Convergence of dopamine and glutamate signaling onto striatal ERK activation in response to drugs of abuse

Abstract

Despite their distinct targets, all addictive drugs commonly abused by humans evoke increases in dopamine (DA) concentration within the striatum. The main DA Guanine nucleotide binding protein couple receptors (GPCRs) expressed by medium-sized spiny neurons of the striatum are the D1R and D2R, which are positively and negatively coupled to cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, respectively. These two DA GPCRs are largely segregated into distinct neuronal populations, where they are co-expressed with glutamate receptors in dendritic spines. Direct and indirect interactions between DA GPCRs and glutamate receptors are the molecular basis by which DA modulates glutamate transmission and controls striatal plasticity and behavior induced by drugs of abuse. A major downstream target of striatal D1R is the extracellular signal-regulated kinase (ERK) kinase pathway. ERK activation by drugs of abuse behaves as a key integrator of D1R and glutamate NMDAR signaling. Once activated, ERK can trigger chromatin remodeling and induce gene expression that permits long-term cellular alterations and drug-induced morphological and behavioral changes. Besides the classical cAMP/PKA pathway, downstream of D1R, recent evidence implicates a cAMP-independent crosstalk mechanism by which the D1R potentiates NMDAR-mediated calcium influx and ERK activation. The mounting evidence of reciprocal modulation of DA and glutamate receptors adds further intricacy to striatal synaptic signaling and is liable to prove relevant for addictive drug-induced signaling, plasticity, and behavior. Herein, we review the evidence that built our understanding of the consequences of this synergistic signaling for the actions of drugs of abuse.

Keywords: ERK; GPCR; addiction; crosstalk; dopamine; receptors; signaling; striatum.

FIGURE 1

Cocaine, similarly to most drugs of abuse, produces long lasting brain changes, that relie on gene expression and new protein synthesis. These long-term neuronal adaptations take place in majority in DA-D1R expressing MSNs that belong to the direct pathway. The ERK pathway is central in this striatal plasticity, and detects a combination of glutamate and DA signals that are essential for long lasting modifications. Cocaine-induced ERK activation depends on complex cascade of phosphorylation events downstream D1-R. Importantly, the triggering event in ERK activation depends on a non-canonical signaling pathway that associates Fyn-induced phosphorylation of GluN2B and increases in calcium influx into D1-R MSNs. The duration and maintenance of ERK activation occurs via cAMP/PKA pathway. The cAMP/PKA pathway, downstream D1 receptors (left panel) triggers deactivation of phosphatases, PP1 on one hand via DARPP-32, and STEP on the other hand (Valjent et al., 2005). By controling the activity of the tyrosine kinase Fyn and the dual specificity protein kinase MEK, this signaling cascade intervenes in the state of phosphorylation of ERK downstream DA-D1R stimulation. However, we propose that triggering ERK activation depends on a “non-canonical signaling” pathway downstream D1-R (right panel). A cAMP-independent activation of Fyn produces tyrosine phosphorylation of GluB2B subunit of NMDA-Rs that in turn facilitates calcium influx (Pascoli et al., 2011a), and activation of the calcium-sensitive Ras-guanine releasing factor (Ras-GRF1) that activates the MEK/ERK pathway (Fasano and Brambilla, 2011). Upon cocaine stimulation ERK translocates to the nucleus where it controls epigenetic and genetic programs. Among the latter, the transcription factor Elk-1 is a component of the ternary complex factor, which binds to SRE (Besnard et al., 2011a). ERK1/2 also phosphorylates the nuclear kinase MSK1which appears to play a prominent role in phosphorylation of histone H3 and cAMP-response element-binding (CREB) protein (Brami-Cherrier et al., 2005). This leads to the expression of immediate-early genes, which are particularly sensitive to CREB (e.g., cFos) or ternary complex factor (e.g., Zif268 a.k.a. Egr-1). These two nuclear pathways downstream from ERK have distinct roles in long-term behavioral adaptations (see text). DA-GPCR and NMDAR, in particular D1R and GluN1, oligomerization has been documented in heterologous systems, hippocampal, and striatal tissues after cocaine exposure. The role of D1R-GluN1 interaction in ERK activation and downstream molecular events remains to be established.