Risperidone, an atypical-antipsychotic drug (AAD) with lower incidence of extrapyramidal side effects compared to typical antipsychotic drugs, is commonly used to treat schizophrenia and bipolar disorder [1
]. Unfortunately, AADs, including risperidone, cause weight gain and may exacerbate risk factors for obesity-related metabolic disorders such as type 2 diabetes [2
]. Although reported less frequently, other side effects related to risperidone treatment include fatigue/tiredness, hyperprolactinemia, akathisia (motor restlessness), and body temperature dysregulation [1
]. The underlying mechanisms responsible for risperidone-induced weight gain are not clearly defined. A better understanding of the pathways involved in these metabolic related side effects would provide groundwork for clinical application in patients treated with risperidone and other AADs.
Patients with schizophrenia are as overweight and obese as the general population [6
] and body mass index increased dramatically and significantly among young women with schizophrenia between 1987 and 1996 [7
]. Due to this underlying risk for obesity among people with mental illness, it is difficult to distinguish between the disease effect and the drug effect on weight gain in patients treated with AADs. To investigate the underlying drug effect without the presence of disease, we developed a mouse model in which normal weight female C57BL/6J mice treated with AADs gain significant body weight relative to PLA-treated mice [4
]. Previous reports investigating the effects of AAD-induced weight gain in animals suggest that AAD-induced weight gain is due primarily to an increase in energy intake [3
]; however, few reports have monitored core body temperature and activity during AAD treatment.
Body temperature regulation (thermoregulation) is important for maintaining body mass homeostasis, especially in small rodents [9
]. Rodents [10
] and humans [11
] possess various abilities to engage in adaptive thermogenesis, suggesting a genetic component for defending body weight. In rats given risperidone, body temperature decreased significantly compared to controls and this effect was seen over a 21-day period without weight gain [12
]. In humans, risperidone treatment has been associated with both hyperthermia [13
] and hypothermia [14
] and in a few cases neuroleptic malignant syndrome with extremely high fever and muscle rigidity [15
]. The effect of risperidone on thermoregulation is possibly related to interactions with dopaminergic and serotoninergic receptors or other receptors in the CNS, but the specific mechanisms of how these temperature modifications affect body weight are not known.
Uncoupling proteins (UCPs), including UCP1 and UCP3, have been investigated for their possible roles in body temperature regulation and energy balance. UCP1, found predominately in brown adipose tissue (BAT), dissipates the pH-gradient generated by oxidative phosphorylation, releasing chemical energy as heat [16
]. UCP1 expression in BAT is decreased in most genetic and hypothalamic obese animals [16
] and overexpression of UCP1 in skeletal muscle decreases the percentage of fat in transgenic mice [18
]. In contrast, mice lacking UCP1 in BAT are not obese on standard chow or high-fat diets [19
]. UCP3, mainly expressed in skeletal muscle, is up-regulated during fasting [21
] and may be involved with the facilitation of fatty acid oxidation in muscle [22
]. UCP3 knockout mice do not become obese on high fat diets [23
]. Most reports do not associate UCP3 with thermogenesis and the exact biological function of UCP3 remains unknown. UCPs may be involved with body temperature alterations and energy balance in risperidone-treated mice. However, there are no previous reports investigating UCP mRNA expressions in mice administered risperidone.
Weight gain results from an increase in food intake and/or a decrease in energy expenditure, including resting energy expenditure and activity related energy expenditure [24
]. Risperidone’s effects on locomotor activity are not well documented. Amphetamine-induced locomotor activity in hippocampal-lesioned Sprague-Dawley rats was prevented with risperidone treatment [25
]. Conversely, BALB/c mice treated with amphetamine to produce hyperactivity and self-injurious behavior do not show reduced activity when treated with risperidone, but the treatment does alleviate self-injurious behavior [26
]. Risperidone treatment reduced hyperactivity in children with bipolar disorder, autism, and attention-deficit/hyperactivity disorder [27
]. Risperidone’s activity-related effects may be associated with increased risk for weight gain in patients treated with risperidone, particularly if the reduced activity decreases total energy expenditure.
Orexins, neuropeptides located in the hypothalamus, have been associated with regulation of the sleep/wake cycle, feeding behavior, spontaneous physical activity, and thermogenesis [29
]. Orexin knockout (KO) mice are unable to reduce their body temperature during inactivity (light phase) and have a phenotype of narcolepsy [30
]. This inability of orexin KO mice to reduce body temperature may provide an explanation for fragmented sleep during narcolepsy, because heat loss is an essential aspect of sleep. Body temperatures were not different between orexin KO mice and wild-type (WT) littermates during sustained wakefulness (dark phase); however, locomotor activity was lower in orexin KO mice compared to wildtypes during wakefulness [30
]. Rats administered orexin A along with risperidone experienced elevated colonic temperature and heart rate [31
]. Risperidone may cause alterations in the gene expression of orexin in the hypothalamus; however, there are no published data showing this relationship.
In this study, we use our mouse model of risperidone-induced weight gain to determine the effect of risperidone on food intake, core body temperature, and locomotor activity. we hypothesized that risperidone-induced weight gain would be associated with increased food intake, decreased body temperature, and decreased activity in mice housed at 22°C (ambient temperature) during three weeks of treatment.