Imbalance of HCN1 and HCN2 expression in hippocampal CA1 area impairs spatial learning and memory in rats with chronic morphine exposure

• Spatial learning and memory is impaired in rat model of chronic morphine exposure.
• Chronic morphine exposure causes a marked inhibition of LTP in the hippocampal CA1 area.
• Chronic morphine exposure causes a marked decrease in HCN1 surface expression, but an increase in HCN2 surface expression in the hippocampal CA1 Area.
• An increase in TRIP8b (1a-4) and TRIP8b (1b-2) expression and the activation of PKA and AP2 μ2 contribute to the imbalance of HCN1/HCN2 surface expression in chronic morphine exposed rats.

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 HCN1 and HCN2 subunits in hippocampal CA1 and the potential molecular mechanisms underlying the modulation of HCN channels in rats with chronic morphine exposure with approaches of electrophysiology, water maze, and Western blotting. We found that chronic morphine exposure (5 mg/kg, sc, for 7 days) caused an inhibition of long-term potentiation (LTP) and impairment of spatial learning and memory, which is associated with a decrease in HCN1, and an increase in HCN2 on cell membrane of hippocampal CA1 area. Additional experiments showed that the imbalance of cell membrane HCN1 and HCN2 expression under chronic morphine exposure was related to an increase in expression of TPR containing Rab8b interacting protein (TRIP8b) (1a-4) and TRIP8b (1b-2), and phosphorylation of protein kinase A (PKA) and adaptor protein 2 μ2 (AP2 μ2). Our results demonstrate the novel information that drug addiction-induced impairment of learning and memory is involved in the imbalance of HCN1 and HCN2 subunits, which is mediated by activation of TRIP8b (1a-4), TRIP8b (1b-2), PKA and AP2 μ2.