Inactivation of ERK1/2 signaling in dopaminergic neurons by map kinase phosphatase MKP3 regulates dopamine signaling and motivation for cocaine

The mesolimbic dopamine system is a crucial component of reward and reinforcement processing, including the psychotropic effects of drugs of abuse such as cocaine. Drugs of abuse can activate intracellular signaling cascades that engender long-term molecular changes to the brain reward circuitry, which can promote further drug use. However, gaps remain about how the activity of these signaling pathways, such as ERK1/2 signaling, can affect cocaine-induced neurochemical plasticity and cocaine-associated behaviors specifically within dopaminergic cells. To enable specific modulation of ERK1/2 signaling in dopaminergic neurons of the ventral tegmental area, we utilize a viral construct that Cre-dependently expresses Map kinase phosphatase 3 (MKP3) to reduce the activity of ERK1/2, in combination with transgenic rats that express Cre in tyrosine hydroxylase (TH)-positive cells. Following viral transfection, we found an increase in the surface expression of the dopamine transporter (DAT), a protein associated with dopamine signaling, dopamine transmission, and cocaine-associated behavior. We found that inactivation of ERK1/2 reduced posttranslational phosphorylation of the DAT, attenuated the ability of cocaine to inhibit the DAT, and decreased motivation for cocaine without affecting associative learning as tested by conditioned place preference. Together, these results indicate that ERK1/2 signaling plays a critical role in shaping the dopamine response to cocaine and may provide additional insights into the function of dopaminergic neurons. Further, these findings lay important groundwork towards the assessment of how signaling pathways and their downstream effectors influence dopamine transmission and could ultimately provide therapeutic targets for treating cocaine use disorders.Significance StatementDopamine signaling is critically involved in mediating cocaine-associated behaviors. Here we demonstrate a role for the ERK1/2 signaling pathway and its associated phosphatase, MKP3, specifically in dopamine neurons in regulating dopamine signaling in rats. Furthermore, we demonstrate that this modulation of the ERK1/2 signaling pathway affects cocaine associated behaviors, including the motivation for cocaine. This work could help identify downstream targets of the ERK1/2 signaling pathway that could be involved in the development of cocaine use disorders.