, Volume 227, Issue 1, pp 55–66 | Cite as

Effects of the 5HT2C antagonist SB242084 on the pramipexole-induced potentiation of water contrafreeloading, a putative animal model of compulsive behavior

  • Chiara Schepisi
  • Lorenza De Carolis
  • Paolo Nencini
Original Investigation



In rats, quinpirole, a dopaminergic D2/D3 receptor agonist, elicits both hyperdipsia and water “contrafreeloading” (CFL), a putative model of compulsivity. The role of D3 receptors in this effect remains unclear. Clomipramine (CIM) was found to contrast both hyperdipsia and CFL, but the role of serotonin in this effect requires further investigation.


We studied the effects of the preferential D3 agonist pramipexole (PPX) in both models. Furthermore, we tested the sensitivity of PPX-induced CFL to CIM and to the 5HT2c antagonist SB242084.


In experiment 1, drinking was measured at 2 and 5 h after eight daily injections of PPX (0 to 1.0 mg/kg intraperitoneally). In the CFL study, every other third lever press, the rat was reinforced by the delivery of water. On days 1–6, water was only available upon lever pressing. On days 7–15, choice between response-contingent and free access was provided. PPX doses as in the experiment 1 were given. In two further experiments, PPX (0.5 mg/kg) was administered alone or in combination with CIM (5 or 10 mg/kg) or SB242084 (0.3 or 1.0 mg/kg).


PPX did not produce hyperdipsia but enhanced spontaneous CFL. SB242084 attenuated PPX-induced CFL more effectively than CIM, restoring the preference for free access to water.


CFL, but not polydipsia, was induced by preferential D3 activation, an effect prevented by 5HT2c receptor blockade. Since PPX interferes with decision making and 5HT2c receptor supersensitivity is involved in the expression of compulsive behaviors, this study supports the compulsive nature of dopaminergic-induced CFL.


Pramipexole Contrafreeloading Polydipsia 5HT2c receptor SB242084 Clomipramine Obsessive–compulsive disorder 



This study was financed by intramural grants from the Sapienza University of Rome. The authors would like to thank Dr. Michele Celentano and Dr. Maria Meringolo for assisting us with informatic support.

Supplementary material

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ESM 1 (JPEG 170 kb)


