The role of CA1 CB1 receptors on lithium-induced spatial memory impairment in rats

Lithium, a glycogen synthase kinase-3β (GSK-3β) inhibitor, prevents cannabinoid withdrawal syndrome, but there is limited data exploring the interaction between lithium and cannabinoid system on memory processes. The present study aimed to test the interaction between dorsal hippocampal (CA1 region) cannabinoid system and lithium on spatial memory in rats. Spatial memory was assessed in Morris Water Maze (MWM) apparatus by a single training session of eight trials. The results showed that pre-training intra-CA1 microinjection of ACPA, the cannabinoid type 1 receptor (CB1r) agonist, at doses of 0.001, 0.01 or 1 µg/rat, or AM251, the cannabinoid type 1 receptor (CB1r) antagonist, at doses of 1, 10 or 100 ng/rat, increased escape latency and traveled distance to the platform, suggesting a spatial learning impairment, whereas intraperitoneal administration of lithium (0.5, 1 or 5 mg/kg) had no effect on spatial learning. Also, rats that received lithium plus a lower dose of ACPA (0.001 µg/rat) or AM251 (1 ng/rat) had successful performance in the MWM. In the probe test, the results showed that pre-training administration of lithium (5 mg/kg) and ACPA (0.01 or 1 µg/rat) but not AM251 (at all doses used) impaired spatial memory retrieval. Also, lower dose of ACPA (0.001 µg/rat) or AM251 (1 ng/rat) potentiated the effect of ineffective doses of lithium (0.5 and 1 mg/kg) on spatial memory retrieval, while restored the effect of effective dose of lithium (5 mg/kg). In conclusion, cannabinoids may have a dual effect on lithium-induced spatial memory impairment in rats.