Skip to main content
SpringerLink
Log in

Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive–compulsive disorder

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

We have proposed rewarded T-maze alternation as a model of obsessive–compulsive disorder (OCD): the serotonin agonist m-chlorophenylpiperazine (mCPP) increments persistence therein, while chronic pretreatment with selective serotonin reuptake inhibitor (SSRI fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increase, counteracted by mCPP pretreatment.

Objectives

This study (a) further explores the cross-tolerance between fluoxetine and mCPP and (b) extends the model by investigating its sensitivity to dopaminergic manipulations (D2, 3 agonism—quinpirole).

Materials and methods

In both experiments, baseline and drug testing were carried out under daily T-maze alternation training. Exp. 1: Matched group (n = 8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration): (1) saline, (2) low-dose fluoxetine (2.5 mg/kg), (3) low-dose mCPP (0.5 mg/kg) or (4) combined fluoxetine + mCPP. One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10 mg/kg), the other with high-dose mCPP (2.5 mg/kg). Exp. 2: One group (n = 12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg).

Results

Exp. 1: Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine + mCPP pretreatment afforded full protection from either challenge. Exp. 2: Quinpirole significantly increased directional persistence after 13 administration days.

Conclusions

These results establish the sensitivity of the rewarded alternation OCD model to D2, 3 receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Austin LS, Lydiard RB, Ballenger JC, Cohen BM, Laraia MT, Zealberg JJ et al (1991) Dopamine blocking activity of clomipramine in patients with obsessive–compulsive disorder. Biol Psychiatry 30:225–232

    Article  PubMed  CAS  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  PubMed  CAS  Google Scholar 

  • Barr LC, Goodman WC, Price LH, McDougle CJ, Charney DS (1992) The serotonin hypothesis of obsessive compulsive disorder: Implications of pharmacologic challenge studies. J Clin Psychiatry 53S:17–28

    Google Scholar 

  • Baumgarten HG, Grozdanovic Z (1998) Role of serotonin in obsessive compulsive disorder. Br J Psychiatry Suppl 13–20

  • Bergqvist PBF, Bouchard C, Blier P (1999) Effect of long-term administration of antidepressant treatments on serotonin release in brain regions involved in obsessive–compulsive disorder. Biol Psychiatry 45:164–174

    Article  PubMed  CAS  Google Scholar 

  • Billett EA, Richter MA, Sam F, Swinson RP, Dai XY, King N, Badri F, Sasaki T, Buchanan JA, Kennedy JL (1998) Investigation of dopamine system genes in obsessive–compulsive disorder. Psychiatr Genet 8:163–169

    Article  PubMed  CAS  Google Scholar 

  • Blier P, de Montigny C (1998) A decade of serotonin research: antidepressant mechanisms and therapeutics. Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive–compulsive disorder responses. Biol Psychiatry 44:313–323

    Article  PubMed  CAS  Google Scholar 

  • Blier P, Bergeron R, Piñeyro G, El Mansari M (2000) Understanding the mechanism of action of serotonin reuptake inhibitors in OCD: a step toward more effective treatments? In: Goodman WK, Rudorfer R, Maser J (eds) Treatment-resistant obsessive–compulsive disorder. Lawrence Erlbaum and Associates, Mahwah, pp 551–571

    Google Scholar 

  • Boulougouris V, Dalley JW, Robbins TW (2007) Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav Brain Res 179:219–228

    Article  PubMed  Google Scholar 

  • Brambilla F, Bellodi L, Perna G, Arancio C, Bertani A (1997) Dopamine function in obsessive–compulsive disorder: growth hormone response to apomorphine stimulation. Biol Psychiatry 42:889–897

    Article  PubMed  CAS  Google Scholar 

  • Broocks A, Pigott TA, Hill JL, Canter S, Grady TA, Francine L’Heureux F, Murphy DL (1998) Acute intravenous administration of ondansetron and m-CPP, alone and in combination, in patients with obsessive–compulsive disorder OCD: behavioral and biological results. Psychiatry Res 79:11–20

