ABSTRACT
Repeated methamphetamine (METH) exposure can cause severe neurotoxicity to the central nervous system, and lead to memory deficits. L-Stepholidine (L-SPD) is a structurally identified alkaloid extract of the Chinese herb Stephania intermedia, which elicits dopamine (DA) D1-type receptors partial agonistic activity and D2-type receptors antagonistic activity. In this study, we investigated the effect of L-SPD on METH-induced memory deficits in mice and its underlying mechanisms. We found that repeated exposure to METH (10 mg/kg, i.p., once per day for 7 consecutive days) impaired memory functions in the novel object recognition experiment. Pretreatment of L-SPD (10 mg/kg, i.p.) significantly improved METH-induced memory deficits in mice. Meanwhile, the protein expression of dopaminergic D2 receptors in hippocampus area was significantly increased by repeated METH exposure, while the protein expression of dopamine transporter (DAT) was significantly reduced. Additionally, the protein expression of phospho-protein kinase A (p-PKA) was significantly increased by repeated METH exposure. The hyperpolarization-activated cyclic-nucleotide-gated non-selective cation 1 (HCN1) channel, which was a key regulator of memory functions and could be regulated by p-PKA, was also significantly increased by repeated METH exposure. These changes caused by METH could be prevented by L-SPD pretreatment. Therefore, our data firstly showed that pretreatment of L-SPD exhibited the protective effect against METH-induced memory deficits, possibly through reducing METH-induced upregulation of dopaminergic pathway and HCN1 channels.
Subject(s)
Berberine/analogs & derivatives , Memory Disorders/chemically induced , Memory Disorders/prevention & control , Methamphetamine/toxicity , Neuroprotective Agents/therapeutic use , Animals , Berberine/therapeutic use , Dopamine Agents/toxicity , Dopamine Agonists/therapeutic use , Dopamine Antagonists/therapeutic use , Locomotion/drug effects , Locomotion/physiology , Male , Memory Disorders/metabolism , Mice , Mice, Inbred C57BL , Random AllocationABSTRACT
Drug dependence and withdrawal syndrome induced by abrupt cessation of opioid administration remain a severe obstacle in the clinical treatment of chronic pain and opioid drug addiction. One of the key symptoms during opioid withdrawal is hyperalgesia. The mechanism of opioid withdrawal-induced hyperalgesia remains unclear. P2X2 and P2X3 receptors, members of P2X receptor subunits, act as the integrator of multiple forms of noxious stimuli and play an important role in nociception transduction of chronic neuropathic and inflammatory pain. The process of P2X2 and P2X3 receptor antagonism inhibits inflammatory hyperalgesia, involving the spinal opioid system. However, the role of P2X receptors involved in opioid withdrawal-induced hyperalgesia has seldom been discussed. To explore the role of P2X2 and P2X3 receptors in the opioid-induced hyperalgesia, heroin self-administration rats were adopted, and the thermal and mechanical nociceptive thresholds were evaluated using the paw withdrawal test after abstinence from heroin for 8 days. In addition, the expressions of P2X2 and P2X3 receptors in dorsal root ganglia were analyzed by immunofluorescence. The results showed that after 8 days of abstinence, heroin self-administration rats showed thermal hyperalgesia and mechanical allodynia. Meanwhile, the expressions of the P2X2 and P2X3 receptors in dorsal root ganglia were increased. These results suggest that upregulation of P2X2 and P2X3 receptors might partially play a role in heroin withdrawal-induced hyperalgesia.
