Olanzapine, an antipsychotic agent mainly used for treating schizophrenia, is frequently associated with body weight gain and diabetes mellitus. Nonetheless, studies have shown that not every individual is equally susceptible to olanzapine's weight-gaining effect. Therefore, Roman high and low avoidance rat strains were examined on their responsiveness to olanzapine treatment. The Roman high avoidance rat shares many behavioral and physiological characteristics with human schizophrenia, such as increased central dopaminergic sensitivity, whereas the Roman low avoidance rat has been shown to be prone to diet-induced obesity and insulin resistance. The data revealed that only the Roman high avoidance rats are susceptible to olanzapine-induced weight gain and attenuated glucose tolerance. Here it is suggested that the specific olanzapine-induced weight gain in Roman high avoidance rats could be related to augmented dopaminergic sensitivity at baseline through increased expression of prefrontal cortex dopamine receptor D1 mRNA and nucleus accumbens dopamine receptor D2 mRNA expression. Regression analyses revealed that olanzapine-induced weight gain in the Roman high avoidance rat is above all related to increased prolactin levels, whereas changes in glucose homeostasis is best explained by differences in central dopaminergic receptor expressions between strains and treatment. Our data indicates that individual differences in dopaminergic receptor expression in the cortico-mesolimbic system are related to susceptibility to olanzapine-induced weight gain.