Effects of the 5HT2C antagonist SB242084 on the pramipexole-induced potentiation of water contrafreeloading, a putative animal model of compulsive behavior
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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.
KeywordsPramipexole 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.
- 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
- Blier P, de Montigny C (2008) Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive–compulsive disorder responses. Biol Psych 44:313–323Google Scholar
- 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
- 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
- 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
- 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
- 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
- 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
- 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