Cellular distribution of AMPA receptor subunits and mGlu5 following acute and repeated administration of morphine or methamphetamine

Abstract

Ionotropic AMPA receptors (AMPAR) and metabotropic glutamate group I subtype 5 receptors (mGlu5) mediate neuronal and behavioral effects of abused drugs. mGlu5 stimulation increases expression of striatal-enriched tyrosine phosphatase isoform 61 (STEP 61 ) which internalizes AMPARs. We determined the rat brain profile of these proteins using two different classes of abused drugs, opiates, and stimulants. STEP 61 levels, and cellular distribution/expression of AMPAR subunits (GluA1, GluA2) and mGlu5, were evaluated via a protein cross-linking assay in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP) harvested 1 day after acute, or fourteen days after repeated morphine (8 mg/kg) or methamphetamine (1 mg/kg) (treatments producing behavioral sensitization). Acute morphine decreased GluA1 and GluA2 surface expression in mPFC and GluA1 in NAc. Fourteen days after repeated morphine or methamphetamine, mGlu5 surface expression increased in VP. In mPFC, mGlu5 were unaltered; however, after methamphetamine, STEP 61 levels decreased and GluA2 surface expression increased. Pre-treatment with a mGlu5-selective negative allosteric modulator, blocked methamphetamine-induced behavioral sensitization and changes in mPFC GluA2 and STEP 61 . These data reveal (i) region-specific distinctions in glutamate receptor trafficking between acute and repeated treatments of morphine and methamphetamine, and (ii) that mGlu5 is necessary for methamphetamineinduced alterations in mPFC GluA2 and STEP 61 . Keywords: GluA1, GluA2, metabotropic glutamatergic receptors, MTEP, sensitization, STEP 61 . J. Neurochem. (2013) 126, 503-517.Repeated administration of opiates and psychomotor stimulants enhances motor activity beyond that induced by a single injection, a phenomenon termed behavioral sensitization. Sensitization can persist long after the cessation of drug administration. The circuitry that underlies behavioral sensitization includes the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP). The mPFC is implicated in the development (Wolf et al. 1995;Pierce et al. 1998;Cador et al. 1999;Hao et al. 2007), while the NAc mediates maintenance and expression (Pierce and Kalivas 1997; Vanderschuren and Kalivas 2000) of sensitization. Our laboratory revealed that the VP is critical for the development, maintenance, and expression of sensitization (Johnson and Napier 2000;McDaid et al. 2005McDaid et al. , 2006aMickiewicz et al. 2009).Behavioral sensitization is thought to reflect neuroadaptations that often involve glutamatergic transmission. The NAc receives glutamatergic input from the mPFC (Christie et al. 1985), amygdala, and hippocampus (Mulder et al. 1998 Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GluA1, AMPA glutamate receptor subunit 1; GluA2, AMPA glutamate receptor subunit 2; mGlu5, metabotropic glutamate receptor group 1 subtype 5; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; STEP 61 , striatal-enriched tyrosine phosph...

AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving

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