Computational model of extracellular glutamate in the nucleus accumbens incorporates neuroadaptations by chronic cocaine

Abstract Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glut...

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Bibliographic Details
Published in:	Neuroscience Vol. 158; no. 4; pp. 1266 - 1276
Main Authors:	Pendyam, S, Mohan, A, Kalivas, P.W, Nair, S.S
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 18-02-2009 Elsevier
Subjects:	Action Potentials - physiology Amino Acid Transport System X-AG - deficiency Anesthetics, Local - pharmacology Animals Biological and medical sciences Cocaine - pharmacology Computer Simulation Cystine - metabolism cystine-glutamate exchange Extracellular Fluid - drug effects Extracellular Fluid - metabolism Fundamental and applied biological sciences. Psychology glial geometries glutamate transporter Glutamic Acid - metabolism Medical sciences mGluR2/3 microdialysis Models, Biological Neuroglia - metabolism Neurology Neurons - physiology Neuropharmacology non-synaptic release Nucleus Accumbens - drug effects Nucleus Accumbens - metabolism Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Rats Receptors, Glutamate - physiology Synapses - physiology Synaptic Transmission - drug effects Synaptic Transmission - physiology Vertebrates: nervous system and sense organs D syn non-synaptic release cystine-glutamate exchange D sh and D ex, diffusion coefficient in the synapse, between the sheath and extracellular space prefrontal cortex metabotropic glutamate receptors glutamate transporter protein N-methyl- d-aspartic acid xc glial geometries PFC P syn G i microdialysis glutamate transporter glial sheath NMDA TTX P mGluR, and P ex, glutamate concentrations at synapse, mGluR and extracellular space mGluR2/3 tetrodotoxin glutamate transporters GLT-1 XAG Gi Dsyn Psyn CNS stimulant Psychotropic Central nervous system cystine- glutamate exchange Basal ganglion Glutamate Extracellular Encephalon Cystine Nucleus accumbens Chronic Microdialysis Excitatory aminoacid Neurotransmitter Drug of abuse Cocaine Models Release Carrier protein
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Summary:	Abstract Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glutamate release, glutamate elimination by glutamate transporters and diffusion, and negative feedback on synaptic release via metabotropic glutamate receptors (mGluR2/3). This framework was used to optimize the geometry of the glial sheath surrounding excitatory synapses, and by inserting physiological values, accounted for known stable extracellular, extrasynaptic concentrations of glutamate measured by microdialysis and glutamatergic tone on mGluR2/3. By using experimental values for cocaine-induced reductions in cystine-glutamate exchange and mGluR2/3 signaling, and by predicting the down-regulation of glutamate transporters, the computational model successfully represented the experimentally observed increase in glutamate that is seen in rats during cocaine-seeking. This model provides a mathematical framework for describing how pharmacological or pathological conditions influence glutamate transmission measured by microdialysis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to the research.
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2008.11.014