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Highly simplified scheme of some common, chronic actions of drugs of abuse on the VTA–NAc circuit. The top panel (Control) shows a VTA dopamine neuron innervating an NAc GABA neuron, and glutamatergic inputs to the VTA and NAc neurons, under normal conditions. After chronic drug administration, several adaptations occur. In the VTA, drug exposure induces tyrosine hydroxylase (TH) and increases AMPA glutamatergic responses, possibly via induction of GluA1 and altered trafficking of AMPA receptors. As well, VTA dopamine neurons decrease in size in response to opiates or cannabinoids but not other drugs of abuse. In the NAc, all drugs of abuse induce the transcription factor ΔFosB, which may then mediate some of the shared aspects of addiction via regulation of numerous target genes. Several, but not all, drugs of abuse also induce CREB activity in this region, which Source: Reinforcement and Addictive Disorders, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3e may be mediated via upregulation of the cAMP pathway. Several additional changes have been found for stimulant exposure. Stimulants induce timeCitation:inNestler Hyman SE, responses Holtzman DM, Malenka RC. Molecular Neuropharmacology: A Foundation for ClinicalofNeuroscience, 3e; or 2015 dependent changes AMPAEJ, glutamatergic in NAc neurons, possibly mediated via altered trafficking or expression AMPA subunits of Available at: http://mhmedical.com/ Accessed: May 11, 2017 several postsynaptic density proteins (eg, PSD95, Homer-1). These changes in postsynaptic glutamate responses are associated with complex changes in © 2017 McGraw-Hill Education. All rights glutamatergicCopyright innervation of the NAc, effects mediated in partreserved via upregulation of AGS3 (activator of G protein signaling) in cortical neurons and downregulation of the cystine–glutamate transporter (system x−c) in glia in response to stimulants. Stimulants and nicotine also induce dendritic outgrowth