Inhibition of Methamphetamine Self-Administration and Reinstatement by Central Blockade of Angiotensin II Receptor in Rats.

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-PLCß-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-PLCß-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.

The effects of early exposure to MK-801 during environmental enrichment on spatial memory, methamphetamine self-administration and cue-induced renewal in rats.

OBJECTIVE: Accumulating evidence indicates an association between improved cognition and the early introduction of environmental enrichment (EE). The beneficial effect of EE has also been examined in the field of methamphetamine (METH) dependence. The present study was designed to examine whether early cognitive alterations by dizocilpine (MK-801) in adolescence can impact the effect of EE on spatial memory, METH self-administration (SA), and cue-induced renewal in adulthood. METHODS: In Experiments 1 and 2, Morris Water Maze (MWM) performance, c-Fos expression and N-methyl d-aspartate receptor subtype 2B (NMDAR2B) levels were determined in various brain regions following a change in rearing condition from EE to an isolation environment (IE) at different points (PD 41-60 or PD 51-70). In Experiments 3 and 4, MWM performance and METH SA behaviors in adulthood were tested following adolescent administration of MK-801 during different periods of adolescence (PD 41-60 or PD 51-70) under EE rearing conditions. RESULTS: The early introduction of the IE at PD 41-60 significantly decreased the beneficial effect of EE on MWM performance in adulthood as compared to IE exposure at PD 51-70. Different rearing conditions also altered c-Fos expression and NMDA2B receptor activity in a regionally specific pattern. EE induced structural and systemic changes in the hippocampus that were associated with improvements in spatial memory. Early administration of MK-801 at PD 41-60 and PD 51-70 produced distinctive effects on the behavioral outcomes of METH SA and cue-induced renewal. CONCLUSION: Early cognitive alterations have a profound impact on spatial memory and METH dependence.