Alteration in AMPA receptor subunit expression and receptor binding among patients with addictive disorders: A systematic review of human postmortem studies

Abstract

Background and Objectives Altered trafficking of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors has been reported in postmortem studies and suggested the involvement of AMPA receptors in the pathophysiology underpinning addictive disorders. However, these findings seemed mixed. Methods A systematic literature search was conducted, using PubMed and Embase (last search, August 2018), to identify human postmortem studies that examined the expression of proteins and mRNA of AMPA receptor subunits in patients with addictive disorders in comparison with healthy controls. Results Twelve (18 studies) out of 954 articles were identified to be relevant. Eight studies included alcohol use disorders, and four studies included heroin/cocaine abusers. The most frequently investigated regions were the hippocampus (three studies), amygdala (three studies), and putamen (three studies). In summary, two out of the three studies showed an increase in the expression of AMPA receptors in the hippocampus, while the other study found no change. Two studies to examine the amygdala demonstrated either a decreased or no change in receptor expression or binding. Concerning putamen, two studies showed no significant change whereas an overexpression of receptors was observed in the other. Conclusions and Scientific Significance The hippocampus and amygdala may be pertinent to addictive disorders through their functions on learning and memory, whereas findings in other regions were inconsistent across the studies. Human postmortem studies are prone to degenerative changes after death. Moreover, only qualitative assessment was conducted because of the limited, heterogenous data. These limitations emphasize the need to investigate AMPA receptors in the living human brains.

Systemic Administration of the AMPA Receptor Antagonist, NBQX, Reduces Alcohol Drinking in Male C57BL/6J, But Not Female C57BL/6J or High‐Alcohol‐Preferring, Mice

“…AMPA receptors are a subtype of ionotropic glutamate receptors that are vital for fast synaptic neurotransmission and long‐term potentiation (LTP) within the central nervous system and have recently been under investigation for their role in modulating alcohol consumption (Corbit et al, 2014; Dannenhoffer and Spear, 2019; Henley and Wilkinson, 2016; Ruda‐Kucerova et al, 2018; Ueno et al, 2019; Wang et al, 2012). LTP is dependent on the insertion of AMPA receptors into the postsynaptic membrane where glutamate binding to AMPA receptors is necessary to cause postsynaptic depolarization of the membrane ultimately leading to an up‐regulation of LTP‐dependent AMPA receptors.…”

Translational medicine of the glutamate AMPA receptor

“…There have been post-mortem brain studies that measure AMPARs in the brain. According to systematic literature reviews, there are differences in AMPAR subunit expression and receptor binding in the postmortem brain between patients with psychiatric conditions, including schizophrenia, depression, and addictive disorders, and healthy controls 68 ) (Uchida et al and Koizumi et al , in preparation for publication); however, the findings regarding their relative quantity in comparison to healthy controls and the affected regions were inconsistent across the studies. Degrading changes after death and the activity-dependent nature of AMPARs render human postmortem studies challenging.…”

“…Degrading changes after death and the activity-dependent nature of AMPARs render human postmortem studies challenging. 68 ) Moreover, subjects included in these post-mortem studies were not comprehensively characterized in terms of their diagnosis and illness severity. Such a stagnating situation clearly highlighted the necessity for examining AMPARs in the living brain of well-characterized patients with psychiatric disorders in the real-world.…”

The effect of CNQX on self-administration: present in nicotine, absent in methamphetamine model

“…There seems to be a particular yet inconclusively described role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the human substance abusers pointing to a single relatively consistent outcome -an increase in the hippocampal expression of AMPA receptor subunits (Ueno et al, 2019). In preclinical research, multiple drugs were shown to exert alterations of AMPA receptor subunits' expression in reward-related brain areas, typically nucleus accumbens or ventral tegmental area, e.g., cocaine (Sutton et al, 2003), amphetamine (Cruz et al, 2008), nicotine (Wang et al, 2007) or methamphetamine (Scheyer et al, 2016;Murray et al, 2019).…”