  1. Ahlskog JE (2011) Pathological behaviors provoked by dopamine agonist therapy of Parkinson’s disease. Physiol Behav 104:168–172PubMedCrossRefGoogle Scholar
  2. Amato D, Milella MS, Badiani A, Nencini P (2006) Compulsive-like effects of repeated administration of quinpirole on drinking behavior in rats. Behav Brain Res 172:1–13PubMedCrossRefGoogle Scholar
  3. Amato D, Milella MS, Badiani A, Nencini P (2007) Compulsive-like effects of quinpirole on drinking behavior in rats are inhibited by substituting ethanol for water. Behav Brain Res 177:340–346PubMedCrossRefGoogle Scholar
  4. Amato D, Stasi MA, Borsini F, Nencini P (2008) Haloperidol both prevents and reverses quinpirole-induced nonregulatory water intake, a putative animal model of psychogenic polydipsia. Psychopharmacology 200:157–165PubMedCrossRefGoogle Scholar
  5. Antonini A, Barone P, Ceravolo R, Fabbrini G, Tinazzi M, Abbruzzese G (2010) Role of pramipexole in the management of Parkinson’s disease. CNS Drugs 24:829–841PubMedCrossRefGoogle Scholar
  6. Attar-Lévy D, Martinot JL, Blin J, Dao-Castellana MH, Crouzel C, Mazoyer B, Poirier MF, Bourdel MC, Aymard N, Syrota A, Féline A (1999) The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biol Psychiatry 45:180–186PubMedCrossRefGoogle Scholar
  7. Badiani A, Vaccaro R, Burdino R, Casini A, Valeri P, Renda TG, Nencini P (2002) Dissociation in the effects of the D2/D3 dopaminergic agonist quinpirole on drinking and on vasopressin levels in the rat. Neurosci Lett 325:79–82PubMedCrossRefGoogle Scholar
  8. Bienfait KL, Menza M, Mark MH, Dobkin RD (2010) Impulsive smoking in a patient with Parkinson’s disease treated with dopamine agonists. J Clin Neurosci 17:539–540PubMedCrossRefGoogle Scholar
  9. Blier P, de Montigny C (2008) Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive–compulsive disorder responses. Biol Psych 44:313–323Google Scholar
  10. Boulouguris V, Robbins TW (2010) Enhancement of spatial reversal learning by 5-HT2C receptor antagonism is neuroanatomically specific. J Neurosci 30:930–938CrossRefGoogle Scholar
  11. Boulouguris V, Glennon JC, Robbins TW (2008) Dissociable effects of selective 5-HT2A and 5HT2C receptor antagonists on serial spatial reversal learning in rats. Neuropsychopharmacology 33:2007–2019CrossRefGoogle Scholar
  12. Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz JC (1991) Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res 564:203–219PubMedCrossRefGoogle Scholar
  13. Bratcher NA, Farmer-Dougan V, Dougan JD, Heidenreich BA, Garris PA (2005) The role of dopamine in reinforcement: changes in reinforcement sensitivity induced by D1-type, D2-type, and nonselective dopamine receptor agonists. J Exp Anal Behav 84:371–399PubMedCrossRefGoogle Scholar
  14. Campbell-Meiklejohn D, Wakeley J, Herbert V, Cook J, Scollo P, Ray MK, Selvaraj S, Passingham RE, Cowen P, Rogers RD (2011) Serotonin and dopamine play complementary roles in gambling to recover losses. Neuropsychopharmacology 36:402–410PubMedCrossRefGoogle Scholar
  15. Chang WL, Geyer MA, Buell MR, Weber M, Swerdlow NR (2010) The effects of pramipexole on prepulse inhibition and locomotor activity in C57BL/6J mice. Behav Pharmacol 21:135–143PubMedCrossRefGoogle Scholar
  16. Chang WL, Breier MR, Yang A, Swerdlow NR (2011) Disparate effects of pramipexole on locomotor activity and sensorimotor gating in Sprague–Dawley rats. Pharmacol Biochem Behav 99:634–638PubMedCrossRefGoogle Scholar
  17. Chang WL, Weber M, Breier MR, Saint Marie RL, Hines SR, Swerdlow NR (2012) Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats. Brain Res 1437:69–76PubMedCrossRefGoogle Scholar
  18. Chernoloz O, El Mansari M, Blier P (2009) Sustained administration of pramipexole modifies the spontaneous firing of dopamine, norepinephrine, and serotonin neurons in the rat brain. Neuropsychopharmacology 34:651–661Google Scholar
