Peripheral injection of risperidone, an atypical antipsychotic, alters the bodyweight gain of rats

Abstract

1. Risperidone is an atypical antipsychotic drug that possesses 5-hydroxytryptamine 5-HT2 receptor antagonism combined with milder dopamine D2 receptor antagonism. 2. Excessive bodyweight gain is one of the side-effects of antipsychotics. Risperidone treatment causes a greater increase in the body mass of patients than treatment with conventional antipsychotics, such as haloperidol. Therefore, the present study was undertaken in order to address the aetiology of the risperidone-induced bodyweight change in rats by examining the expression of leptin, an appetite-regulating hormone produced in white adipose tissue (WAT), and uncoupling protein (UCP)-1, a substance promoting energy expenditure in the brown adipose tissues (BAT). 3. Eight-week-old male rats were injected subcutaneously with risperidone (0.005, 0.05 or 0.5 mg/kg) twice daily for 21 days. Both bodyweight and food intake were monitored daily. On day 21, rats were decapitated and their serum leptin and prolactin concentrations were measured. Expression levels of leptin, Ucp1 and beta3-adrenoceptor (beta3-AR) genes in WAT and BAT were quantified using real-time polymerase chain reaction amplification. 4. Injection of 0.005 mg/kg risperidone into rats increased food intake and the rate of bodyweight gain, as well as the augmentation of leptin gene expression in WAT. Injection of 0.05 mg/kg risperidone increased food intake and leptin gene expression in WAT, but the rate of bodyweight gain was not affected. Injection of 0.5 mg/kg risperidone caused a reduction in bodyweight gain, as well as enhanced Ucp1 gene expression in BAT and serum prolactin concentrations. The serum leptin concentration and beta3-AR gene expression in WAT and BAT were not affected by injection of 0.5 mg/kg risperidone. 5. Although the changes in food intake observed in risperidone-injected rats were rationalized neither by serum leptin nor prolactin concentrations, the reduction in the rate of bodyweight gain following injection of 0.5 mg/kg can be explained, in part, by increased energy expenditure, as revealed by the remarkable increase in the UCP-1 mRNA expression level in BAT. The role of leptin in risperidone-induced alterations in bodyweight gain remain to be clarified.

Antipsychotic-induced metabolic effects in the female rat: Direct comparison between long-acting injections of risperidone and olanzapine

“…Through these experiments, we demonstrated for the first time that intramuscular injection of long-acting risperidone, like long-acting olanzapine, results in rapid and significant hyperphagia and resultant weight gain in the female rat. This is in agreement with former experiments involving other administration methods of risperidone (Baptista et al, 2002;Fell et al, 2004;Ota et al, 2002). Our experiments demonstrated that the use of long-acting risperidone results in significant increase in parameters not extensively examined in previous rat experiments, such as several plasma lipid species and transcription of genes involved in lipid biosynthesis in the liver.…”

Antipsychotic-induced metabolic effects in the female rat: Direct comparison between long-acting injections of risperidone and olanzapine

“…Through these experiments, we demonstrated for the first time that intramuscular injection of long-acting risperidone, like long-acting olanzapine, results in rapid and significant hyperphagia and resultant weight gain in the female rat. This is in agreement with former experiments involving other administration methods of risperidone (Baptista et al, 2002;Fell et al, 2004;Ota et al, 2002). Our experiments demonstrated that the use of long-acting risperidone results in significant increase in parameters not extensively examined in previous rat experiments, such as several plasma lipid species and transcription of genes involved in lipid biosynthesis in the liver.…”

Effects of risperidone on energy balance in female C57BL/6J mice

“…In this study, risperidone treatment was associated with weight gain and hyperphagia in female C57BL/6J mice, findings that agree with our previous work , other animal models , and human studies . 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 .…”

“…Risperidone induced an increase of UCP1 mRNA after 3 weeks treatment, which agrees with our previous work . Similarly, Ota et al found increased expression of UCP1 after risperidone injection to male Sprague–Dawley rats. In contrast, olanzapine caused a decrease in UCP1 protein relative to placebo‐treated mice, indicating the inhibition of thermogenic capacity contributed to olanzapine induced‐weight gain .…”

