Abstract
Chronic exposure to methamphetamine causes adaptive changes in brain, which underlie dependence symptoms. We have found that the transmembrane protein 168 (TMEM168) is overexpressed in the nucleus accumbens of mice upon repeated methamphetamine administration. Here, we firstly demonstrate the inhibitory effect of TMEM168 on methamphetamine-induced behavioral changes in mice, and attempt to elucidate the mechanism of this inhibition. We overexpressed TMEM168 in the nucleus accumbens of mice by using an adeno-associated virus vector (NAc-TMEM mice). Methamphetamine-induced hyperlocomotion and conditioned place preference were attenuated in NAc-TMEM mice. Additionally, methamphetamine-induced extracellular dopamine elevation was suppressed in the nucleus accumbens of NAc-TMEM mice. Next, we identified extracellular matrix protein osteopontin as an interacting partner of TMEM168, by conducting immunoprecipitation in cultured COS-7 cells. TMEM168 overexpression in COS-7 cells induced the enhancement of extracellular and intracellular osteopontin. Similarly, osteopontin enhancement was also observed in the nucleus accumbens of NAc-TMEM mice, in in vivo studies. Furthermore, the infusion of osteopontin proteins into the nucleus accumbens of mice was found to inhibit methamphetamine-induced hyperlocomotion and conditioned place preference. Our studies suggest that the TMEM168-regulated osteopontin system is a novel target pathway for the therapy of methamphetamine dependence, via regulating the dopaminergic function in the nucleus accumbens.
Highlights
Methamphetamine (METH) dependence remains a serious social health problem in the world because of its association with addictive syndromes
Since the nucleus accumbens (NAc) is one of the important regions in brain for the reward system[9], we investigated the molecules whose mRNA expression increased in the NAc after repeated METH administration in mice, by PCR-selected cDNA subtraction method
We found that transmembrane protein 168 (TMEM168) mRNA increased significantly in the NAc of the repeated administered mice
Summary
Methamphetamine (METH) dependence remains a serious social health problem in the world because of its association with addictive syndromes. Chronic METH exposure results in a neuropsychiatric disorder thought to be induced by adaptive changes at the molecular, cellular, and tissue levels, which are complex and often brain-region specific[3]. After repeated METH exposure, investigations on the adaptive changes in brain functions suggest that alterations in gene regulation contribute to the addictive phenotype in humans and animals. The expression patterns of the tmem[168] gene have been detected both in humans and in mice[11], the neuronal function of TMEM168 protein has not been revealed yet. TMEM168 mRNA has been reported as a candidate target of age-related miRNA miR-125b in human dermal fibroblasts; the protein level of TMEM168 does not significantly alter with age[14]. We suggested a mechanistic linkage between TMEM168 and OPN to study METH dependence
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