Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia

Rationale Repeated administration of the dopamine D2/D3 agonist quinpirole (QNP) progressively increases non-regulatory water intake. This effect may model psychotic polydipsia, a potentially fatal but poorly understood condition. Objectives The growing evidence for a role of orexin in mediating arousal and cognition has linked this peptide to schizophrenia, hence we examined whether manipulations of dopaminergic and orexinergic systems, as well as of setting, would further characterize the model. Methods Water intake was measured in rats sequentially tested in home and then operant conditioning setting, with chronic administration of D2 antagonist haloperidol (Hal) prior to QNP treatment. A group of rats similarly treated was also assessed for orexin A (OxA) expression in the cortex. Finally, the effect of the orexin-1 receptor antagonist SB-334867 on QNP-induced polydipsia was evaluated. Results In rats made polydipsic by QNP the amount of water drank during the first 4 h was strongly correlated with the degree of dissociation between appetitive and consummatory components of drinking behavior in the following hour of operant access to water. Hal 0.2 mg/kg prevented both polydipsia and the dissociation, while 0.1 mg/kg only blocked the dissociation. Chronic QNP treatment increased, in a Hal-reversible way, OxA expression in the somatosensory cortex (SI). Moreover, pretreatment with SB-334867 sped up and potentiated QNP-induced polydipsia. Conclusions Results disclose compulsive components in QNP-induced polydipsia that are mediated by dopamine D2 receptors. QNP also regulates OxA expression in the SI, while the block of orexin-1 receptors enhances QNP-induced polydipsia. We suggest that dopamine and OxA play opposite roles in QNP-induced polydipsia.