussion of clinical and experimental findings. J Psychopharmacol 13:180–192PubMedGoogle Scholar
  7. Evenden JL (1999b) Varieties of impulsivity. Psychopharmacology 146:348–361PubMedGoogle Scholar
  8. Evenden JL, Ryan CN (1996) The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice with varying delays of reinforcement. Psychopharmacology 128:161–170Google Scholar
  9. Evenden JL, Ryan CN (1999) The pharmacology of impulsive behaviour in rats VI: the effects of ethanol and sedative serotonergic drugs on response choice with varying delays of reinforcement. Psychopharmacology 146:413–421Google Scholar
  10. Gallagher M, McMahon RW, Schoenbaum G (1999) Orbitofrontal cortex and representation of incentive value in associative learning. J Neurosci 19:6610–6614PubMedGoogle Scholar
  11. Gibbon J, Church RM, Fairhurst S, Kacelnik A (1988) Scalar expectancy and choice between delayed rewards. Psychol Rev 95:102–114PubMedGoogle Scholar
  12. Grace RC (1994) A contextual model of concurrent chains choice. J Exp Anal Behav 61:113–129Google Scholar
  13. Groenewegen HJ, Uylings HBM (2000) The prefrontal cortex and the integration of sensory, limbic and autonomic information. Prog Brain Res 85:31–62Google Scholar
  14. Heffner TG, Hartman JA, Seiden LS (1988) A method for regional dissection of the rat brain. Pharmacol Biochem Behav 13:453–456CrossRefGoogle Scholar
  15. Herrnstein RJ (1981) Self-control as response strength. In: Bradshaw CM, Szabadi E, Lowe CF (eds) Quantification of steady-state operant behaviour. Elsevier, Amsterdam, pp 3–20Google Scholar
  16. Ho M-Y, Bradshaw CM, Szabadi E (1997) Choice between delayed reinforcers: interaction between delay and deprivation level. Q J Exp Psychol 50B:193–202Google Scholar
  17. Ho M-Y, Al-Zahrani SSA, Al-Ruwaitea ASA, Bradshaw CM, Szabadi E (1998) 5-Hydroxytryptamine and impulse control: prospects for a behavioural analysis. J Psychopharmacol 12:68–78PubMedGoogle Scholar
  18. Ho M-Y, Mobini S, Chiang T-J, Bradshaw CM, Szabadi E (1999) Theory and method in the quantitative analysis of impulsive choice behaviour: implications for psychopharmacology. Psychopharmacology 146:362–372PubMedGoogle Scholar
  19. Iversen SD, Mishkin M (1970) Perseverative interference in monkey following selective lesions of the inferior prefrontal convexity. Exp Brain Res 11:376–386PubMedGoogle Scholar
  20. Jones B, Mishkin M (1972) Limbic lesions and the problem of stimulus-reinforcement associations. Exp Neurol 36:362–377PubMedGoogle Scholar
  21. Kacelnik A (1997) Normative and descriptive models of decision making: time discounting and risk sensitivity. Ciba Foundation Symposium, 208: Characterizing human psychological adaptations. Wiley, ChichesterGoogle Scholar
  22. Kheramin S, Body S, Mobini S, Ho M-Y, Velazquez Martinez DN, Bradshaw CM, Szabadi E, Deakin JFW, Anderson IM (2002) Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on inter-temporal choice: a quantitative analysis. Psychopharmacology 165:9–17CrossRefPubMedGoogle Scholar
  23. Kheramin S, Body S, Ho M-Y, Velazquez Martinez DN, Bradshaw CM, Szabadi E, Deakin JFW, Anderson IM (2003) Role of the orbital prefrontal cortex in choice between delayed and uncertain reinforcers: a quantitative analysis. Behav Proc 64:239–250CrossRefGoogle Scholar
  24. Kolb B (1984) Functions of the frontal cortex of the rat: a comparative review. Brain Res Rev 8:65–98CrossRefGoogle Scholar
  25. Kolb B (1990) Animal models for human PFC-related disorders. In: Uylings CG, Van Eden CG, De Bruin JPC, Corner MA, Feenstra MGP (eds) Progress in brain research, vol 85. Elsevier, Amsterdam, pp 501–520Google Scholar
  26. Lishman WA (1998) Organic psychiatry, 3rd edn. Blackwell Science, OxfordGoogle Scholar
  27. Logue AW (1988) Research on self-control: an integrated framework. Behav Brain Sci 11:665–709Google Scholar
  28. Mazur JE (1987) An adjusting procedure for studying delayed reinforcement. In: Commons ML, Mazur JE, Nevin JA, Rachlin HC (eds) Quantitative analyses of behavior, vol 5. The effect of delay and intervening events on reinforcement value. Erlbaum, Hillsdale, N.J., pp 55–73Google Scholar
  29. Mazur JE (1995) Conditioned reinforcement and choice with delayed and uncertain primary reinforcers. J Exp Anal Behav 63:139–150Google Scholar
  30. Mazur JE (1997) Choice, delay, probability, and conditioned reinforcement. Anim Learn Behav 25:131–147Google Scholar
