Rats that are fed for 90 min per day can stabilize their weight after an initial drop; however, if rats on this feeding schedule are also given access to a running wheel, they run excessively, eat less, lose weight, and often die. To investigate this phenomenon as a possible animal model of obsessive-compulsive disorder (OCD), rats were treated for 5 weeks with fluoxetine, an antidepressant that relieves OCD symptoms in humans (5 mg/kg, 2.5 mg/kg), or imipramine, an antidepressant that does not affect OCD symptoms (5 mg/kg), or saline prior to exposure to food restriction and the running wheel. In addition, because chronic fluoxetine treatment is thought to enhance serotonergic neurotransmission, for contrast an additional group of rats were treated with parachlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor that depletes serotonin. Rats treated with fluoxetine lost significantly less weight, ran significantly less, and increased food intake more rapidly during restriction of food availability than saline-treated rats. Rats treated with imipramine did not differ from those treated with saline on these parameters. Compared to saline-treated rats, rats treated with PCPA lost more weight, ate less food, and increased running more rapidly. These effects of pharmacological treatment indicate an inverse relationship between central serotonergic activity and vulnerability to develop food-restriction-induced anorexia and compulsive running. In addition, like OCD in humans, this phenomenon in rats seems to be blocked by chronic treatment with a serotonin selective reuptake inhibitor but not a less selective monoamine reuptake inhibitor.