    Article  PubMed  CAS  Google Scholar 

  • Campbell KM, de Lecea L, Severynse DM, Caron MG, McGrath MJ, Sparber SB et al (1999) OCD-like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+ neurons. J Neurosci 19:5044–5053

    PubMed  CAS  Google Scholar 

  • Catalano M, Sciuto G, Di Bella D, Novelli E, Nobile M, Bellodi L (1994) Lack of association between obsessive–compulsive disorder and the dopamine D3 receptor gene: some preliminary considerations. Am J Med Genet 54:253–255

    Article  PubMed  CAS  Google Scholar 

  • Chaput Y, de Montigny C, Blier P (1986) Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: electrophysiological studies in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 333:342–348

    Article  CAS  Google Scholar 

  • Charney DS, Goodman WK, Price LH, Woods SW, Rasmussen SA, Heninger GR (1988) Serotonin function in obsessive–compulsive disorder. A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects. Arch Gen Psychiatry 45:177–185

    PubMed  CAS  Google Scholar 

  • Chudasama Y, Robbins TW (2003) Dissociable contributions of the orbitofrontal and infralimbic cortex to Pavlovian autoshaping and discrimination reversal learning: further evidence for the functional heterogeneity of the rodent frontal cortex. J Neurosci 23:8771–8780

    PubMed  CAS  Google Scholar 

  • Delgado PL (2000) Future pharmacotherapy for obsessive–compulsive disorder: 5-HT2 agonists and beyond. In: Maj M, Sartorius N, Okasha A, Zohar J (eds) Obsessive–compulsive disorder. WPA series evidence and experience in psychiatry, vol. 4. Wiley, New York, pp 68–70

    Google Scholar 

  • Denys D, Zohar J, Westenberg HG (2004a) The role of dopamine in obsessive–compulsive disorder: preclinical and clinical evidence. J Clin Psychiatry 65(Suppl 14):11–17

    PubMed  CAS  Google Scholar 

  • Denys D, van der Wee N, Janssen J, De Geus F, Westenberg HG (2004b) Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder. Biol Psychiatry 55:1041–1045

    Article  PubMed  CAS  Google Scholar 

  • Eilam D, Szechtman H (2005) Psychostimulant-induced behavior as an animal model of obsessive–compulsive disorder: an ethological approach to the form of compulsive rituals. CNS Spectrums 10:191–202

    PubMed  Google Scholar 

  • Eilam D, Golani I, Szechtman H (1989) D2-agonist quinpirole induces perseveration of routes and hyperactivity but no perseveration of movements. Brain Res 490:255–267

    Article  PubMed  CAS  Google Scholar 

  • el Mansari M, Bouchard C, Blier P (1995) Alteration of serotonin release in the guinea pig orbito-frontal cortex by selective serotonin reuptake inhibitors. Relevance to treatment of obsessive–compulsive disorder. Neuropsychopharmacology 13(2):117–127

    Article  PubMed  Google Scholar 

  • Foley KA, Fudge MA, Kavaliers M, Ossenkopp KP (2006) Quinpirole-induced behavioral sensitization is enhanced by prior scheduled exposure to sucrose: a multi-variable examination of locomotor activity. Behav Brain Res 167(1):49–56

    Article  PubMed  CAS  Google Scholar 

  • Goodman WK, Price LH, Delgado PL, Palumbo J, Krystal JH, Nagy LM et al (1990a) Specificity of serotonin reuptake inhibitors in the treatment of obsessive–compulsive disorder. Comparison of fluvoxamine and desipramine. Arch Gen Psychiatry 47:577–585

    PubMed  CAS  Google Scholar 

  • Goodman WK, McDougle CJ, Price LH, Riddle MA, Pauls DL, Leckman JF (1990b) Beyond the serotonin hypothesis: a role for dopamine in some forms of obsessive compulsive disorder? J Clin Psychiatry 51:S36–S43

