Involvement of the Extracellular Signal-Regulated Kinase Cascade for Cocaine-Rewarding Properties

Abstract

A central feature of drugs of abuse is to induce gene expression in discrete brain structures that are critically involved in behavioral responses related to addictive processes. Although extracellular signal-regulated kinase (ERK) has been implicated in several neurobiological processes, including neuronal plasticity, its role in drug addiction remains poorly understood. This study was designed to analyze the activation of ERK by cocaine, its involvement in cocaine-induced early and long-term behavioral effects, as well as in gene expression. We show, by immunocytochemistry, that acute cocaine administration activates ERK throughout the striatum, rapidly but transiently. This activation was blocked when SCH 23390 [a specific dopamine (DA)-D1 antagonist] but not raclopride (a DA-D2 antagonist) was injected before cocaine. Glutamate receptors of NMDA subtypes also participated in ERK activation, as shown after injection of the NMDA receptor antagonist MK 801. The systemic injection of SL327, a selective inhibitor of the ERK kinase MEK, before cocaine, abolished the cocaine-induced ERK activation and decreased cocaine-induced hyperlocomotion, indicating a role of this pathway in events underlying early behavioral responses. Moreover, the rewarding effects of cocaine were abolished by SL327 in the place-conditioning paradigm. Because SL327 antagonized cocaine-induced c-fos expression and Elk-1 hyperphosphorylation, we suggest that the ERK intracellular signaling cascade is also involved in the prime burst of gene expression underlying long-term behavioral changes induced by cocaine. Altogether, these results reveal a new mechanism to explain behavioral responses of cocaine related to its addictive properties.

Alcohol Relapse Induced by Discrete Cues Activates Components of AP-1 Transcription Factor and ERK Pathway in the Rat Basolateral and Central Amygdala

“…Phospho-c-Jun (P-c-Jun) expression: The activity of cJun protein as a transcription regulator is mainly regulated by its phosphorylated state (Hibi et al, 1993;Gupta et al, 1996;Sgambato et al, 1998;Valjent et al, 2000). Thus, we analyzed the intensity of the phosphorylated form of c-Jun (Ser73).…”

“…The P-ERK1/2 immunoreactivity was observed within nuclei of the cells, cell bodies as well as in neuropil (Figure 2e). Since nuclear localization of activated ERK1/2 is believed to be associated with the control of gene expression (Valjent et al, 2000), only immunostained cell nuclei were counted. The alcohol and control animals were killed immediately after the 30-min reinstatement session and the naive animals were anesthetized 30 min after the brief handling episode.…”

“…The alcohol and control animals were killed immediately after the 30-min reinstatement session and the naive animals were anesthetized 30 min after the brief handling episode. This time point was chosen due to the very short half-life of the phosphorylated forms of ERKs (Valjent et al, 2000).…”

“…It can also be speculated that c-Fos expression induced by drugrelated cues is driven by ERK-dependent phosphorylation of Elk-1 and CREB transcription factors (Sgambato et al, 1998;Vanhoutte et al, 1999;Valjent et al, 2000). c-Fos protein expression and the ERK pathway have been shown to be activated in the amygdala after reexposure to drugpaired stimuli (Neisewander et al, 2000;Lu et al, 2005), what may suggest the involvement of ERK pathway in the regulation of c-Fos expression.…”

Quantitative Changes in Gαolf Protein Levels, but not D1 Receptor, Alter Specifically Acute Responses to Psychostimulants

“…A good candidate was the mitogenactivated protein kinase (MAP kinase) extracellular signal-regulated kinase (ERK), which is activated in the striatum after acute injection of psychostimulants (Valjent et al, 2000. ERK activation is dependent on D1R activation since it is prevented by a D1R antagonist or in D1R knockout mice (Valjent et al, 2000.…”