Both
olanzapine and
sibutramine target serotonergic and noradrenergic neurotransmission and influence
body weight, but in opposite ways. The second-generation
antipsychotic olanzapine, an antagonist at serotonergic and noradrenergic receptors, frequently induces
weight gain as a side-effect, whereas
sibutramine, a
noradrenaline/
serotonin reuptake inhibitor, is known as a weight-
reducing agent. To investigate whether altered motivation for palatable food influences the effect of these drugs on
body weight, we determined their effects on responding for
sucrose pellets under a progressive ratio schedule of reinforcement in rats. We found that a low dose of
olanzapine selectively increased responding to
sucrose, without affecting free-feeding intake of
sucrose. In contrast,
sibutramine dose-dependently reduced responding to
sucrose and similarly reduced free-feeding intake. Furthermore, coadministration of a dose of
sibutramine that failed to affect responding to
sucrose when administered alone prevented the increase in motivation by the effective dose of
olanzapine. These data show that increased motivation for palatable food is likely to be a significant contributor to
olanzapine-induced
weight gain. Moreover, the ability of
sibutramine to reduce this motivation for palatable food may play an important role in the efficacy of
sibutramine as an add-on treatment to counteract
olanzapine-induced
weight gain.