    Google Scholar 

  • Goodman WK, McDougle CJ, Price LH, Barr LC, Hills OF, Caplik JF et al (1995) m-Chlorophenylpiperazine in patients with obsessive-compulsive disorder: absence of symptom exacerbation. Biol Psychiatry 38:138–149

    Article  PubMed  CAS  Google Scholar 

  • Hoehn-Saric R, Ninan B, Black DW, Stahl S, Greist GH, Lydiard B et al (2000) Multicenter double-blind comparison of sertraline and desipramine for concurrent obsessive–compulsive and major depressive disorders. Arch Gen Psychiatry 57:76–82

    Article  PubMed  CAS  Google Scholar 

  • Hollander E, DeCaria C, Gully R, Nitescu A, Suckow RF, Gorman JM et al (1991) Effects of chronic fluoxetine treatment on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine in obsessive–compulsive disorder. Psychiatry Res 36:1–17

    Article  PubMed  CAS  Google Scholar 

  • Hollander E, DeCaria CM, Nitescu A, Gully R, Suckow RF, Cooper TB et al (1992) Serotonergic function in obsessive–compulsive disorder. Behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers. Arch Gen Psychiatry 49:21–28

    PubMed  CAS  Google Scholar 

  • Hollander E, Bienstock CA, Koran LM, Pallanti S, Marazziti D, Rasmussen SA et al (2002) Refractory obsessive–compulsive disorder: state-of-the-art treatment. J Clin Psychiatry 63(Suppl. 6):20–29

    PubMed  Google Scholar 

  • Hunt PR, Aggleton JP (1998) Neurotoxic lesions of the dorsomedial thalamus impair the acquisition but not the performance of delayed matching to place by rats: a deficit in shifting response rules. J Neurosci 18:10045–10052

    PubMed  CAS  Google Scholar 

  • Joel D, Dolijansky J (2003) Selective alleviation of compulsive lever-pressing in rats by D1, but not D2 blockade: Possible implications for the involvement of D1 receptors in obsessive-compulsive disorder. Neuropsychopharmacology 28:77–85

    Article  PubMed  CAS  Google Scholar 

  • Jones B, Mishkin M (1972) Limbic lesions and the problem of stimulus-reinforcement associations. Exp Neurol 36:362–377

    Article  PubMed  CAS  Google Scholar 

  • Karno M, Goldin JM, Sorenson SB, Burnam MA (1988) The epidemiology of obsessive compulsive disorder in five US communities. Arch Gen Psychiatry 45:1094–1099

    PubMed  CAS  Google Scholar 

  • Khanna S, John JP, Reddy LP (2001) Neuroendocrine and behavioral responses to mCPP in obsessive–compulsive disorder. Psychoneuroendocrinology 26:209–223

    Article  PubMed  CAS  Google Scholar 

  • Marazziti D, Hollander E, Lensi P, Ravagli S, Cassano GB (1992) Peripheral markers of serotonin and dopamine function in obsessive–compulsive disorder. Psychiatry Res 42:41–51

    Article  PubMed  CAS  Google Scholar 

  • Marek GJ, Martin-Ruiz R, Abo A, Artiga F (2005) The selective 5HT2A receptor antagonist M100907 enhances antidepressant-like behavioural effects of the SSRI fluoxetine. Neuropsychopharmacology 30:2205–2215

    Article  PubMed  CAS  Google Scholar 

  • Martin JR, Bos M, Jenck F et al (1998) 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 286:913–924

    PubMed  CAS  Google Scholar 

  • McDonough M, Kennedy N (2002) Pharmacological management of obsessive–compulsive disorder: a review for clinicians. Harv Rev Psychiatr 10:127–137

    Article  CAS  Google Scholar 

  • McDougle CJ, Goodman WK, Price LH (1994a) Dopamine antagonists in tic-related and psychotic spectrum obsessive compulsive disorder. J Clin Psychiatry 55(Suppl 13):24–31

    PubMed  Google Scholar 

  • McDougle CJ, Goodman WK, Leckman JF, Lee NC, Heninger GR, Price LH (1994b) Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder. A double-blind placebo controlled study in patients with and without tics. Arch Gen Psychiatry 51:302–308

