Acute metabolic effects of olanzapine depend on dose and injection site

Atypical antipsychotics (AAPs), such as olanzapine (OLZ), are associated with metabolic side effects, including hyperglycemia. Although a central mechanism of action for the acute effects on glycemia has been suggested, evidence for peripheral versus central effects of AAPs has been mixed and has not been explored for an effect of OLZ on the respiratory exchange ratio (RER). Here, we tested the hypothesis that some inconsistencies in the glycemic responses are likely a result of different doses and central sites of injection. We also compared the effects of central versus peripherally administered OLZ on the RER of unsedated rats. Third ventricle infusion of OLZ at 0.3 mg/kg caused hyperglycemia within 30 minutes, with a higher dose (1.8 mg/kg) needed to elicit a similar response in the lateral ventricles. In contrast, 3 mg/kg of OLZ was needed to raise blood glucose within 30 minutes when given intragastrically, and 10 mg/kg resulted in a prolonged hyperglycemia lasting at least 60 minutes. Third ventricle injection of OLZ significantly decreased RER after 75 minutes, whereas intragastric OLZ resulted in a faster drop in RER after 30 minutes. Since changes in glycemia were most sensitive when OLZ was infused into the third ventricle, but effects on RER were more rapidly and efficaciously observed when the drug was given peripherally, these results raise the likelihood of a dual mechanism of action involving hypothalamic and peripheral mechanisms. Some discrepancies in the literature arising from central administration appear to result from the injection site and dose.