Shiva Amiri1, Majid Jafari-Sabet2,3, Fariborz Keyhanfar1, Reza Falak4, Mohammad Shabani5, Ameneh Rezayof6. 1. Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. 2. Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. jafarisabet.m@iums.ac.ir. 3. Razi Drug Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. jafarisabet.m@iums.ac.ir. 4. Immunology Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. 5. Kerman Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran. 6. Department of Animal Biology, School of Biology and Center of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran.
Abstract
RATIONALE: Treatment of bipolar disorder (BPD) with lithium and olanzapine concurrent administration is a major medicine issue with the elusive neurobiological mechanisms underlying the cognitive function. OBJECTIVE: To clarify the precise mechanisms involved, the possible role of the hippocampus (HPC) and prefrontal cortical (PFC) NMDA receptors and CAMKII-CREB signaling pathway in the interactive effects of lithium and olanzapine in memory consolidation was evaluated. The dorsal hippocampal CA1 regions of adult male Wistar rats were bilaterally cannulated and a step-through inhibitory avoidance apparatus was used to assess memory consolidation. The changes in p-CAMKII/CAMKII and p-CREB/CREB ratio in the HPC and the PFC were measured by Western blot analysis. RESULTS: Post-training administration of lithium (20, 30, and 40 mg/kg, i.p.) dose-dependently decreased memory consolidation whereas post-training administration olanzapine (2 and 5 mg/kg, i.p.) increased memory consolidation. Post-training administration of certain doses of olanzapine (1, 2, and 5 mg/kg, i.p.) dose-dependently improved lithium-induced memory impairment. Post-training administration of ineffective doses of the NMDA (10-5 and 10-4 μg/rat, intra-CA1) plus an ineffective dose of olanzapine (1 mg/kg, i.p.) dose-dependently improved the lithium-induced memory impairment. Post-training microinjection of ineffective doses of the NMDA (10-5 and 10-4 μg/rat, intra-CA1) dose-dependently potentiated the memory improvement induced by olanzapine (1 mg/kg, i.p.) on lithium-induced memory impairment which was associated with the enhancement of the levels of p-CAMKII and p-CREB in the HPC and the PFC. Post-training microinjection of ineffective doses of the noncompetitive NMDA receptor antagonist, MK-801 (0.0625 and 0.0125 μg/rat, intra-CA1), dose-dependently decreased the memory improvement induced by olanzapine (5 mg/kg, i.p.) on lithium-induced memory impairment which was related to the reduced levels of HPC and PFC CAMKII-CREB. CONCLUSION: The results strongly revealed that there is a functional interaction among lithium and olanzapine through the HPC and the PFC NMDA receptor mechanism in memory consolidation which is mediated with the CAMKII-CREB signaling pathway.
RATIONALE: Treatment of bipolar disorder (BPD) with lithium and olanzapine concurrent administration is a major medicine issue with the elusive neurobiological mechanisms underlying the cognitive function. OBJECTIVE: To clarify the precise mechanisms involved, the possible role of the hippocampus (HPC) and prefrontal cortical (PFC) NMDA receptors and CAMKII-CREB signaling pathway in the interactive effects of lithium and olanzapine in memory consolidation was evaluated. The dorsal hippocampal CA1 regions of adult male Wistar rats were bilaterally cannulated and a step-through inhibitory avoidance apparatus was used to assess memory consolidation. The changes in p-CAMKII/CAMKII and p-CREB/CREB ratio in the HPC and the PFC were measured by Western blot analysis. RESULTS: Post-training administration of lithium (20, 30, and 40 mg/kg, i.p.) dose-dependently decreased memory consolidation whereas post-training administration olanzapine (2 and 5 mg/kg, i.p.) increased memory consolidation. Post-training administration of certain doses of olanzapine (1, 2, and 5 mg/kg, i.p.) dose-dependently improved lithium-induced memory impairment. Post-training administration of ineffective doses of the NMDA (10-5 and 10-4 μg/rat, intra-CA1) plus an ineffective dose of olanzapine (1 mg/kg, i.p.) dose-dependently improved the lithium-induced memory impairment. Post-training microinjection of ineffective doses of the NMDA (10-5 and 10-4 μg/rat, intra-CA1) dose-dependently potentiated the memory improvement induced by olanzapine (1 mg/kg, i.p.) on lithium-induced memory impairment which was associated with the enhancement of the levels of p-CAMKII and p-CREB in the HPC and the PFC. Post-training microinjection of ineffective doses of the noncompetitive NMDA receptor antagonist, MK-801 (0.0625 and 0.0125 μg/rat, intra-CA1), dose-dependently decreased the memory improvement induced by olanzapine (5 mg/kg, i.p.) on lithium-induced memory impairment which was related to the reduced levels of HPC and PFC CAMKII-CREB. CONCLUSION: The results strongly revealed that there is a functional interaction among lithium and olanzapine through the HPC and the PFC NMDA receptor mechanism in memory consolidation which is mediated with the CAMKII-CREB signaling pathway.