Linking cocaine to endoplasmic reticulum in striatal neurons: Role of glutamate receptors

Abstract

The endoplasmic reticulum (ER) controls protein folding. Accumulation of unfolded and misfolded proteins in the ER triggers an ER stress response to accelerate normal protein folding or if failed to cause apoptosis. The ER stress response is a conserved cellular response in mammalian cells and is sensitive to various physiological or pathophysiological stimuli. Recent studies unravel that this response in striatal neurons is subject to the tight modulation by psychostimulants. Cocaine and amphetamines markedly increased expression of multiple ER stress reporter proteins in the dorsal striatum (caudate putamen) and other basal ganglia sites. This evoked ER stress response is mediated by activation of group I metabotropic glutamate receptors and N-methyl-D-aspartate receptors. Converging Ca2+ signals derived from activation of these receptors activate the c-Jun N-terminal kinase pathway to evoke ER stress responses. The discovery of robust ER stress responses to stimulant exposure establishes a previously unrecognized stimulant-ER coupling. This inducible coupling seems to contribute to neurotoxicity of stimulants related to various neuropsychiatric and neurodegenerative illnesses. Elucidating cellular mechanisms linking cocaine and other stimulants to ER is therefore important for the development of therapeutic agents for treating neurological disorders resulted from stimulant toxicity.

Role of Endoplasmic Reticulum (ER) Stress in Cocaine-Induced Microglial Cell Death

“…Prolonged microglial activation however, not only causes neurotoxicity (Block & Hong, 2007; Block et al, 2007) but is also reported to result in cell apoptosis via different mechanisms (Ji et al, 2007; Yang et al, 2006; Yang et al, 2002). Recent studies have identified the effect of cocaine on ER stress with the role of glutamate receptors in mediating neurotoxicity (Choe et al, 2011). It has also been reported that in the rat dorsal striatum cocaine administration induces ER stress and activates c-Jun N-terminal kinase pathway resulting in cell death (Go et al, 2010).…”

A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol

“…ER is involved in the synthesis of proteins and lipids, in cellular detoxification and intracellular transport (Choe et al 2011). Cocaine administration increases extracellular levels of Glu in dorsal striatum that alter calcium homeostasis, inducing ER stress, by two different routes.…”

Interactions of Dopamine D1 and N-methyl-D-Aspartate Receptors Are Required for Acute Cocaine-Evoked Nitric Oxide Efflux in the Dorsal Striatum

“…Collectively, these findings suggest that dopamine D1 receptor-dependent Ca 2+ influx via NMDA receptor stimulation after acute injection of cocaine is required for the regulation of NO efflux in the dorsal striatum. It is important to note that repeated cocaine synergistically activates NMDA receptors via stimulation of dopamine and group I mGluRs, while in acute cocaine only dopamine signals contribute to activate NMDA receptors for the production of NO efflux in the dorsal striatum ( Choe et al, 2011 ).…”

“…Increased levels of extracellular dopamine and glutamate as a result of repeated cocaine administration interact with dopamine and glutamate receptors, respectively, that are integrated to the activation of N -methyl-D-aspartate (NMDA) receptors ( Schilström et al, 2006 ; Go et al, 2010 ). Accumulative evidence demonstrates that activation of NMDA receptors dynamically alters Ca 2+ -dependent neural activity as well as gene expression in the medium spiny neurons of the dorsal striatum ( Lee et al, 2010 ; Choe et al, unpublished observations ). These responses may cause a plastic change contributing to the addictive properties of cocaine.…”