Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: when, how, and why?

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 Ca(2+) 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.

Keywords: addiction; calcium-permeable AMPA receptor; cocaine; nucleus accumbens; ventral tegmental area.

Figure 1

Changes in AMPAR-mediated synaptic transmission rectification index (RI) measured in NAc core MSNs following withdrawal from extended access cocaine self-administration. Compared to saline-treated animals (n = 17, pooled from withdrawal days [WD] 35–70), no apparent changes in RI were observed during the first month of withdrawal from cocaine self-administration (WD16, n = 5; WD25, n = 5). However, a significant increase in RI was observed after a month of withdrawal (WD30–35, n = 7). The increased RI persisted through WD70 (WD35–45, n = 10; WD45–55, n = 13; WD55–70, n = 7), the latest time-point measured. ^*P < 0.01 vs. saline, Tukey post-hoc test after significant ANOVA.