  19. Cioli I, Caricati A, Nencini P (2000) Quinpirole- and amphetamine-induced hyperdipsia: influence of fluid palatability and behavioral cost. Behav Brain Res 109:9–18PubMedCrossRefGoogle Scholar
  20. Comella CL (2002) Restless legs syndrome: treatment with dopaminergic agents. Neurology 58:S87–S92PubMedCrossRefGoogle Scholar
  21. De Carolis L, Stasi MA, Serlupi-Crescenzi O, Borsini F, Nencini P (2010) The effects of clozapine on quinpirole-induced non-regulatory drinking and prepulse inhibition disruption in rats. Psychopharmacology (Berl) 212:105–115CrossRefGoogle Scholar
  22. De Carolis L, Schepisi C, Milella MS, Nencini P (2011) Clomipramine, but not haloperidol or aripiprazole, inhibits quinpirole-induced water contrafreeloading, a putative animal model of compulsive behavior. Psychopharmacology (Berl) 218:749–759CrossRefGoogle Scholar
  23. de Leeuw AS, Westenberg HG (2008) Hypersensitivity of 5-HT2 receptors in OCD patients. An increased prolactin response after a challenge with meta-chlorophenylpiperazine and pre-treatment with ritanserin and placebo. J Psychiatr Res 42:894–901PubMedCrossRefGoogle Scholar
  24. de Leon (2003) Polydipsia—a study in a long-term psychiatric unit. Eur Arch Psychiatry Clin Neurosci 253:37–39PubMedCrossRefGoogle Scholar
  25. de Leon J, Verghese C, Tracy JI, Josiassen RC, Simpson GM (1994) Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature. Biol Psychiatry 35:408–419PubMedCrossRefGoogle Scholar
  26. Deas-Nesmith D, Brewerton TD (1992) A case of fluoxetine-responsive psychogenic polydipsia: a variant of obsessive–compulsive disorder? J Nerv Ment Dis 180:338–339PubMedCrossRefGoogle Scholar
  27. Diaz J, Levesque D, Lammers CH, Griffon N, Martres MP, Schwartz JC, Sokoloff P (1995) Phenotypical characterization of neurons expressing the dopamine D3 receptor in rat brain. Neuroscience 65:731–745PubMedCrossRefGoogle Scholar
  28. Diaz MR, Chappell AM, Christian DT, Anderson NJ, McCool BA (2011) Dopamine D3-like receptors modulate anxiety-like behavior and regulate GABAergic transmission in the rat lateral/basolateral amygdala. Neuropsychopharmacology 36:1090–1103PubMedCrossRefGoogle Scholar
  29. Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, Ahiskog JE (2005) Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 62:1377–1381PubMedCrossRefGoogle Scholar
  30. Fineberg NA, Gale TM (2005) Evidence-based pharmacotherapy of obsessive–compulsive disorder. Int J Neuropsychopharmacol 8:107–129PubMedCrossRefGoogle Scholar
  31. Fleischer-Grinberg S, Klavir O, Joel D (2008) The role of 5HT2A and 5HT2C receptors in the signal attenuation rat model of obsessive–compulsive disorder. Int J Neuropsychopharmacol 11:811–825Google Scholar
  32. Fox SH, Katzenschlager R, Lim SY, Ravina B, Seppi K, Coelho M, Poewe W, Rascol O, Goetz CG, Sampaio C (2011) The movement disorder society evidence-based medicine review update: treatments for the motor symptoms of Parkinson’s disease. Mov Disord 3:S2–S41CrossRefGoogle Scholar
  33. Fraioli S, Cioli I, Nencini P (1997) Amphetamine reinstates polydipsia induced by chronic exposure to quinpirole, a dopaminergic D2 agonist, in rats. Behav Brain Res 89:199–215PubMedCrossRefGoogle Scholar
  34. Greene-Schloesser DM, Van der Zee EA, Sheppard DK, Castillo MR, Gregg KA, Burrow T, Foltz H, Slater M, Bult-Ito A (2011) Predictive validity of a non-induced mouse model of compulsive-like behavior. Behav Brain Res 221:55–62PubMedCrossRefGoogle Scholar
  35. Hassan A, Bower JH, Kumar N, Matsumoto JY, Fealey RD, Josephs KA, Ahlskog JE (2011) Dopamine agonist-triggered pathological behaviors: surveillance in the PD clinic reveals high frequencies. Parkinsonism Relat Disord 17:260–264PubMedCrossRefGoogle Scholar
