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Published on: July 30, 2013
Knockout of ERK1 enhances cocaine-evoked immediate early gene expression and behavioral plasticity
Susan M Ferguson1, Stefania Fasano, Pengwei Yang
1Neuroscience Program, University of Michigan, Ann Arbor, MI 48109-1109, USA.
Abstract:
The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.
Insights
Removing ERK1 in mice enhances cocaine-induced behaviors and gene expression, suggesting ERK2 signaling drives addiction-related neural plasticity. This highlights ERK isoforms' roles in cocaine
Area of Science:
- Neuroscience
- Molecular Biology
- Addiction Research
Background:
- Cocaine addiction is linked to lasting neural changes in the brain's reward pathways.
- The Raf-MEK-ERK signaling pathway is involved in cocaine's effects, but the roles of ERK1 and ERK2 are unclear.
Purpose of the Study:
- To investigate the specific roles of ERK1 and ERK2 isoforms in cocaine-induced behavioral plasticity and neurobiological adaptations.
- To determine how altering ERK signaling affects cocaine's impact on the brain and behavior.
Main Methods:
- Utilized ERK1-deficient mice to examine the effects of ERK1 absence on cocaine responses.
- Administered cocaine to assess psychomotor sensitization and conditioned place preference.
- Analyzed cocaine-evoked gene expression in mesocorticolimbic brain regions.
- Employed pharmacological blockade of ERK signaling to study its influence on sensitization.
Main Results:
- Deletion of ERK1, leading to increased ERK2 signaling, facilitated cocaine-induced psychomotor sensitization and conditioned place preference.
- Pharmacological blockade of ERK signaling reduced cocaine-induced psychomotor sensitization.
- Cocaine-evoked gene expression was potentiated in ERK1-deficient mice.
Conclusions:
- ERK signaling alterations significantly influence the neurobiological effects of cocaine and its capacity to induce lasting behavioral changes.
- Enhanced ERK2 signaling following repeated cocaine exposure may contribute to addiction-related neural plasticity.
- Findings suggest specific ERK isoforms play critical roles in the development and maintenance of cocaine addiction.
