Risperidone alters food intake, core body temperature, and locomotor activity in mice

Department of Biostatistics, University of Alabama at Birmingham, United States
Physiology & Behavior (Impact Factor: 2.98). 03/2009; 96(3):457-463. DOI: 10.1016/j.physbeh.2008.11.011


Risperidone induces significant weight gain in female mice; however, the underlying mechanisms related to this effect are unknown. We investigated the effects of risperidone on locomotor activity, core body temperature, and uncoupling protein (UCP) and hypothalamic orexin mRNA expression. Female C57BL/6J mice were acclimated to individual housing and randomly assigned to either risperidone (4 mg/kg BW day) or placebo (PLA). Activity and body temperature were measured over 48-hour periods twice a week for 3 weeks. Food intake and body weights were measured weekly. UCP1 (BAT), UCP3 (gastrocnemius), and orexin (hypothalamus) mRNA expressions were measured using RT-PCR. Risperidone-treated mice consumed more food (p = 0.050) and gained more weight (p = 0.0001) than PLA-treated mice after 3 weeks. During the initial 2 days of treatment, there was an acute effect of treatment on activity (p = 0.046), but not body temperature (p = 0.290). During 3 weeks of treatment, average core body temperatures were higher in risperidone-treated mice compared to controls during the light phase (p = 0.0001), and tended to be higher during the dark phase (p = 0.057). Risperidone-treated mice exhibited lower activity levels than controls during the dark phase (p = 0.006); there were no differences in activity during the light phase (p = 0.47). UCP1 (p < 0.01) and UCP3 (p < 0.05) mRNA expressions were greater in risperidone-treated mice compared to controls, whereas, orexin mRNA expression was lower in risperidone-treated mice (p < 0.01). These results suggest that risperidone-induced weight gain in mice is a consequence of increased energy intake and reduced activity, while the elevation in body temperature may be a result of thermogenic effect of food intake and elevated UCP1, UCP3, and a reduced hypothalamic orexin expression.

