Reversible Palmitoylation Regulates Surface Stability of AMPA Receptors in the Nucleus Accumbens in Response to Cocaine In Vivo

BackgroundPalmitoylation is emerging as one of the most important posttranslational modifications of excitatory synaptic proteins in mammalian brain cells. As a reversible and regulatable modification sensitive to changing synaptic inputs, palmitoylation of ionotropic glutamate receptors contributes not only to the modulation of normal receptor and synaptic activities but also to the pathogenesis of various neuropsychiatric disorders. Here we report that palmitoylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is regulated by the psychostimulant, cocaine, and such regulation is involved in cocaine action.MethodsWe tested palmitoylation and surface expression of AMPA receptors in striatal neurons and psychomotor behavior in response to cocaine in rats.ResultsAll four AMPA receptor subunits (GluA1-4 or GluR1-4) are palmitoylated in the nucleus accumbens (NAc) of adult rats. Among them, GluA1 and GluA3 are preferentially upregulated in their palmitoylation levels by a systemic injection of cocaine. The upregulated GluA1 and 3 palmitoylation is a transient and reversible event. Consequently, it increases the susceptibility of surface-expressed GluA1 and 3 to internalization trafficking, leading to a temporal loss of surface receptor expression. Blockade of the regulated GluA1/3 palmitoylation with a palmitoylation inhibitor in the local NAc reverses the loss of surface GluA1/3. The inhibition of palmitoylation concurrently sustains behavioral responsivity to cocaine as well.ConclusionsOur data identify a novel drug-palmitoylation coupling in the center of limbic reward circuits. Through palmitoylating selective AMPA receptor subunits, cocaine activity dependently regulates trafficking and subcellular localization of the receptor in NAc neurons and dynamically controls psychomotor sensitivity to the psychoactive drug in vivo.