Separate mechanisms for development and performance of compulsive checking in the quinpirole sensitization rat model of obsessive-compulsive disorder (OCD)
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Acute administration of serotonergic agonist, meta-chlorophenylpiperazine (mCPP), attenuates performance of compulsive checking in an animal model of obsessive-compulsive disorder (OCD). It is not known whether mCPP has a similar effect on development of compulsive checking.
The objective of the study was to examine whether similar mechanisms mediate the development versus the performance of compulsive checking in the rat model.
Four groups of male rats (N = 14/group) were tested: two experimental groups co-injected with D2/D3 dopamine agonist quinpirole (0.25 mg/kg) and mCPP (0.625 mg/kg or 1.25 mg/kg), and two control groups, one co-injected with quinpirole and saline, the other receiving injections of saline. The time course of development of compulsive checking across injections 1 to 10 in quinpirole-treated rats was compared to rats co-injected with quinpirole and mCPP.
Results showed that during the course of chronic treatment, mCPP (1.25 mg/kg) significantly attenuated performance of checking behavior. However, when these rats were retested for expression of compulsive checking (that is, with an injection of quinpirole only), their profile of compulsive checking was no different from the control rats treated throughout with quinpirole only.
Findings show that mCPP inhibits performance of compulsive checking but does not block quinpirole from inducing the neural substrate underlying this compulsive behavior. Hence, a separate mechanism underlies the induction of compulsive checking and the performance of it. It is suggested that development of the OCD endophenotype reflects neuroplastic changes produced by repeated dopamine D2/D3 receptor stimulation, while stimulation of serotonergic receptors mediates a negative feedback signal that shuts down the motor performance of checking.
KeywordsCompulsive checking behavior Dopamine-serotonin interaction Security motivation mCPP Quinpirole
We thank Ms. Dawn Graham for excellent technical assistance in carrying out this study and Dr Erik Woody for advise with statistical analysis. This study was supported by operating grants to HS from the Canadian Institutes of Health Research (CIHR MOP-64424), the Natural Sciences and Engineering Research Council of Canada (RGPIN A0544), and the Ontario Mental Health Foundation, and by an Ontario Graduate Scholarship award to MCT.
Conflict of interest
The authors declare no conflict of interests.
- Bos M, Jenck F, Martin JR, Moreau JL, Sleight AJ, Wichmann J, Widmer U (1997) Novel agonists of 5HT2C receptors. Synthesis and biological evaluation of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines. Improved therapeutics for obsessive compulsive disorder. J Med Chem 40:2762–2769PubMedCrossRefGoogle Scholar
- Broocks A, Pigott TA, Hill JL, Stephanie C, Grady TA, 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 79:11–20PubMedCrossRefGoogle Scholar
- Joel D, Avisar A, Doljansky J (2001) Enhancement of excessive lever-pressing after post-training signal attenuation in rats by repeated administration of the D1 antagonist SCH 23390 or the D2 agonist quinpirole, but not the D1 agonist SKF 38393 or the D2 antagonist haloperidol. Behav Neurosci 115:1291–1300PubMedCrossRefGoogle Scholar
- Kontis D, Tsaltas E, Boulougouris V, Papakosta VM, Kalogerakou S, Papadopoulos S, Papadimitriou G (2008) 5-HT2A and 5-HT2C receptor involvement in the acute effects of mCPP and fluoxetine on persistence behaviour. Int J Neuropsychopharmacol 11:282–282Google Scholar
- Murphy DL, Zohar J, Benkelfat C, Pato MT, Pigott TA, Insel TR (1989) Obsessive-compulsive disorder as a 5-HT subsystem-related behavioural disorder. Br J Psychiatry Suppl 15–24Google Scholar
- Papakosta VM, Kalogerakou S, Kontis D, Anyfandi E, Theochari E, Boulougouris V, Papadopoulos S, Panagis G, Tsaltas E (2013) 5-HT2C receptor involvement in the control of persistence in the reinforced spatial alternation animal model of obsessive-compulsive disorder. Behav Brain Res 243:176–83PubMedCrossRefGoogle Scholar
- Sesia T, Bizup B, Grace AA (2013) Evaluation of animal models of obsessive-compulsive disorder: correlation with phasic dopamine neuron activity. International Journal of Neuropsychopharmacology: 1-13Google Scholar
- Szechtman H, Eilam D (2005) Psychiatric models. In: Whishaw IQ, Kolb B (eds) The behavior of the laboratory rat: a handbook with tests. Oxford University Press, New York, pp 462–474Google Scholar
- Szechtman H, Talangbayan H, Canaran G, Dai H, Eilam D (1994b) Dynamics of behavioral sensitization induced by the dopamine agonist quinpirole and a proposed central energy control mechanism [published erratum appears in Psychopharmacology (Berl) 1994 Sep;116(1):124]. Psychopharmacol (Berl) 115:95–104CrossRefGoogle Scholar
- Szechtman H, Shivji S, Woody EZ (2013) Pathophysiology of obsessive-compulsive disorder: insights from normal function and neurotoxic effects of drugs, infection and brain injury. In: Kostrzewa RM (ed) Handbook of neurotoxicity. Springer London, LimitedGoogle Scholar
- Szumlinski KK, Allan M, Talangbayan H, Tracey A, Szechtman H (1997) Locomotor sensitization to quinpirole: environment-modulated increase in efficacy and context-dependent increase in potency. Psychopharmacoly (Berl) 134:193–200Google Scholar
- Vermeire S, Audenaert K, De Meester R, Vandermeulen E, Waelbers T, De Spiegeleer B, Eersels J, Dobbeleir A, Peremans K (2012) Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder. Psychiatry Res Neuroimaging 201:78–87CrossRefGoogle Scholar
- Wise S, Rapoport JL (1989) Obsessive compulsive disorder—is it a basal ganglia dysfunction? In: Rapoport J (ed) Obsessive compulsive disorder in children and adolescence. American Psychiatric Press, Washington, DC, pp 327–344Google Scholar