Abstract
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.
Highlights
One way to classify AMPA receptors is according to whether or not they contain the GluA2 subunit
Similar conclusions about the functional significance of CP-AMPAR synaptic incorporation were reached using NR1DATCreERT2 mice in which NMDARs are lacking in DA neurons (Mameli et al, 2009)
Recordings performed within 48 h of the behavioral test revealed CP-AMPARs in ventral tegmental area (VTA) DA neurons and nucleus accumbens (NAc) shell MSN in the control cocaine-exposed mice, but not in the NR1DATCreERT2 mice
Summary
Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: when, how, and why?. 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). 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. 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 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.
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