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Available from: Patricia Jumbo-Lucioni
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    • "A number of studies have also indicated that risperidone administration in rats through different routes increased food intake and body weight in a four-week period (Baptista et al., 2002; Ota et al., 2002, Cope et al., 2005; Pouzet et al., 2003; Davoodi et al., 2009). Previous studies have found that animals in the risperidone group consumed more food compared to the vehicle group, which may have caused increased adipose tissue mass and subsequent obesity (Cope et al., 2009). In addition, plasma leptin levels increased in the risperidone group compared with the vehicle group. "
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    ABSTRACT: Although the use of atypical antipsychotic drugs has been successful in the treatment of schizophrenia, they can cause some complications in the long-term use, including weight gain. Patients using these drugs tend to disrupt treatment primarily due to side effects. The atypical antipsychotic mechanism of action regulates a number of highly disrupted neurotransmitter pathways in the brains of psychotic patients but may also cause impairment of neurohormonal pathways in different brain areas. In this study, we investigated the circulating levels of hypothalamic neurohormones, which are related to appetite regulation; neuropeptide Y (NPY); alpha melanocyte stimulating hormone (α-MSH); cocaine and amphetamine regulated transcript (CART); agouti-related peptide (AgRP); and leptin in male Wistar rats, which were treated with risperidone, a serotonin antagonist, for four weeks. Alterations in the mRNA expression levels of these candidate genes in the hypothalamus were also analyzed. We hypothesized that risperidone treatment might alter both hypothalamic and circulating levels of neuropeptides through serotonergic antagonism, resulting in weight gain. Gene expression studies revealed that the mRNA expression levels of proopiomelanocortin (POMC), AgRP, and NPY decreased as well as their plasma levels, except for NPY. Unexpectedly, CART mRNA levels increased when their plasma levels decreased. Because POMC neurons express the serotonin receptor (5HT2C), the serotonergic antagonism of risperidone on POMC neurons may cause an increase in appetite and thus increase food consumption even in a short-term trial in rats. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Nov 2014 · Brain Research
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    • "The significantly increased food intake in only PAL-treated group might be due to its action through histamine H 1 receptor (Kim et al., 2007). Several AAPDs such as RIS and olanzapine increased the food intake in rodents (Cope et al., 2009; Davoodi et al., 2009). Prenatally LPSexposed neonates showed varied types of abnormalities in reflex responses. "
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    ABSTRACT: Studies on animal models provide enough evidences that old age appearance of psychosis on exposures to various insults during critical period of brain development could be prevented on antipsychotic drug treatment. Presently, gestational intervention of the atypical antipsychotic paliperidone (PAL) was done along with the exposure of bacterial endotoxin lipopolysaccharide/LPS hypothesizing that the drug would counteract and/or prevent the immune activation-induced behavioral deficits in mice. Effect of the PAL (0.05mg/kg; GD 15-PND 28) in preventing reflex, sensorimotor and anxiety deficits in prenatally LPS-challenged (800µg/kg; GD 15 and GD 17) mice was assessed at three different life stages: neonatal (PND 4-PND 14), adolescence (PND 35) and at adulthood (PND 85). LPS-induced behavioral deficits were recognizable even at neonatal and adolescence stages, though more pronounced at adulthood. In only PAL-treated group few behavioral deficits though observed both at neonatal and adult stages but less prominent than LPS group. PAL co-treatment prevented the abnormalities in nest-seeking behavior in neonates, anxiety abnormalities at adolescence and adulthood but not the sensorimotor impairment. The drug might have maintained the stress homeostasis to counteract the behavioral abnormalities as LPS-induced hypercorticosteronemia was prevented on PAL co-treatment. In view of the in utero exposure, comparatively low drug dose was selected. Though efficacy has been predicted, the dose was not effective to prevent all psychopathological impairments. Considering the wider objectives, it was not possible to conduct multi dose study simultaneously. Our ongoing study with higher dose may predict the effective PAL dose in prevention of psychiatric illness.
    Full-text · Article · Sep 2014 · European Journal of Pharmacology
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    • "In the present study, risperidone treatment was associated with weight gain and hyperphagia in female C57BL/6J mice, findings that agree with our previous work (6), other animal models (2, 5) and human studies (1). . However, risperidone failed to induce the accumulation of body fat mass in C57BL/6J mice associated with weight gain, a result that is similar to our previous studies (6). In fact, the effect of AADs on body composition and its association with weight gain are still discrepant. "
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    ABSTRACT: Objective To investigate the effect of risperidone on energy expenditure and weight gain in female C57BL/6J mice. Design and Methods Body weight and composition, food intake, energy expenditure, and activity were determined weekly. mRNA expression of uncoupling protein 1 in brown adipose tissue, orexin and brain-derived neurotrophic factor in the hypothalamus were quantified by Real-Time PCR. Results Risperidone tended to induce a greater body weight gain (P=0.052) and significantly higher food intake (P=0.038) relative to the placebo-treated group. Risperidone-treated mice had a higher resting energy expenditure (P=0.001), and total energy expenditure (P=0.005) than the placebo group. There were no effects of treatment, time, and treatment by time on NREE between groups. Risperidone-treated mice showed a significantly lesser locomotor activity than placebo-treated mice over 3 weeks (P<0.001). Risperidone induced a higher UCP1 mRNA (P=0.003) and a lower orexin mRNA (P=0.001) than placebo. Discussion Risperidone-induced weight gain is associated with hyperphagia and a reduction in locomotor activity in C57BL/6J mice. Additionally, higher total and resting energy expenditure were accompanied by higher levels of UCP1 mRNA in BAT. The increased total energy expenditure could not offset the total intake of energy through risperidone-induced hyperphagia, therefore resulting in weight gain in female C57BL/6J mice.
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