We examined the relationship between lithium-induced head twitches and serotonergic neurons. Head twitches were elicited by combined treatment with lithium chloride (2 or 5 mEq/kg x 5, s.c. administered hourly) and rauwolfia alkaloids, i.e., reserpine (5 mg/kg, s.c.), tetrabenazine (20 mg/kg, s.c.), and syrosingopine (10 mg/kg, s.c.). Neither lithium nor the alkaloid alone induced the twitches; nor did combined administration of lithium with methamphetamine or p-chloroamphetamine. The head twitches induced by lithium in combination with reserpine were strongly inhibited by antiserotonin drugs, methysergide and cyproheptadine, and also by a serotonin synthesis inhibitor, p-chlorophenylalanine (PCPA), when administered between lithium and reserpine. When PCPA was administered before lithium for 3 days, the head twitches were potentiated. In addition, the head twitches were potentiated by a serotonin receptor stimulant, 5-methoxy-N,N-dimethyltryptamine. The results imply that lithium can induce head twitches in the presence of rauwolfia alkaloids and may exert its effect in part by acting on the serotonergic neuron system.