The effects of clozapine on quinpirole-induced non-regulatory drinking and prepulse inhibition disruption in rats.

Rationale: The biological underpinnings of schizophrenic polydipsia are poorly understood.

Objectives: This study is aimed at fulfilling the requisites of an experimental model of this syndrome through the quinpirole (QNP) induction of non-regulatory drinking in rats.

Methods: In a first experiment, clozapine (10 and 40 mg/kg p.o.) was substituted for haloperidol during the last 5 days of 10 days QNP (0.5 mg/kg i.p.) administration and water intake measured at 5 h. In a second experiment, animals treated with QNP alone or in combination with clozapine were assessed for water intake and prepulse inhibition (PPI). Expression of genes coding for the dopaminergic D2 receptor, as well as for the early genes BDNF (brain-derived neurotrophic factor) and c-Fos in prefrontal cortex, hippocampus, and striatum was also evaluated.

Results: Clozapine prevented QNP-induced drinking at 10 and 40 mg/kg, but only at 40 mg/kg when it was substituted for haloperidol. In the second experiment, QNP-treated rats showed both non-regulatory drinking and PPI disruption. Both these effects were prevented by clozapine 40 mg/kg. QNP-reduced BDNF expression in the hippocampus and increased c-Fos in the prefrontal cortex. This effect was prevented by clozapine. Given by itself, clozapine reduced the expression of both D2 receptors and BDNF in the prefrontal cortex and striatum.

Conclusions: The present study lends further support to the hypothesis that non-regulatory drinking induced by QNP in rats is a robust and reliable pharmacological effect that might model psychotic polydipsia also in its sensitivity to clozapine.