The serotonin syndrome, a behavioral response produced by the activation of serotonin receptors, and 3H-serotonin binding were examined after repeated treatment of rats with different types of antidepressant drugs. The serotonin syndrome was produced by the direct-acting serotonin receptor agonists 5-methoxy-N,N-dimethyltryptamine (5-MeDMT) or d-lysergic acid diethylamide (LSD). Repeated, but not acute treatment of rats with monoamine oxidase inhibitors (nialamide, pargyline, and phenelzine) prevented the serotonin syndrome in response to either 5-MeDMT or LSD and also reduced 3H-serotonin binding in the brain stem and spinal cord. Pretreatment of rats with p-chlorophenylalanine blocked the ability of nialamide treatment to inhibit the serotonin syndrome caused by 5-MeDMT. By contrast, neither the serotonin syndrome or 3H-serotonin binding was affected significantly by the repeated administration of tricyclic antidepressants (amitriptyline, desmethylimipramine, and chlorimipramine) or iprindole. Repeated monoamine oxidase inhibitor treatments may prevent the serotonin syndrome by causing a reduction of 3H-serotonin receptor binding sites in the brain stem and/or spinal cord.