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

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.

AKT Kinase Activity Is Required for Lithium to Modulate Mood-Related Behaviors in Mice

“…Dopamine signaling driven by amphetamine or cocaine administration has been reported to induce a biphasic change in the phosphorylation state of AKT within striatum, with an initial increase in the level of pAKT(308) within 15 min followed by a decrease in pAKT after 60 min (Beaulieu et al, 2004;Brami-Cherrier et al, 2002;McGinty et al, 2008). Conversely, the dopamine receptor antagonist haloperidol induces an increase in striatal pAKT within 2 h (Emamian et al, 2004).…”

Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

“…Cocaine has been shown to act on G proteins and on signalling cascades in NAc, PFC and DStr (82)(83)(84) and G proteins have been implicated in the effects of prenatal exposure to cocaine (85). Downstream in the cascade, DA and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32) has been identified as a major target for DA and protein kinase A (PKA) and recently, the regulation of the specific state of DARPP-32 phosphorylation has provided an integrated mechanism for the study of dopaminoceptive neurons; both cocaine and caffeine act via DARPP-32 (cf 86 for review).…”

Differential susceptibility to ethanol and amphetamine sensitization in dopamine D3 receptor-deficient mice

“…Detailed reviews of other brain changes associated with sensitization have been described elsewhere (Anderson and Pierce 2005;McGinty et al 2008;Robinson and Kolb 2004;Tassin 2008). While the roles of D1 and D2 receptors (D1R and D2Rs) have received most of the attention, it has been recently hypothesized that the DA D3 receptor (D3R) may play an important role in the expression of behavioral sensitization (Guillin et al 2001;Richtand et al 2000Richtand et al , 2003Richtand et al , 2001.…”