Regulation of psychostimulant‐induced signaling and gene expression in the striatum

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Abstract
J. Neurochem. (2008) 104, 1440–1449. Abstract Amphetamine (AMPH) and cocaine are indirect dopamine agonists that activate multiple signaling cascades in the striatum. Each cascade has a different subcellular location and duration of action that depend on the strength of the drug stimulus. In addition to activating D1 dopamine‐Gs‐coupled‐protein kinase A signaling, acute psychostimulant administration activates extracellular‐regulated kinase transiently in striatal cells; conversely, inhibition of extracellular‐regulated kinase phosphorylation decreases the ability of psychostimulants to elevate locomotor behavior and opioid peptide gene expression. Moreover, a drug challenge in rats with a drug history augments and prolongs striatal extracellular‐regulated kinase phosphorylation, possibly contributing to behavioral sensitization. In contrast, AMPH activates phosphoinositide‐3 kinase substrates, like protein kinase B/Akt, only in the nuclei of striatal cells but this transient increase induced by AMPH is followed by a delayed decrease in protein kinase B/Akt phosphorylation whether or not the rats have a drug history, suggesting that the phosphoinositide‐3 kinase pathway is not essential for AMPH‐induced behavioral sensitization. Chronic AMPH or cocaine also alters the regulation of inhibitory G protein‐coupled receptors in the striatum, as evident by a prolonged decrease in the level of regulator of G protein signaling 4 after non‐contingent or contingent (self‐administered) drug exposure. This decrease is exacerbated in behaviorally sensitized rats and reversed by re‐exposure to a cocaine‐paired environment. A decrease in regulator of G protein signaling 4 levels may weaken its interactions with metabotropic glutamate receptor 5, Gαq, and phospholipase C β that may enhance drug‐induced signaling. Alteration of these protein–protein interactions suggests that the striatum responds to psychostimulants with a complex molecular repertoire that both modulates psychomotor effects and leads to long‐term neuroadaptations.

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