Cocaine‐induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non‐human primates

Abstract

Chronic cocaine and withdrawal induce significant alterations in nucleus accumbens (NAc) glutamatergic function in humans and rodent models of cocaine addiction. Dysregulation of glutamatergic function of the prefrontal cortical-NAc pathway has been proposed as a critical substrate for unmanageable drug seeking. Previously, we demonstrated significant up-regulation of NMDA, (±)-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunit mRNAs and protein levels in the ventral tegmental area (VTA), but not the substantia nigra, of cocaine overdose victims (COD). The present study was undertaken to examine the extent of altered ionotropic glutamate receptor (iGluR) subunit expression in the NAc and the putamen in cocaine overdose victims. Results revealed statistically significant increases in the NAc, but not in the putamen, of NMDA receptor subunit (NR)1 and glutamate receptor subunit (GluR)2/3 wit trends in GluR1 and GluR5 in COD. These results extend our previous finding and indicate pathwayspecific alterations in iGluRs in COD. In order to determine that changes were related to cocaine intake and not to other factors in the COD victims, we examined the effects of cocaine intravenous self-administration in rhesus monkeys for 18 months (unit dose of 0.1 mg/kg/injection and daily drug intake of 0.5 mg/kg/session). Total drug intake for the group of four monkeys was 37.9 ± 4.6 mg/kg. Statistically significant elevations were observed for NR1, GluR1, GluR2/3 and GluR5 (p < 0.05) and a trend towards increased NR1 phosphorylated at serine 896 (p ¼ 0.07) in the NAc but not putamen of monkeys self-administering cocaine compared with controls. These results extend previous results by demonstrating an up-regulation of NR1, GluR2/3 and GluR5 in the NAc and suggest these alterations are pathway specific. Furthermore, these changes may mediate persistent drug intake and craving in the human cocaine abuser.

Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims

“…Increased TUB2 protein expression in the NAc of human COD victims is an original documentation of the current study. The highly acidic carboxyterminal region binds cations such as calcium, which is particularly interesting in the light of previous findings showing elevated NR1 and GluR2 protein levels in the NAc of COD victims, 44 which mediate increased calcium flux in this region. Interestingly, calcium currents are decreased in the NAc following cocaine withdrawal.…”

“…43 Recently, we reported increased protein levels of NR1, GluR2/3, GluR1 and GluR5 in the NAc of rhesus monkeys selfadministering cocaine; however, humans with COD showed a significant increase of only NR1 and GluR2/ 3 in NAc. 44 The increased expression of liprin-a in human COD victims probably plays an important role in mediating the AMPA and NMDA receptor movement along the microtubular track to the synaptic membrane.…”

“…Subcellular fractionation into membrane, nuclear and cytoplasmic fractions was performed as described previously. 43,44 For the purposes of this study, only cytosolic fractions were evaluated. Studies are underway to assess the membrane and nuclear proteomes using alternative separation methodologies to enable detection of hydrophobic proteins difficult to detect by gel-based methods.…”

“…In a separate cohort, Hemby and colleagues evaluated a targeted set of transcripts in the VTA and lateral substantia nigra (l-SN) and found significant upregulation of numerous transcripts and their encoded proteins in the VTA, but not l-SN, of cocaine overdose victims including the N-methyl-D-asparatate receptor subunit NR1, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR2 and kainate receptor subunits GluR5 and KA2 mRNAs. 43 Similarly, protein levels of NR1 and GluR2/3, with trends in GluR1 and GluR5, were found to be increased in the NAc but not putamen of cocaine overdose victims, 44 suggesting that these alterations are pathway specific and may contribute to persistent drug intake and craving in the human cocaine abuser. These studies suggest that multiple pathways are involved in the neuropathology and altered neuronal function of cocaine addicts.…”

“…[33][34][35][36][37][38][39][40][41] Genomic analyses in human post-mortem tissue of cocaine overdose (COD) victims have confirmed the findings of studies employing rodent models and have revealed novel mechanisms of drug-induced neuronal and non-neuronal dysregulation in human post-mortem brain tissue. [42][43][44][45] For example, Bannon and co-workers 42 examined gene expression in the NAc of post-mortem brain tissue of human cocaine abusers and controls and found significant alterations in several novel functional classes and transcripts including signal transduction, transcriptional and translational processing, neurotransmission and synaptic function, glia, structural and cell adhesion, receptors/transporters/ion channels, cell cycle and growth and lipid and protein processing. Interestingly, they identified several myelin-associated transcripts that were significantly decreased in the NAc of cocaine abusers including myelin basic protein (MBP), proteolipid protein 1 (PLP) and myelinassociated oligodendrocyte basic protein (MOBP), which were confirmed by quantitative PCR.…”