Objective To investigate the effect of lithium chloride on amphetamine-induced behavioral sensitization in rats and the possible involvement of the Akt/GSK-3β pathway. Methods A total of 40 male SD rats were randomly divided into control group（ S-S group， n=13）， amphetamine group（ S-A group， n=13） and lithium chloride and amphetamine group（ L-A group， n=14）. S-S rats were pretreated with normal saline （10 ml/kg） and intraperitoneally injected with normal saline（ 10 ml/kg） for 5 consecutive days. S-A rats were pretreated with normal saline（ 10 ml/kg） and intraperitoneally injected with amphetamine（ 1.5 mg/kg） for 5 consecutive days. L-A rats were pretreated with lithium chloride（ 100 mg/kg） and intraperitoneally injected with amphetamine（ 1.5 mg/kg） for 5 consecutive days. All injections came to a stop during the ensuing 6 days. On day 12， randomized 6 rats in each group were injected with a lower dosage of amphetamine. The spontaneous activity of three groups of rats was recorded by video recording system within 150 minutes on the 1st day and the 12th day of treatment， respectively. On day 12， 6 rats that did not receive the behavioral test were selected from each group. Western blot was used to detect the expression of phosphorylated Akt（ p-Akt）/Akt and phosphorylated GSK-3 β（ p-GSK-3 β）/GSK-3 β in prefrontal cortex. Results Compared to S-S［ （1 861.50±612.49） cm］ and L-A［ （7 599.00±4 778.14） cm］rats， a significant increase in spontaneous locomotor activity was observed in S-A rats［ （26 826.50±5 987.96） cm］on the first day， and the differences were statistically significant （P＜ 0.05）. On day 12， S-A rats were associated with a significantly increased spontaneous locomotor activity ［（43 823.83±5 831.88） cm］ relative to S-S［ （14 274.50±4 724.98） cm］and L-A［ （17 823.50±4 313.64） cm］ rats， and the differences were statistically significant（ P＜0.05）. Ratios of p-Akt to Akt and p-GSK-3β to GSK- 3β showed a significant decline in the prefrontal cortex of S-A rats compared to those in the prefrontal cortex of S-S（ P＜0.05） and L-A rats（ P＜0.05）. Conclusions Lithium chloride can inhibit amphetamine-induced behavioral sensitization in rats， and the potential mechanisms may be related to the Akt/GSK-3β pathway.