Hamsters inoculated with scrapie virus show a dramatic hypersensitivity to serotoninergic drugs, developing a behavioral syndrome not unlike that obtained with pharmacologically induced lesions of the raphe nuclei. In an attempt to explain the state of hypersensitivity and to determine whether or not serotoninergic neurons were targets of the scrapie virus, pre- and postsynaptic serotoninergic sites were studied in the cerebral cortices of scrapie-infected and sham-inoculated hamsters. [3H]Imipramine binding and the uptake of endogenous 5-hydroxytryptamine (5-HT, serotonin) in synaptosomes prepared from scrapie-inoculated animals were not different from those of controls. This suggests integrity of the serotoninergic neurons in scrapie-infected hamsters. In contrast, affinity for the 5-HT1 receptor (which modulates inhibitory response) was diminished whereas that for the 5-HT2 receptor (which modulates excitatory response) was increased. This "imbalance" between the two receptors which is amplified in in vivo responses may account for the 5-HT hypersensitivity. The alteration in the affinity of the two postsynaptic 5-HT receptors supports the observation that scrapie virus alters cell plasma membranes.