Regulatory Effect of Bee Venom on Methamphetamine-Induced Cellular Activities in Prefrontal Cortex and Nucleus Accumbens in Mice

Abstract

Our previous studies demonstrated that subcutaneous injection of bee venom (BV) into the Zusanli (ST36) acupuncture point, namely BV acupuncture, dose-dependently prevents conditioned place preference (CPP) induced by repeated injection of methamphetamine (METH) in mice. To expand on our observations, the present study was designed to determine the suppressive mechanisms of BV acupuncture in the development of METH-induced CPP by evaluating the changes in expression of ΔFosB, phosphorylated extracellular signal-regulated kinase 1/2 (pERK), and phosphorylated calcium/calmodulin-dependent protein kinase type II (pCaMKII) in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in mice. Pre-emptive treatment with BV at 30 min before repeated METH injection completely suppressed acquisition of CPP at the day 7 test session. METH-induced upregulation of ΔFosB and pERK in PFC and NAc was significantly reduced by BV pretreatment. Expression of pCaMKII was significantly elevated by METH in NAc and reduced in PFC. BV pretreatment reversed the changes of pCaMKII expression in PFC and NAc. These findings suggest that BV acupuncture may exert a suppressive effect on METH-induced addiction via regulation of signaling cascades of ΔFosB, ERK, and CaMKII in PFC and NAc. Key words methamphetamine (METH); bee venom (BV); conditioned place preference (CPP); prefrontal cortex (PFC); nucleus accumbens (NAc)Addiction to methamphetamine (METH) is an international public health problem. Acute administration of METH results in a sense of euphoria and hyperactivity in association with increased extracellular release of monoamine neurotransmitters, including dopamine, norepinephrine and serotonin. 1,2) Chronic METH abuse produces several negative side effects, including dopaminergic nerve terminal toxicity, altered morphology in the central nervous systems and an increased risk of developing Parkinson's disease.3) Nevertheless, exacerbating the problem of METH-induced neurotoxicity is the current lack of Food and Drug Administration (FDA)-approved pharmacotherapies for treating the negative health effects of METH abuse. 4)Numerous studies have been performed to evaluate the most effective therapeutic methods to treat METH addiction through the long-lasting prevention of relapse to METH use without side effect. Some of these studies have investigated needle acupuncture, which has been used to treat various drug addictions in humans. However, most studies revealed that needle acupuncture produces a significant but only partial therapeutic effect compared with the placebo control. 5) Our recent studies firstly demonstrated that acupuncture with bee venom (BV), which is a potent peripheral stimulant that is dissolved in saline and administered into Zusanli acupuncture point (ST36), could dose-dependently reduce the hyperactivity induced by a single injection of METH as compared with other acupuncture points [Yinlingquan (SP9) and Xuanzhong (GB39)] or non-acupuncture point (tail base).6) This result indicated that BV injection into Zusanli a...

ERK-Directed Phosphorylation of mGlu5 Gates Methamphetamine Reward and Reinforcement in Mouse

“…However, our data extend to the mPFC, the results of earlier drug-induced place-conditioning studies in which systemic pretreatment with ERK inhibitors [58][59][60][61][62] or targeted ERK inhibition within the nucleus accumbens [51,63] were reported to inhibit drug-induced place-preference in rodents. The present data also align with other studies linking the efficacy of potential anti-addiction medications at blocking CPP with a reduction in phospho-ERK expression within mPFC, e.g., [53,64].…”

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

“…The increase of pERK, pElk-1, pCREB, and/or ΔFosB protein expression in the CPu, NAc or PFC is related to METH-induced CPP 180,181 . Specifically, the acquisition of CPP and pERK induction in the NAc by METH-CPP require D1-R but not NMDA-R activation.…”

Thioredoxin-1 Protects Spinal Cord from Demyelination Induced by Methamphetamine through Suppressing Endoplasmic Reticulum Stress and Inflammation

“…It has been reported that inflammatory factors are induced by ERK ( 39 ). METH exposure significantly increases the activity of ERK ( 40 , 41 ). Several lines of evidence have shown that ERK activation might activate NF-κB ( 42 , 43 ).…”