Ketamine induces opposite changes in AMPA receptor calcium permeability in the ventral tegmental area and nucleus accumbens

• Ketamine elicits rapid and durable antidepressant actions in treatment-resistant patients with mood disorders such as major depressive disorder and bipolar depression. The mechanisms might involve the induction of metaplasticity in brain regions associated with reward-related behaviors, mood, and hedonic drive, particularly the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We have examined if ketamine alters the insertion of the GluA2 subunit of AMPA receptors (AMPAR), which determines calcium permeability of the channel, at glutamatergic synapses onto dopamine (DA) neurons in the VTA and spiny projection neurons (SPNs) in the Core region of the NAc. Mice received one injection of either saline or a low dose of ketamine 24 h before electrophysiological recordings were performed. We found that GluA2-lacking calcium-permeable (CP) AMPARs were present in DA neurons in the VTA of mice treated with saline, and that ketamine-induced the removal of a fraction of these receptors. In NAc SPNs, ketamine induced the opposite change, i.e., GluA2-lacking CP-AMPARs were inserted at glutamatergic synapses. Ketamine-induced metaplasticity was independent of group I metabotropic glutamate receptors (mGluRs) because an agonist of these receptors had similar effects on glutamatergic transmission in mice treated with saline and in mice treated with ketamine in both VTA DA neurons and in the NAc. Thus, ketamine reduces the insertion of CP-AMPARs in VTA DA neurons and induces their insertion in the NAc. The mechanism by which ketamine elicits antidepressant actions might thus involve an alteration in the contribution of GluA2 to AMPARs thereby modulating synaptic plasticity in the mesolimbic circuit.

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