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 α-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.
Karolinska Institutet, Stockholm, Sweden.
Anna
A
Okvist
Pernilla
P
Fagergren
John
J
Whittard
Ana
A
Garcia-Osta
Katarina
K
Drakenberg
Monika Cs
MC
Horvath
Carl J
CJ
Schmidt
Eva
E
Keller
Michael J
MJ
Bannon
Yasmin L
YL
Hurd
D000328:Adult; D000367:Age Factors; D000679:Amygdala / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D034286:Dynamin III / Q000378:metabolism; D005260:Female; D006556:Heroin Dependence / Q000378:metabolism*; D000072233:Homer Scaffolding Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D057907:Post-Synaptic Density / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism
D002352:Carrier Proteins; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018091:Receptors, AMPA; D034286:Dynamin III