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

Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Italy.
Psychopharmacology (Impact Factor: 3.88). 09/2010; 212(1):105-15. DOI: 10.1007/s00213-010-1937-1
Source: PubMed


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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    • "Co-administration of the tricyclic antidepressant clomipramine, effective in ameliorating symptoms in the treatment of OCD (Piccinelli et al., 1995), adds to the predictive validity of QNP-sensitization as a rat model of OCD (Szechtman et al., 1998). Additionally, the behavioral effects of chronic QNP administration are considered also to mimic some of behavioral characteristics of schizophrenia, specifically psychotic polydipsia (Goldman et al., 1988; De Carolis et al., 2010, 2011; Milella et al., 2010). "
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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. DOI:10.3389/fnbeh.2014.00122 · 3.27 Impact Factor
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    • "Treatments were administered daily between 9 and 9.30A.M. for five consecutive days, just before the session started. Session duration (5 h) was set in accordance with previous studies on QNP-induced hyperdipsia (Fraioli et al. 1997; Amato et al. 2008; De Carolis et al. 2010; Milella et al. 2010). At the end of the last session (on the fifth day), rats were sacrificed and brains were collected for neurochemical analysis. "
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    ABSTRACT: Dopaminergic D2/D3 agonist quinpirole (QNP) elicits nonregulatory drinking in rats, a model of psychotic polydipsia. Why only a fraction of QNP-treated rats responds to the treatment becoming polydipsic is still unclear. To unveil possible factors contributing to such variability, we analyzed drinking microstructure in saline and QNP-treated rats, the hypothalamic expression of the cocaine and amphetamine regulated transcript (CART), and the monoaminergic turnover in selected brain areas. Rats were daily treated with saline or QNP 0.5 mg/kg, and their 5-h water intake was measured for five consecutive days. The number of bouts and episodes of licking, and their duration, were also measured. Brain CART expression was measured by in situ hybridization and monoamines turnover by HPLC analysis of tissue extracts. Based on the amount of water ingested during the 5-h session, QNP-treated rats were post hoc grouped in polydipsic (PD) and in nonpolydipsic (NPD) rats, and the results compared accordingly. The number of drinking bouts and episodes increased in PD rats, while NPD rats behaved as the controls. CART expression decreased in the arcuate nucleus of the hypothalamus of the PD rats. In contrast, both PD and NPD rats showed a reduction of DA turnover in both ventral tegmental area (VTA) and nucleus accumbens (NAcc). No difference was detected in the turnover of 5HT and NA. Microstructure analysis confirms that QNP acts on the appetitive component of drinking behavior, making it compulsive. CART expression reduction in response to dopaminergic hyperstimulation might sustain excessive drinking in PD rats.
    Psychopharmacology 03/2014; 231(19). DOI:10.1007/s00213-014-3527-0 · 3.88 Impact Factor
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    • "The average consumption for subjects preexposed to vehicle was 15.4896 (+/−0.5930). Although the basis for these differences is not known, it is possible that indirect DA agonist activity (as a result of DAT inhibition) may have impacted overall drinking either directly or indirectly via compensation (see Amato et al., 2008; De Carolis et al., 2010; Milella et al., 2010 "
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    ABSTRACT: Although cocaine readily induces taste aversions, little is known about the mechanisms underlying this effect. It has been suggested that its inhibitory effects at one of the monoamine transporters may be mediating this suppression. Using the cross-drug preexposure preparation, the present series of studies examined a possible role of dopamine (DA) in this effect. Male Sprague-Dawley rats were exposed to cocaine (18 mg/kg; Experiment 1) or the selective DA transporter (DAT) inhibitor GBR 12909 (50 mg/kg; Experiment 2) prior to the pairing of a novel saccharin solution with injections of GBR 12909 (32 mg/kg), cocaine (18 mg/kg) or vehicle in a conditioned taste aversion (CTA) procedure. Preexposure to cocaine attenuated aversions induced by itself but not aversions induced by GBR 12909 (Experiment 1). Conversely, preexposure to GBR 12909 attenuated aversions induced by itself and cocaine (Experiment 2). This asymmetry suggests that cocaine and GBR 12909 induce CTAs via similar, but non-identical, mechanisms. These data are discussed in the context of previous work demonstrating roles for dopamine, norepinephrine and serotonin in cocaine-induced CTAs.
    Pharmacology Biochemistry and Behavior 05/2012; 102(2):269-74. DOI:10.1016/j.pbb.2012.04.012 · 2.78 Impact Factor
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