    PubMed  CAS  Google Scholar 

  • McDougle CJ, Barr LC, Goodman WK, Pelton GH, Aronson SC, Anand A (1995) Lack of efficacy of clozapine monotherapy in refractory obsessive–compulsive disorder. Am J Psychiatr 152:1812–1814

    PubMed  CAS  Google Scholar 

  • Micallef J, Blin O (2001) Neurobiology and clinical pharmacology of obsessive–compulsive disorder. Clin Neuropharmacol 24:191–207

    Article  PubMed  CAS  Google Scholar 

  • Modell JG, Mountz JM, Curtis GC, Greden JF (1989) Neurophysiologic dysfunction in basal ganglia/limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive–compulsive disorder. J Neuropsychiatry Clin Neurosci 1:27–36

    PubMed  CAS  Google Scholar 

  • Nurnberg HG, Keith SJ, Paxton DM (1997) Consideration relevance of ethology animal models for human repetitive behavioral spectrum disorders. Biol Psychiatry 41:226–229

    Article  PubMed  CAS  Google Scholar 

  • Pauls DL, Towbin KE, Leckman JF, Zahner GE, Cohen DJ (1986) Gilles de la Tourette's syndrome and obsessive–compulsive disorder. Evidence supporting a genetic relationship. Arch Gen Psychiatry 43:1180–1182

    PubMed  CAS  Google Scholar 

  • Pigott TA, Zohar J, Hill JL, Bernstein SE, Grover GN, Zohar-Kadouch RC, Murphy DL (1991) Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive–compulsive disorder. Biol Psychiatry 29:418–426

    Article  PubMed  CAS  Google Scholar 

  • Pigott TA, L’ Hereux F, Bernstein SE, Hill JL, Murphy DL (1992a) A controlled comparative therapeutic trial of clomipramine and m-chlorophenylpiperazine (mCPP) in patients with obsessive–compulsive disorder. NCDEU Annual Meeting Abstracts, May 26–29

  • Pigott TA, L’ Hereux F, Hill JL, Bihari K, Bernstein SE, Murphy DL (1992b) A double-blind study of adjuvant buspirone hydrochloride in clomipramine treated patients with obsessive–compulsive disorder. J Clin Psychopharmacol 12:11–18

    PubMed  CAS  Google Scholar 

  • Rapoport JL, Ryland DH, Kriete M (1992) Drug treatment of canine acral lick. An animal model of obsessive–compulsive disorder. Arch Gen Psychiatry 49:517–521

    PubMed  CAS  Google Scholar 

  • Sareen J, Kirshner A, Lander M, Kjernisted KD, Eleff MK, Reiss JP (2004) Do antipsychotics ameliorate or exacerbate obsessive compulsive disorder symptoms? A systematic review. J Affect Disord 82:167–174

    Article  PubMed  CAS  Google Scholar 

  • Saxena S, Rauch S (2000) Functional neuroimaging and the neuroanatomy of obsessive–compulsive disorder. Psychiatr Clin North Am 23:563–586

    Article  PubMed  CAS  Google Scholar 

  • Saxena S, Brody AL, Schwartz JM, Baxter LR (1998) Neuroimaging and frontal–subcortical circuitry in obsessive–compulsive disorder. Br J Psychiatr 173:26–37

    Google Scholar 

  • Stahl SM (1998) Essential psychopharmacology: neuroscience basic and practical applications. Cambridge University Press, Cambridge

    Google Scholar 

  • Sullivan RM, Talangbayan H, Einat H, Szechtman H (1998) Effects of quinpirole on central dopamine systems in sensitized and non-sensitized rats. Neuroscience 83:781–789

    Article  PubMed  CAS  Google Scholar 

  • Szechtman H, Dai H, Mustafa S, Einat H, Sullivan RM (1994) Effects of dose and interdose interval on locomotor sensitization to the dopamine agonist quinpirole. Pharmacol Biochem Behav 48(4):921–928

