The antipsychotic drug sulpiride does not affect bodyweight in male rats. Is insulin resistance involved?

Previous studies have shown that prolonged administration of antipsychotic drugs induces obesity in female but not in male rats. To explore the mechanisms involved in this sex-dependent effect, we administered the dopamine antagonist sulpiride (20 mg/kg i.p.) or vehicle (0.1 N HCl) to adult male rats during 21 days and daily assessed bodyweight and food intake. Then, we evaluated the glucose tolerance and the serum levels of insulin, leptin, total testosterone, dehydroepiandrosterone-sulfate (DHEA-S), thyroid hormones and blood lipids. In another experiment, food intake and water intake were assessed after acute injections of sulpiride or vehicle into the perifornical lateral hypothalamus. Lastly, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) in the lateral hypothalamus were assessed by in vivo microdialysis after acute systemic injections of sulpiride and vehicle. Chronic sulpiride administration did not affect bodyweight gain and food intake. However, prolactin levels and the area under the glucose and insulin curves were significantly elevated. Acute sulpiride significantly increased food intake, water intake, DOPAC and HVA levels. The acute effects of sulpiride show that this drug is active at the perifornical lateral hypothalamus, which is a brain area where blockade of dopamine receptors stimulates feeding. However, after prolonged administration, sulpiride did not affect body weight. This lack of effect may be related to the impairment of insulin sensitivity, which may prevent body weight gain, and counteract other effects of sulpiride that promote adiposity such as hyperprolactinemia. These findings noticeably contrast with those observed in sulpiride-treated female rats that appear to display enhanced insulin sensitivity. The changes in insulin sensitivity do not appear related to a decrease in androgenic activity, because testosterone and DHEA-S levels were not affected by sulpiride. However, these results should be considered as preliminary because other relevant endocrine variables such as free testosterone, steroid binding globulin and pituitary gonadotrophin levels were not evaluated. Since the same sex-dependent effect on body weight and food intake in rats has been observed during administration of risperidone, which has a different pharmacological profile than sulpiride, future studies must evaluate other neurotransmitters involved in food intake regulation such as serotonin, noradrenaline and histamine.