  36. Inglis IR, Ferguson NJ (1986) Starlings search for food rather than eat freely-available, identical food. Anim Behav 34:614–617CrossRefGoogle Scholar
  37. Inglis IR, Forkman B, Lazarus J (1997) Free food or earned food? A review and fuzzy model of contrafreeloading. Anim Behav 53:1171–1191PubMedCrossRefGoogle Scholar
  38. Jensen ED (1963) Preference for bar pressing over “free-loading” as a function of unrewarded presses. J Exp Psychol 65:451–454PubMedCrossRefGoogle Scholar
  39. Joel D, Avisar A (2001) Excessive lever pressing following post-training signal attenuation in rats: a possible animal model of obsessive compulsive disorder? Behav Brain Res 123:77–87PubMedCrossRefGoogle Scholar
  40. Johnson PS, Madden GJ, Brewer AT, Pinkston JW, Fowler SC (2011) Effects of acute pramipexole on preference for gambling-like schedules of reinforcement in rats. Psychopharmacology (Berl):11–18Google Scholar
  41. Kolla BP, Mansukhani MP, Barraza R, Bostwick JM (2010) Impact of dopamine agonists on compulsive behaviors: a case series of pramipexole-induced pathological gambling. Psychosomatics 51:271–273PubMedGoogle Scholar
  42. Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB, American Psychiatric Association (2007) Practice guideline for the treatment of patients with obsessive–compulsive disorder. Am J Psychiatry 164:5–53PubMedGoogle Scholar
  43. Kurylo DD (2004) Effects of quinpirole on operant conditioning: perseveration of behavioral components. Behav Brain Res 155:117–124PubMedCrossRefGoogle Scholar
  44. Kvernmo T, Härtter S, Bürger E (2006) A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther 28:1065–1078PubMedCrossRefGoogle Scholar
  45. Lader M (2008) Antiparkinsonian medication and pathological gambling. CNS Drugs 22:407–416PubMedCrossRefGoogle Scholar
  46. Leggio GM, Cathala A, Moison D, Cunningham KA, Piazza PV, Spampinato U (2009) Serotonin2C receptors in the medial prefrontal cortex facilitate cocaine-induced dopamine release in the rat nucleus accumbens. Neuropharmacology 56:507–513PubMedCrossRefGoogle Scholar
  47. Levant B (1998) Differential distribution of D3 dopamine receptors in the brains of several mammalian species. Brain Res 800:269–274PubMedCrossRefGoogle Scholar
  48. Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxyl-N, N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci USA 89:815CrossRefGoogle Scholar
  49. Li X, Morrow D, Witkin JM (2006) Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying. Life Sci 78(17):1933–1939PubMedCrossRefGoogle Scholar
  50. Manconi M, Ferri R, Zucconi M, Clemens S, Giarolli L, Bottasini V, Ferini-Strambi L (2011) Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome. Neurology 77:110–117PubMedCrossRefGoogle Scholar
  51. McGowan RT, Robbins CT, Alldredge JR, Newberry RC (2010) Contrafreeloading in grizzly bears: implications for captive foraging enrichment. Zoo Biol 29:484–502PubMedGoogle Scholar
  52. Mierau J, Schneider FJ, Ensinger HA, Chio CL, Lajiness ME, Huff RM (1995) Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors. Eur J Pharmacol 290:29–36PubMedCrossRefGoogle Scholar
  53. Milella MS, Amato D, Badiani A, Nencini P (2008) The influence of cost manipulation on water contrafreeloading induced by repeated exposure to quinpirole in the rat. Psychopharmacology 197:379–390PubMedCrossRefGoogle Scholar
  54. Milella MS, Passarelli F, De Carolis L, Schepisi C, Nativio P, Scaccianoce S, Nencini P (2010) Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia. Psychopharmacology (Berl) 211:355–366CrossRefGoogle Scholar
  55. 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
  56. Navailles S, Moison D, Cunningham KA, Spampinato U (2008) Differential regulation of the mesoaccumbens dopamine circuit by serotonin2C receptors in the ventral tegmental area and the nucleus accumbens: an in vivo microdialysis study with cocaine. Neuropsychopharmacology 33:237–246PubMedCrossRefGoogle Scholar
