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

• Published in: Progress in neuro-psychopharmacology & biological psychiatry 2015-01, Vol.56, p.207-214
• Main Authors: Zhou, Mei, Luo, Pan, Lu, Yun, Li, Chang-jun, Wang, Dian-shi, Lu, Qing, Xu, Xu-lin, He, Zhi, Guo, Lian-jun
• Format: Article
• Language: English
• Subjects: Animals; CA1 Region, Hippocampal - drug effects; Chronic morphine exposure; Disease Models, Animal; Electric Stimulation; Excitatory Postsynaptic Potentials - drug effects; Gene Expression Regulation - drug effects; HCN channels; Hippocampus; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism; Male; Maze Learning - drug effects; Membrane Proteins - metabolism; Memory Disorders - chemically induced; Memory Disorders - pathology; Morphine - toxicity; Motor Activity - drug effects; Narcotics - toxicity; Nerve Tissue Proteins - metabolism; Protein-Serine-Threonine Kinases - metabolism; Rats; Rats, Sprague-Dawley; Spatial Learning - drug effects; Spatial learning and memory
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2014.09.010

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 (5mg/kg, sc, for 7days) 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. •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.