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Involvement of the accumbal osteopontin-interacting transmembrane protein 168 in methamphetamine-induced place preference and hyperlocomotion in mice.

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.

SUBMITTER: Fu K

PROVIDER: S-EPMC5638853 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Involvement of the accumbal osteopontin-interacting transmembrane protein 168 in methamphetamine-induced place preference and hyperlocomotion in mice.

Fu Kequan K Miyamoto Yoshiaki Y Otake Kazuya K Sumi Kazuyuki K Saika Eriko E Matsumura Shohei S Sato Naoki N Ueno Yuka Y Seo Seunghee S Uno Kyosuke K Muramatsu Shin-Ichi SI Nitta Atsumi A

Scientific reports 20171012 1

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 us ...[more]

PMID: 29026117

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Project description:Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains unclear. Our recent research has identified a specific subpopulation of choline acetyltransferase (ChAT+) neurons localized in the external lateral portion of parabrachial nucleus (eLPBChAT), which modulates METH primed-reinstatement of conditioned place preference (CPP). Here, the anatomical structures and functional roles of eLPBChAT projections in METH withdrawal anxiety and primed reinstatement were further explored. Methods: In the present study, a multifaceted approach was employed to dissect the LPBChAT+ projections in male mice, including anterograde and retrograde tracing, acetylcholine (Ach) indicator combined with fiber photometry recording, photogenetic and chemogenetic regulation, as well as electrophysiological recording. METH withdrawal anxiety-like behaviors and METH-primed reinstatement of conditioned place preference (CPP) were assessed in male mice. Results: We identified that eLPBChAT send projections to PKCδ-positive (PKCδ+) neurons in lateral portion of central nucleus of amygdala (lCeAPKCδ) and oval portion of bed nucleus of the stria terminalis (ovBNSTPKCδ), forming eLPBChAT-lCeAPKCδ and eLPBChAT-ovBNSTPKCδ pathways. At least in part, the eLPBChAT neurons positively innervate lCeAPKCδ neurons and ovBNSTPKCδ neurons through regulating synaptic elements of presynaptic Ach release and postsynaptic nicotinic acetylcholine receptors (nAChRs). METH withdrawal anxiety and METH-primed reinstatement of CPP respectively recruit eLPBChAT-lCeAPKCδ pathway and eLPBChAT-ovBNSTPKCδ pathway in male mice. Conclusion: Our findings put new insights into the complex neural networks, especially focusing on the eLPBChAT projections. The eLPBChAT is a critical node in the neural networks governing METH withdrawal anxiety and primed-reinstatement of CPP through its projections to the lCeAPKCδ and ovBNSTPKCδ, respectively.

Project description:Abstract Drug relapse is a big clinical challenge in the treatment of addiction, but its neural circuit mechanism is far from being fully understood. Here, we identified a novel cholinergic pathway from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeAGABA) and explored its role in methamphetamine priming-induced reinstatement of conditioned place preference. The anatomical structure and functional innervation of the eLPBChAT–CeAGABA pathway were investigated by various methods such as fluorescent micro-optical sectioning tomography, virus-based neural tracing, fibre photometry, patch-clamp and designer receptor exclusively activated by a designer drug. The role of the eLPBChAT–CeAGABA pathway in methamphetamine relapse was assessed using methamphetamine priming-induced reinstatement of conditioned place preference behaviours in male mice. We found that the eLPBChAT neurons mainly projected to the central nucleus of the amygdala. A chemogenetic activation of the eLPBChAT neurons in vitro or in vivo triggered the excitabilities of the CeAGABA neurons, which is at least in part mediated via the cholinergic receptor system. Most importantly, the chemogenetic activation of either the eLPBChAT neurons or the eLPBChAT neurons that project onto the central nucleus of the amygdala decreased the methamphetamine priming-induced reinstatement of conditioned place preference in mice. Our findings revealed a previously undiscovered cholinergic pathway of the eLPBChAT–CeAGABA and showed that the activation of this pathway decreased the methamphetamine priming-induced reinstatement of conditioned place preference. He et al. identified a novel cholinergic projection from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeAGABA), which is involved in methamphetamine relapse. The chemogenetic activation of either the LPBChAT neurons or the eLPBChAT–CeAGABA pathway attenuated the methamphetamine-primed reinstatement of conditioned place preference. Graphical Abstract Graphical abstract

Dataset Information

Involvement of the accumbal osteopontin-interacting transmembrane protein 168 in methamphetamine-induced place preference and hyperlocomotion in mice.

Publications

Involvement of the accumbal osteopontin-interacting transmembrane protein 168 in methamphetamine-induced place preference and hyperlocomotion in mice.

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