  31. Mischel W (1983) Delay of gratification as a process and a person variable in development. In: Magnussen D, Allen VL (eds) Human development. Academic Press, New YorkGoogle Scholar
  32. Mobini S, Chiang T-J, Al-Ruwaitea ASA, Ho M-Y, Bradshaw CM, Szabadi E (2000a) Effects of central 5-hydroxytryptamine depletion on inter-temporal choice: a quantitative analysis. Psychopharmacology 149:313–318Google Scholar
  33. Mobini S, Body S, Ho M-Y, Bradshaw CM, Szabadi E (2000b) Effects of lesions of the orbitofrontal cortex on sensitivity to delayed and probabilistic reinforcement. Psychopharmacology 160:290–298CrossRefGoogle Scholar
  34. Mobini S, Chiang T-J, Ho M-Y, Bradshaw CM, Szabadi E (2000c) Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement. Psychopharmacology 152:390–397PubMedGoogle Scholar
  35. Monterosso J, Ainslie GW (1999) Beyond discounting: possible experimental models of impulse control. Psychopharmacology 146:339–347PubMedGoogle Scholar
  36. Oades RD, Halliday GM (1987) Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res Rev 12:117–165CrossRefGoogle Scholar
  37. Otto T, Eichenbaum H (1992) Complementary roles of the orbital prefrontal cortex and perirhinal–entorhinal cortices in an odor-guided delayed-nonmatching-to-sample task. Behav Neurosci 106:762–775PubMedGoogle Scholar
  38. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, New YorkGoogle Scholar
  39. Rachlin H (1974) Self-control. Behaviorism 2:94–107Google Scholar
  40. Rachlin H (1995) Self-control: beyond commitment. Behav Brain Sci 18:109–159Google Scholar
  41. Richards JB, Mitchell SH, de Wit H, Seiden LS (1997) Determination of discount functions in rats with an adjusting-amount procedure. J Exp Anal Behav 67:353–366PubMedGoogle Scholar
  42. Richards JB, Sabol KE, de Wit H (1999) Effects of methamphetamine and the adjusting amount procedure: a model of impulsive beavior in rats. Psychopharmacology 146:432–439PubMedGoogle Scholar
  43. Rolls ET (1999) The brain and emotion. Oxford University Press, OxfordGoogle Scholar
  44. Rolls ET (2000) The orbitofrontal cortex and reward. Cereb Cortex 10:284–294CrossRefPubMedGoogle Scholar
  45. Rushworth MFS, Nixon PD, Eacott MJ, Passingham RE (1997) Ventral prefrontal cortex is not essential for working memory. J Neurosci 17:4829–4838PubMedGoogle Scholar
  46. Schoenbaum G, Nugent SL, Saddoris MP, Setlow B (2002) Orbitofrontal lesions in rats impair reversal but not acquisition of go, no-go odor discrimination. Neuroreport 13:885–890CrossRefPubMedGoogle Scholar
  47. Schultz W (2000) Multiple reward signals in the brain. Nature Neurosci 1:199–207Google Scholar
  48. Schultz W (2002) Getting formal with dopamine and reward. Neuron 36:241–263PubMedGoogle Scholar
  49. Tzschentke TM (2001) Pharmacology and behavioral pharmacology of the mesocortical dopamine system. Prog Neurobiol 63:241–320Google Scholar
  50. Wade TR, de Wit H, Richards JB (2000) Effects of dopaminergic drugs on delayed reward as a measure of impulsive behavior in rats. Psychopharmacology 150:90–101Google Scholar
  51. Winer BJ (1991) Statistical principles in experimental design, 3rd edn. McGraw-Hill, New YorkGoogle Scholar
  52. de Wit H, Engagasser JL, Richards JB (2002) Acute administration of d-amphetamine decreases impulsivity in healthy volunteers. Neuropsychopharmacology 27:813–825CrossRefPubMedGoogle Scholar
  53. Wogar MA, Bradshaw CM, Szabadi E (1992) Impaired acquisition of temporal differentiation performance following lesions of the ascending 5-hydroxytryptaminergic pathways. Psychopharmacology 111:373–378Google Scholar
  54. Zavitsanou K, Cranney J, Richardson R (1999) Dopamine antagonists in the orbital prefrontal cortex reduce prepulse inhibition of the acoustic startle reflex in the rat. Pharmacol Biochem Behav 63:55–61PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • S. Kheramin
    • 1
  • S. Body
    • 1
  • M.-Y. Ho
    • 2
  • D. N. Velázquez-Martinez
    • 3
  • C. M. Bradshaw
    • 1
  • E. Szabadi
    • 1
  • J. F. W. Deakin
    • 4
  • I. M. Anderson
    • 4
  1. 1.Psychopharmacology Section, Division of Psychiatry, Queen’s Medical CentreUniversity of NottinghamNottinghamUK
  2. 2.Institute of Clinical Behavioral SciencesChang Gung UniversityTao YuanTaiwan, ROC
  3. 3.Departamento Psicofisiologia, Facultad de PsicologiaUniversidad Nacional Autónoma de MéxicoMexicoMexico
  4. 4.Neuroscience & Psychiatry Unit, School of Psychiatry & Behavioural SciencesUniversity of ManchesterManchesterUK

Personalised recommendations