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

Abstract

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 5h after eight daily injections of PPX (0 to 1.0mg/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 (0.5mg/kg) was administered alone or in combination with CIM (5 or 10mg/kg) or SB242084 (0.3 or 1.0mg/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.