The molecular mechanism and treatment of methamphetamine (METH) use disorder remain unclear. The current study aimed to investigate the role of central angiotensin II receptor (ATR) in drug taking and seeking behavior associated with METH use disorder. The effect of an ATR type 1 (AT1R) antagonist, candesartan cilexetil, on the reinforcing and motivational effects of METH was first assessed using the animal model of METH self-administration (SA) and reinstatement. The levels of dopamine D2 receptor (D2R) and AT1R were subsequently examined. Furthermore, the present study determined the expression of microRNAs (miRNAs) by comparing METH SA, METH-yoked, and Saline-yoked groups. The target miRNAs were further overexpressed in the nucleus accumbens (NAc) via a lentivirus vector to investigate the effects of target miRNAs on METH SA maintained under a fixed ratio 1, progressive ratio, and cue/drug reinstatement of METH SA. The potential role of the AT1R-PLCb-CREB signaling pathway was finally investigated. The results suggest that AT1R blockade effectively reduced METH SA and reinstatement, in conjunction with the counter-regulation of D2R and AT1R. A total of 17 miRNAs targeting Ang II in NAc were found to be associated with the voluntary intake of METH. Furthermore, overexpression of specific miR-219a-5p targeting AT1R-regulated METH SA and reinstatement. The AT1R-PLCb-CREB signaling pathway was found to be associated with the effect of AT1R on the drug-taking and drug-seeking behavior involving METH use disorder.Both yoked-METH SA (yoked-METH) and yoked-Saline groups were tested simultaneously with the METH SA group in different conditions. Either a yoked-METH or a yoked-Saline rat was paired with one METH SA rat. Yoked-METH rats received the intravenous infusions of METH at the same dose, number, and rate as the METH SA group. The yoked-Saline group received the intravenous infusions of saline at the same number and rate as the METH SA group. The nose-pokes by the yoked rats were recorded but had no programmed consequences. Cue-and Drug-Induced Reinstatement of METH SAAfter METH SA, the animals were subjected to extinction for 7 days. During the extinction phase, the animals were placed in chambers, AT1R Blockade of Methamphetamine Self-Administration in Rats

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