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

“…Elevated food intake can cause elevated body temperature due to the thermogenic effect of food [37] and elevated UCP1 in BAT can lead to elevated body temperature [38]. Similar to our findings, UCP1 expression in BAT was enhanced following twenty-one days of risperidone treatment (0.5 mg/kg BW*day) in rats [39]. In addition, UCP3 expression was higher in the gastrocnemius muscle of risperidone-treated mice.…”

Antipsychotic-induced metabolic effects in the female rat: Direct comparison between long-acting injections of risperidone and olanzapine

“…Through these experiments, we demonstrated for the first time that intramuscular injection of long-acting risperidone, like long-acting olanzapine, results in rapid and significant hyperphagia and resultant weight gain in the female rat. This is in agreement with former experiments involving other administration methods of risperidone (Baptista et al, 2002;Fell et al, 2004;Ota et al, 2002). Our experiments demonstrated that the use of long-acting risperidone results in significant increase in parameters not extensively examined in previous rat experiments, such as several plasma lipid species and transcription of genes involved in lipid biosynthesis in the liver.…”

Effects of risperidone on energy balance in female C57BL/6J mice

“…In this study, risperidone treatment was associated with weight gain and hyperphagia in female C57BL/6J mice, findings that agree with our previous work , other animal models , and human studies . 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 .…”

“…Risperidone induced an increase of UCP1 mRNA after 3 weeks treatment, which agrees with our previous work . Similarly, Ota et al found increased expression of UCP1 after risperidone injection to male Sprague–Dawley rats. In contrast, olanzapine caused a decrease in UCP1 protein relative to placebo‐treated mice, indicating the inhibition of thermogenic capacity contributed to olanzapine induced‐weight gain .…”

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

“…Elevated food intake can cause elevated body temperature due to the thermogenic effect of food [37] and elevated UCP1 in BAT can lead to elevated body temperature [38]. Similar to our findings, UCP1 expression in BAT was enhanced following twenty-one days of risperidone treatment (0.5 mg/kg BW*day) in rats [39]. In addition, UCP3 expression was higher in the gastrocnemius muscle of risperidone-treated mice.…”

Antipsychotic-induced metabolic effects in the female rat: Direct comparison between long-acting injections of risperidone and olanzapine

“…Through these experiments, we demonstrated for the first time that intramuscular injection of long-acting risperidone, like long-acting olanzapine, results in rapid and significant hyperphagia and resultant weight gain in the female rat. This is in agreement with former experiments involving other administration methods of risperidone (Baptista et al, 2002;Fell et al, 2004;Ota et al, 2002). Our experiments demonstrated that the use of long-acting risperidone results in significant increase in parameters not extensively examined in previous rat experiments, such as several plasma lipid species and transcription of genes involved in lipid biosynthesis in the liver.…”

Effects of risperidone on energy balance in female C57BL/6J mice

“…In this study, risperidone treatment was associated with weight gain and hyperphagia in female C57BL/6J mice, findings that agree with our previous work , other animal models , and human studies . 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 .…”

“…Risperidone induced an increase of UCP1 mRNA after 3 weeks treatment, which agrees with our previous work . Similarly, Ota et al found increased expression of UCP1 after risperidone injection to male Sprague–Dawley rats. In contrast, olanzapine caused a decrease in UCP1 protein relative to placebo‐treated mice, indicating the inhibition of thermogenic capacity contributed to olanzapine induced‐weight gain .…”

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

“…Elevated food intake can cause elevated body temperature due to the thermogenic effect of food [37] and elevated UCP1 in BAT can lead to elevated body temperature [38]. Similar to our findings, UCP1 expression in BAT was enhanced following twenty-one days of risperidone treatment (0.5 mg/kg BW*day) in rats [39]. In addition, UCP3 expression was higher in the gastrocnemius muscle of risperidone-treated mice.…”