The effects of clozapine on quinpirole-induced non-regulatory drinking and prepulse inhibition disruption in rats.
ABSTRACT The biological underpinnings of schizophrenic polydipsia are poorly understood.
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.
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.
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.
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.
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ABSTRACT: Dopamine plays a role in generating flexible adaptive responses in changing environments. Chronic administration of D2-like agonist quinpirole (QNP) induces behavioral sensitization and stereotypical behaviors reminiscent of obsessive-compulsive disorder (OCD). Some of these symptoms persist even after QNP discontinuation. In QNP-sensitization, perseverative behavior has often been implicated. To test the effect of QNP-sensitization on reversal learning and its association with perseveration we selected an aversively motivated hippocampus-dependent task, active place avoidance on a Carousel. Performance was measured as the number of entrances into a to-be-avoided sector (errors). We tested separately QNP-sensitized rats in QNP-drugged and QNP-undrugged state in acquisition and reversal tasks on the Carousel. In acquisition learning there were no significant differences between groups and their respective controls. In reversal, QNP-sensitized drugged rats showed a robust but transient increase in number of errors compared to controls. QNP-sensitized rats in an undrugged state were not overtly different from the control animals but displayed an altered learning manifested by more errors at the beginning compensated by quicker learning in the second session compared to control animals. Importantly, performance was not associated with perseveration in neither QNP-sensitized drugged nor QNP-sensitized undrugged animals. The present results show that chronic QNP treatment induces robust reversal learning deficit only when the substance is continuously administered, and suggest that QNP animal model of OCD is also feasible model of cognitive alterations in this disorder.Frontiers in Behavioral Neuroscience 04/2014; 8:122. · 4.16 Impact Factor
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ABSTRACT: Altered brain-derived neurotrophic factor (BDNF) signalling and dopaminergic neurotransmission have been shown in the forebrain in schizophrenia. The 'two hit' hypothesis proposes that two major disruptions during development are involved in the pathophysiology of this illness. We therefore used a 'two hit' rat model of combined neonatal and young-adult stress to assess effects on BDNF signalling and dopamine receptor expression. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. At adulthood the medial prefrontal cortex (mPFC), caudate putamen (CPu) and nucleus accumbens (NAc) were analysed by qPCR and Western blot. The 'two hit' combination of MS and CORT treatment caused significant increases in BDNF mRNA and protein levels in the mPFC of male, but not female rats. BDNF mRNA expression was unchanged in the CPu but was significantly reduced by CORT in the NAc. DR3 and DR2 mRNA were significantly up-regulated in the mPFC of two-hit rats and a positive correlation was found between BDNF and DR3 expression in male, but not female rats. DR2 and DR3 expression were significantly increased following CORT treatment in the NAc and a significant negative correlation between BDNF and DR3 and DR2 mRNA levels was found. Our data demonstrate male-specific two-hit effects of developmental stress on BDNF and DR3 expression in the mPFC. Furthermore, following chronic adolescent CORT treatment, the relationship between BDNF and dopamine receptor expression was significantly altered in the NAc. These results elucidate the long-term effects of 'two hit' developmental stress on behaviour.Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 08/2014; · 5.09 Impact Factor
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ABSTRACT: To identify the mechanism of unexplained hyponatremia and primary polydipsia in schizophrenia and its relationship to the underlying psychiatric illness.Schizophrenia Research 06/2014; · 4.43 Impact Factor