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Updated: Aug 28, 2025
Spectral Confocal Imaging of Fluorescently tagged Nicotinic Receptors in Knock-in Mice with Chronic Nicotine Administration
Published on: February 10, 2012
Nicotine self-administration and ERK signaling are altered in RasGRF2 knockout mice
Ilaria Morella1,2, Veronika Pohořalá3, Claudia Calpe-López3
1Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, United Kingdom.
Abstract:
Ras/Raf/MEK/ERK (Ras-ERK) signaling has been demonstrated to play a role in the effects of drugs of abuse such as cocaine and alcohol, but has not been extensively examined in nicotine-related reward behaviors. We examined the role of Ras Guanine Nucleotide Releasing Factor 2 (RasGRF2), an upstream mediator of the Ras-ERK signaling pathway, on nicotine self-administration (SA) in RasGRF2 KO and WT mice. We first demonstrated that acute nicotine exposure (0.4 mg/kg) resulted in an increase in phosphorylated ERK1/2 (pERK1/2) in the striatum, consistent with previous reports. We also demonstrated that increases in pERK1/2 resulting from acute (0.4 mg/kg) and repeated (0.4 mg/kg, 10 daily injections) exposure to nicotine in WT mice were not present in RasGRF2 KO mice, confirming that RasGRF2 at least partly regulates the activity of the Ras-ERK signaling pathway following nicotine exposure. We then performed intravenous nicotine SA (0.03 mg/kg/infusion for 10 days) in RasGRF2 KO and WT mice. Consistent with a previous report using cocaine SA, RasGRF2 KO mice demonstrated an increase in nicotine SA relative to WT controls. These findings suggest a role for RasGRF2 in the reinforcing effects of nicotine, and implicate the Ras-ERK signaling pathway as a common mediator of the response to drugs of abuse.
Insights
Ras Guanine Nucleotide Releasing Factor 2 (RasGRF2) influences nicotine reward behaviors. Mice lacking RasGRF2 showed increased nicotine self-administration, suggesting its role in the reinforcing effects of nicotine.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The Ras/Raf/MEK/ERK (Ras-ERK) signaling pathway is implicated in the effects of various drugs of abuse.
- Its role in nicotine-related reward behaviors, however, remains less understood.
- Ras Guanine Nucleotide Releasing Factor 2 (RasGRF2) is an upstream regulator of the Ras-ERK pathway.
Purpose of the Study:
- To investigate the role of RasGRF2 in nicotine self-administration (SA) and its impact on the Ras-ERK signaling pathway.
- To determine if RasGRF2 mediates the effects of nicotine on reward behaviors.
Main Methods:
- Utilized RasGRF2 knockout (KO) and wild-type (WT) mice.
- Administered acute and repeated nicotine exposure to assess phosphorylated ERK1/2 (pERK1/2) levels in the striatum.
- Conducted intravenous nicotine SA in RasGRF2 KO and WT mice.
Main Results:
- Acute and repeated nicotine exposure increased pERK1/2 in WT mice, but not in RasGRF2 KO mice, indicating RasGRF2's role in nicotine-induced Ras-ERK pathway activation.
- RasGRF2 KO mice exhibited significantly higher nicotine SA compared to WT controls.
- These findings align with previous studies on cocaine SA.
Conclusions:
- RasGRF2 plays a significant role in modulating the reinforcing effects of nicotine.
- The Ras-ERK signaling pathway, regulated by RasGRF2, is implicated as a common mediator in the behavioral responses to drugs of abuse, including nicotine.
