%A Wolf,Marina %A Tseng,Kuei-Yuan %D 2012 %J Frontiers in Molecular Neuroscience %C %F %G English %K Addiction,calcium-permeable AMPA receptor,Cocaine,Nucleus Accumbens,Ventral Tegmental Area %Q %R 10.3389/fnmol.2012.00072 %W %L %M %P %7 %8 2012-June-27 %9 Review %+ Dr Marina Wolf,Rosalind Franklin University of Medicine and Science,Neuroscience,3333 Green Bay Road,North Chicago,60064-3095,IL,United States,Marina.Wolf@rosalindfranklin.edu %# %! CP-AMPARs in the VTA and nucleus accumbens after cocaine exposure %* %< %T Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: when, how, and why? %U https://www.frontiersin.org/articles/10.3389/fnmol.2012.00072 %V 5 %0 JOURNAL ARTICLE %@ 1662-5099 %X In animal models of drug addiction, cocaine exposure has been shown to increase levels of calcium-permeable AMPA receptors (CP-AMPARs) in two brain regions that are critical for motivation and reward—the ventral tegmental area (VTA) and the nucleus accumbens (NAc). This review compares CP-AMPAR plasticity in the two brain regions and addresses its functional significance. In VTA dopamine neurons, cocaine exposure results in synaptic insertion of high conductance CP-AMPARs in exchange for lower conductance calcium-impermeable AMPARs (CI-AMPARs). This plasticity is rapid in onset (hours), GluA2-dependent, and can be observed with a single cocaine injection. Whereas it is short-lived after experimenter-administered cocaine, it persists for months after cocaine self-administration. In addition to strengthening synapses and altering Ca2+ signaling, CP-AMPAR insertion alters subsequent induction of plasticity at VTA synapses. However, CP-AMPAR insertion is unlikely to mediate the increased DA cell activity that occurs during early withdrawal from cocaine exposure. Metabotropic glutamate receptor 1 (mGluR1) exerts a negative influence on CP-AMPAR accumulation in the VTA. Acutely, mGluR1 stimulation elicits a form of LTD resulting from CP-AMPAR removal and CI-AMPAR insertion. In medium spiny neurons (MSNs) of the NAc, extended access cocaine self-administration is required to increase CP-AMPAR levels. This is first detected after approximately a month of withdrawal and then persists. Once present in NAc synapses, CP-AMPARs mediate the expression of incubation of cue-induced cocaine craving. The mechanism of their accumulation may be GluA1-dependent, which differs from that observed in the VTA. However, similar to VTA, mGluR1 stimulation removes CP-AMPARs from MSN synapses. Loss of mGluR1 tone during cocaine withdrawal may contribute to CP-AMPAR accumulation in the NAc. Thus, results in both brain regions point to the possibility of using positive modulators of mGluR1 as treatments for cocaine addiction.