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

TLDR

Drugs of abuse induce gene expression in brain regions linked to addiction, yet the contribution of extracellular signal‑regulated kinase (ERK) to drug‑induced plasticity remains poorly understood. This study aimed to determine how cocaine activates ERK and whether this signaling underlies both acute and long‑term behavioral and gene‑expression changes. The authors used immunocytochemistry to map ERK activation, and pharmacological interventions—including the D1 antagonist SCH 23390, the NMDA antagonist MK 801, and the MEK inhibitor SL327—to dissect the pathway’s role. Cocaine rapidly and transiently activated ERK throughout the striatum; blockade by SCH 23390, MK 801, or SL327 abolished this activation, reduced cocaine‑induced hyperlocomotion and place‑conditioning, and suppressed c‑fos and Elk‑1 phosphorylation, demonstrating that ERK signaling mediates cocaine’s rewarding and gene‑expression effects.

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.