    Article  PubMed  CAS  Google Scholar 

  • 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 112:1475–1485

    Article  PubMed  CAS  Google Scholar 

  • Szechtman H, Eckert MJ, Tse WS, Boersma JT, Bonura CA, McClelland JZ, Culver KE, Eilam D (2001) Compulsive checking behavior of quinpirole-sensitized rats as an animal model of obsessive–compulsive disorder (OCD): form and control. BMC Neuroscience 2:4

    Article  PubMed  CAS  Google Scholar 

  • Tizabi Y, Louis VA, Taylor CT, Waxman D, Culver KE, Szechtman H (2002) Effect of nicotine on quinpirole-induced checking behavior in rats: implications for obsessive–compulsive disorder. Biol Psychiatry 51:164–171

    Article  PubMed  CAS  Google Scholar 

  • Tsaltas E, Kontis D, Chrysikakou S, Giannou H, Biba A, Pallidi S, Christodoulou A, Maillis A, Rabavilas A (2005) Reinforced spatial alternation as an animal model of obsessive–compulsive disorder (OCD): investigation of 5-HT2C and 5-HT1D receptor involvement in OCD pathophysiology. Biol Psychiatry 57:1176–1185

    Article  PubMed  CAS  Google Scholar 

  • Tsaltas E, Kontis D, Boulougouris V, Papakosta VM, Giannou H, Poulopoulou C, Soldatos C (2007a) Enhancing effects of chronic lithium on memory in the rat. Behav Brain Res 177:51–60

    Article  PubMed  CAS  Google Scholar 

  • Tsaltas E, Kyriazi T, Poulopoulou C, Kontis D, Maillis A (2007b) Enhancing effects of lithium on memory are not by-products of learning or attentional deficits. Behav Brain Res 180(2):241–245 2007

    Article  PubMed  CAS  Google Scholar 

  • Zohar J, Insel TR (1987) Obsessive–compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology. Biol Psychiatry 22:667–687

    Article  PubMed  CAS  Google Scholar 

  • Zohar J, Mueller EA, Insel TR, Zohar-Kadouch RC, Murphy DL (1987) Serotonergic responsivity in obsessive–compulsive disorder. Comparison of patients and healthy controls. Arch Gen Psychiatry 44:946–951

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant 70/4/9100 from the Special Account for Research Grants, National and Kapodistrian University of Athens to Dr E. Tsaltas

Author information

Authors and Affiliations

  1. Experimental Psychology Laboratory, Department of Psychiatry, Eginition Hospital, Athens University Medical School, 74, Vas. Sofias Ave., 115 28, Athens, Greece

    Dimitris Kontis, Vasiliki Maria Papakosta, Stamatina Kalogerakou & Eleftheria Tsaltas

  2. Department of Experimental Psychology and the Behavioural and Clinical Neuroscience Institute (BCNI), University of Cambridge, Downing Site, CB2 3EB, Cambridge, UK

    Vasileios Boulougouris

  3. Psychiatric Hospital of Attica, Athens, Greece

    Dimitris Kontis & Socrates Papadopoulos

  4. Department of Neurology, Eginition Hospital, Athens University Medical School, 74, Vas. Sofias Ave., 115 28, Athens, Greece

    Cornelia Poulopoulou

  5. Department of Psychiatry, Eginition Hospital, Athens University Medical School, Athens, Greece

    George N. Papadimitriou

Authors
  1. Dimitris Kontis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vasileios Boulougouris
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vasiliki Maria Papakosta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stamatina Kalogerakou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Socrates Papadopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cornelia Poulopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. George N. Papadimitriou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eleftheria Tsaltas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eleftheria Tsaltas.

Additional information

We would like to thank Pharmacerb-Lilly AEBE (Athens, Greece) for supplying the fluoxetine hydrochloride.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kontis, D., Boulougouris, V., Papakosta, V.M. et al. Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive–compulsive disorder. Psychopharmacology 200, 597–610 (2008). https://doi.org/10.1007/s00213-008-1241-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1241-5

Keywords

Search

Navigation