Effects of dopamine and NMDA receptors on cocaine-induced Fos expression in the striatum of Fischer rats

Abstract

Cocaine is an addictive psychostimulant that induces immediate early gene (IEG) expression by activating dopamine (DA) D1 and glutamate NMDA receptors in the striatum. In this study, we show that a single cocaine administration (30 mg/kg) time-dependently increases ERK phosphorylation, c-Fos and FosB protein expression, and MKP-1 phosphorylation (p-MKP-1), in the caudate-putamen (CPu) and nucleus accumbens (NAc) of Fischer rats. In the CPu, one hour after cocaine injection, the increase in c-Fos and FosB proteins expression is totally abolished by pre-administration of DA-D1 receptor antagonist, SCH23390. In the NAc, SCH23390 also inhibits cocaine-induced c-Fos protein expression. The pre-treatment of NMDA receptor antagonist, MK801, partially reduces cocaine-activated c-Fos protein expression in the CPu. Furthermore, the escalation of p-MKP-1 after acute cocaine administration is dependent on both DA-D1 and NMDA receptors activation in both brain regions examined. Our data suggest that cocaine may modulate ERK pathway signaling through the activation of DA-D1 and NMDA receptors, subsequently influencing the IEG protein expression.

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

“…In terms of PPs of pERK, acute cocaine has been shown to result in an increase of MKP-1 mRNA in the CPu and cortex 81 . In addition, depending on D1- and NMDA-Rs, the phosphorylation of MKP-1 was also enhanced in the CPu and NAc 45–60 min after acute cocaine, contributing to the transient pERK induction 76 . Further, the pSTEP was also downregulated after acute cocaine in the CPu with corresponding pERK induction 77 .…”

“…The increased pERK and its downstream targets including pMSK-1, pElk-1, pCREB, phosphorylation of GluN2B (pGluN2B) and IEGs by acute cocaine are dependent on the activation of MEK, D1-R/DARPP-32, and NMDA-R 51,63,66,67,70,71,74,76,78–80 . In addition to pMSK-1 induction, the pRSKs in the CPu are also increased by acute cocaine leading to the indirect activation of CREB by pERK 77,79 .…”

Cocaine-Induced Changes in NMDA Receptor Signaling

“…Cocaine exposure is known to increase ERK phosphorylation, an effect that requires activation of both the NMDAR and D1DRs (Valjent et al, 2000; Jenab et al, 2005; Sun et al, 2008; Jiao et al, 2007; Sarantis et al, 2009; Lu et al, 2006). Blockade of D2DR signaling does not interfere with cocaine activation of ERK (Valjent et al, 2000) while disruption of D3 receptor signaling in a D3 knock-out mouse has been shown to potentiate cocaine-induced phosphorylation of ERK (Jiao et al, 2007).…”

“…Activation of the ERK pathway by synergistic action of NMDARs and D1DRs may critically contribute to neuroadaptations precipitated by exposure to cocaine. Thus, transcription of the immediate early gene c-fos, that has been suggested to identify neuronal pools selectively activated by cocaine exposure (Berretta et al, 1992; Koya et al, 2012) may be dependent on ERK signaling and may be attenuated by D1DR and NMDAR blockade (Torres and Rivier, 1993; Jenab et al, 2003; Sun et al, 2008). Activation of the MAPK/ERK pathway has also been found to influence NMDAR subunit composition (Suzuki et al, 2005; Yuen et al, 2005; Rani et al, 2005).…”

NMDAR dependent intracellular responses associated with cocaine conditioned place preference behavior

“…These brain regions undergo cocaine-induced neuroplastic changes in intracellular signaling similar to those underlying long-term memory processes [5] [6] [7]. For example, ERK, CREB and Fos proteins are signaling molecules that have been implicated in memory processes [5] [7] [8] [9] [10] [11] [12]. …”