Dysregulated Postsynaptic Density and Endocytic Zone in the Amygdala of Human Heroin and Cocaine Abusers

Background: Glutamatergic transmission in the amygdala is hypothesized as an important mediator of stimulus-reward associations contributing to drug-seeking behavior and relapse. Insight is, however, lacking regarding the amygdala glutamatergic system in human drug abusers. Methods: We examined glutamate receptors and scaffolding proteins associated with the postsynaptic density in the human postmortem amygdala. Messenger RNA or protein levels were studied in a population of multidrug (seven heroin, eight cocaine, seven heroin/cocaine, and seven controls) or predominant heroin (29 heroin and 15 controls) subjects. Results: The amygdala of drug abusers was characterized by a striking positive correlation (r > .8) between alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptor subunit 1 (GluA1) and postsynaptic density protein-95 (PSD-95) mRNA levels, which was not evident in control subjects. Structural equation multigroup analysis of protein correlations also identified the relationship between GluA1 and PSD-95 protein levels as the distinguishing feature of abusers. In line with the GluA1-PSD-95 implications of enhanced synaptic plasticity, Homer 1b/c protein expression was increased in both heroin and cocaine users as was its binding partner, dynamin-3. Furthermore, there was a positive relationship between Homer 1b/c and dynamin-3 in drug abusers that reflected an increase in the direct physical coupling between the proteins. A noted age-related decline of Homer 1b/c-dynamin-3 interactions, as well as GluA1 levels, was blunted in abusers. Conclusions: Impairment of key components of the amygdala postsynaptic density and coupling to the endocytic zone, critical for the regulation of glutamate receptor cycling, may underlie heightened synaptic plasticity in human drug abusers.