  57. Nirenberg MJ, Waters C (2006) Compulsive eating and weight gain related to dopamine agonist use. Mov Disord 21:524–529PubMedCrossRefGoogle Scholar
  58. Ogura T (2011) Contrafreeloading and the value of control over visual stimuli in Japanese macaques (Macaca fuscata). Anim Cogn 14:427–431PubMedCrossRefGoogle Scholar
  59. Pittenger C (2011) Pathophysiological modeling of obsessive–compulsive disorder: challenges, and progress. Biol Psychiatry 70:1002–1003PubMedCrossRefGoogle Scholar
  60. Rendell M, McGrane D, Cuesta M (1978) Fatal compulsive water drinking. JAMA 240:2557–2559PubMedCrossRefGoogle Scholar
  61. Riba J, Krämer UM, Heldmann M, Richter S, Münte TF (2008) Dopamine agonist increases risk taking but blunts reward-related brain activity. PLoS One 3:e2479PubMedCrossRefGoogle Scholar
  62. Robertson LC, Anderson SC (1975) The effects of differing type and magnitude of reward on the contrafreeloading phenomenon in rats. Anim Learn Behav 3:325–328Google Scholar
  63. Schilman EA, Klavir O, Winter C, Sohr R, Joel D (2010) The role of the striatum in compulsive behavior in intact and orbitofrontal-cortex-lesioned rats: possible involvement of the serotonergic system. Neuropsychopharmacology 35:1026–1039PubMedCrossRefGoogle Scholar
  64. Serretti A, Artioli P, De Ronchi D (2004) The 5HT2C receptor as a target for mood disorders. Expert Opin Ther Targets 8:15–23PubMedCrossRefGoogle Scholar
  65. Shanahan NA, Velez LP, Masten VL, Dulawa SC (2011) Essential role for orbitofrontal serotonin 1B receptors in obsessive–compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice. Biol Psychiatry 70:1039–1048PubMedCrossRefGoogle Scholar
  66. Shutty MS Jr, McCulley K, Pigott B (1995) Association between stereotypic behavior and polydipsia in chronic schizophrenic patients. J Behav Ther Exp Psychiatry 26:339–343PubMedCrossRefGoogle Scholar
  67. Simpson HB (2010) Pharmacological treatment of obsessive–compulsive disorder. Curr Top Behav Neurosci 2:527–543PubMedCrossRefGoogle Scholar
  68. Singh D (1970) Preference for bar pressing to obtain reward over freeloading in rats and children. J Comp Physiol Psychol 73:320–327CrossRefGoogle Scholar
  69. Sotty F, Folgering JH, Hogg S, Mork A, Hertel P, Cremers TI (2009) Relevance of dorsal raphe nucleus firing in serotonin 5-HT(2C) receptor blockade-induced augmentation of SSRI effects. Neuropharmacology 57:18–24PubMedCrossRefGoogle Scholar
  70. Szechtman H, Sulis W, Eilam D (1998) Quinpirole induces compulsive checking behavior in rats: a potential animal model of obsessive–compulsive disorder (OCD). Behav Neurosci 112:1475–1485PubMedCrossRefGoogle Scholar
  71. Tarte RD (1981) Contrafreeloading in humans. Psychol Rep 49:859–866CrossRefGoogle Scholar
  72. van Eimeren T, Ballanger B, Pellecchia G, Miyasaki JM, Lang AE, Strafella AP (2009) Dopamine agonists diminish value sensitivity of the orbitofrontal cortex: a trigger for pathological gambling in Parkinson’s disease? Neuropsychopharmacology 34:2758–2766PubMedCrossRefGoogle Scholar
  73. Yamauchi M, Tatebayashi T, Nagase K, Kojima M, Imanishi T (2004) Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats. Pharmacol Biochem Behav 78:683–689PubMedCrossRefGoogle Scholar
  74. Ye Z, Hammer A, Camara E, Münte TF (2011) Pramipexole modulates the neural network of reward anticipation. Hum Brain Mapp 32:800–811PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Chiara Schepisi
    • 1
  • Lorenza De Carolis
    • 1
  • Paolo Nencini
    • 1
  1. 1.Department of Physiology and Pharmacology “Vittorio Erspamer”Sapienza University of RomeRomeItaly

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