Glycogen synthase kinase-3 signaling in cellular and behavioral responses to psychostimulant drugs

Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase implicated in numerous physiological processes and cellular functions through its ability to regulate the function of many proteins, including transcription factors and structural proteins. GSK-3β has been demonstrated to function as a regulator of multiple behavioral processes induced by drugs of abuse, particularly psychostimulant drugs. In this review, we provide an overview of the regulation of GSK-3β activity produced by psychostimulants, and the role of GSK-3β signaling in psychostimulant-induced behaviors including drug reward, associative learning and memory which play a role in the maintenance of drug-seeking. Evidence supports the conclusion that GSK-3β is an important component of the actions of psychostimulant drugs and that GSK-3β is a valid target for developing novel therapeutics. Additional studies are required to examine the role of GSK-3β in distinct cell types within the mesolimbic and memory circuits to further elucidate the mechanisms related to the acquisition, consolidation, and recall of drug-related memories, and potentially countering neuroadaptations that reinforce drug-seeking behaviors that maintain drug dependence.

Keywords: Addiction; Amphetamine; Cocaine; Drug reward; Mesolimbic pathway; Neuroplasticity.

Figure 1:. Schematic depiction of the mesocorticolimbic circuit in the rodent brain important for the development and maintenance of behaviors underlying drug-seeking and influenced by GSK-3β activity.

The ventral tegmental area (VTA) sends dopaminergic projections (purple) to the nucleus accumbens (NAc), prefrontal cortex (PFC), and basolateral amygdala (BLA). Glutamatergic projections from the PFC, amygdala, and hippocampus (green) innervate the NAc to modulate GABAergic transmission to the VTA (blue), as well as directly regulate VTA neuronal activity. Additional structures have been omitted for clarity.

Figure 2.. GSK-3β activity is regulated by several neurotransmitters whose synaptic levels are affected by psychostimulants.

Through their effects on dopamine, serotonin and glutamate transmission, psychostimulants can regulate the activity of GSK-3β. Examples of upstream signaling pathways resulting in GSK-3β regulation are shown. GSK-3β has numerous potential substrates including transcription factors, structural proteins, receptors, signaling molecules and metabolic enzymes. As such, GSK-3β well-positioned to influence neuroplasticity, gene transcription, and learning and memory processes. βArr, beta-arrestin; PKA, protein kinase A; PLC, phospholipase C; PP2, protein phosphatase 2; PP1, protein phosphatase 1; PI3K, phosphatidylinositol 3-kinase; TF, transcription factor; p, phosphorylated.

Figure 3:. Potential signaling pathway underlying reconsolidation of stimulant-associated contextual memories.

Activation of NMDA receptors in the nucleus accumbens and hippocampus following the reactivation of cocaine-contextual memories stimulates a protein phosphatase cascade, through PP2B and PP1, resulting in dephosphorylation of Akt and GSK-3β. GSK-3β can regulate mTORC1 and CREB. Arrows indicate changes in enzyme activity following reactivation of cocaine-associated memories. GSK, glycogen synthase kinase; mTORC1, mammalian target of rapamycin complex 1; PI3K, phosphatidylinositol 3-kinase; PP1, protein phosphatase 1; PP2B, protein phosphatase 2B. CREB, cAMP response element-binding protein. Adapted from Shi et al., 2014 & .