Abstract
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 angiotensin II receptor type 1 (AT1R) antagonist, candesartan cilexetil (CAN), on the reinforcing and motivational effects of METH was firstly assessed, using the animal model of METH self-administration (SA) and reinstatement. The level of dopamine D2 receptor (D2R) and AT1R was subsequently examined. Furthermore, the present study determined the expression of microRNAs by comparing METH SA, METH-yoked and saline-yoked groups. The target microRNAs were further overexpressed in the nucleus accumbens (NAc) via a lentivirus vector to investigate the effects of target microRNAs on METH SA maintained under a fixed ratio 1 (FR1), progressive ratio (PR) and cue-/drug-reinstatement of METH SA. The potential role of AT1R-PLCβ-CREB signaling pathway was finally investigated. The results suggest that AT1R blockade effectively reduced METH SA and reinstatement, in conjunction with counter-regulation of D2R and AT1R. A total of 17 miRNAs targeting AngII in NAc were found to be associated with voluntary intake of METH. Furthermore, overexpression of specific miR-219a-5p targeting AT1R regulated METH SA and reinstatement. The AT1R-PLCβ-CREB signaling pathway was found to be associated with the effect of AT1R on the drug-taking and seeking behavior involving METH use disorder.
- The American Society for Pharmacology and Experimental Therapeutics