| Objective:The hyperpolarization-activated cyclic-nucleotide-gated non-selective cation (HCN) channels play a vital role in the neurological basis underlying nervous system diseases. However, the role of HCN channels in drug addiction is not fully understood. In the present study, we investigated the expression of HCN1and HCN2subunits in hippocampal CA1/DG area and the potential mechanisms underlying the modulation of HCN channels in rats with chronic morphine exposure and withdrawal.Methods:Rats in chronic morphine exposure and chronic morphine withdrawal group were injected with morphine (5mg/kg, s.c.) once per day for7days. Then, rats in chronic morphine withdrawal group were without morphine for7days. Rats in saline group were injected with isovolumetric saline. Morris water maze (MWM) was performed to evaluate the spatial learning and memory performances of rats. Novel object recognition test (NOR) was performed to evaluate the cognitive function of rats. After behavioral tests, electrophysiological and molecular biology studies in the hippocampal CA1and DG area were carried out.Results:1. Chronic morphine exposure (5mg/kg, sc, for7days) caused a marked impairment of spatial learning and memory function and cognitive function. Compared with chronic morphine exposure rats, the spatial learning and memory function and cognitive function in chronic morphine withdrawal rats returned to normal.2. Chronic morphine exposure induced a significant inhibition of long-term potentiation (LTP) in hippocampal CA1area, which was associated with a decrease in HCN1, and an increase in HCN2on cell membrane. Additional experiments showed that the imbalance of cell membrane HCN1and HCN2expression under chronic morphine exposure in hippocampal CA1area was related to an increase in expression of TPR containing Rab8b interacting protein (TRIP8b)(1a-4) and TR1P8b (1b-2), and phosphorylation of protein kinase A (PKA) and adaptor protein2μ2(AP2μ2).3. Compared with chronic morphine exposure rats, HCN1expresion on cell membrane was increased in hippocampal CA1area in chronic morphine withdrawal rats, while HCN2expresion on cell membrane was decreased. These changes in IICN1and HCN2cell membrane expression under chronic morphine withdrawal in hippocampal CA1area was related to an increase in expression of TRIP8b (1b-2) and phosphorylation of AP2μ2.4. We also found that chronic morphine exposure induced a significant inhibition of LTP in hippocampal DG area, which was associated with a significant decrease in both HCN1and HCN2cell membrane expression in hippocampal DG area. The disorder of HCN1and HCN2membrane expression under chronic morphine exposure in DG area was related to a marked decrease in the phosphorylation of PKA and AP2μ2.5. In addiction, compared with chronic morphine exposure rats, HCN1and HCN2membrane expresion was increased in DG area in chronic morphine withdrawal rats. These changes in HCN1and HCN2expression under chronic morphine withdrawal in DG area were related to an increase in the phosphorylation of PKA and a decrease in the phosphorylation of AP2μ2.Conclusion:Our results demonstrate the novel information that the impairment of learning and memory function and cognitive function induced by chronic morphine exposure is related to the inhibition of synaptic transmission in hippocampal CA1and DG area. Meanwhile, changes in synaptic transmission caused by chronic morphine exposure were associated with the imbalance of HCN1and HCN2subunits in the hippocampal CA1and DG area, which was mediated by activation of TRIP8b (1a-4), TRIP8b (1b-2), PKA and AP2μ2. In addiction, through the regulation of TRIP8b (1b-2), p-PKA and p-AP2μ2, the membrane expresion of HCN1and HCN2subunits under chronic morphine withdrawal for7days in the hippocampal CA1and DG area returned to normal, which was related to the improvement of learning and memory function and cognitive function. |
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