Relationship of ERK1/2 phosphorylation to D1 dopamine receptor activation, behavioral sensitization, and structural plasticity in the neonate 6-hydroxydopamine-lesioned rat Public Deposited

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  • March 21, 2019
  • Papadeas, Sophia T.
    • Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum
  • Repeated administration of the D1-dopamine receptor agonist SKF-38393 to adult rats lesioned with 6-hydroxydopamine (6-OHDA) as neonates results in increasingly greater behavioral responsiveness with each dose, a phenomenon known as "priming of D1 receptor sensitivity." This dissertation examines the role of the extracellular signal-regulated kinase 1/2 (ERK), an intracellular mediator of signal transduction, in D1-dopamine receptor activation, priming of behavioral sensitivity, and structural plasticity in the neonate-lesioned rat. Using immunohistochemistry, I found that repeated administration of SKF-38393 produced a prolonged increase in phosphorylated (phospho-) ERK in the medial prefrontal cortex (mPFC) of neonate-lesioned rats. A corresponding increase in the phosphorylation of CREB (cyclic AMP-response element binding protein), a downstream target of ERK signaling, implied a functional consequence for the prolonged ERK activation in mPFC. Pretreatment with the D1 antagonist SCH-23390, but not the 5-HT2 antagonist ketanserin, prior to each dose of SKF-38393 blocked the persistently increased phospho-ERK. The competitive and non-competitive NMDA receptor antagonists MK-801 and CGS-19755, which inhibit the induction of behavioral sensitization in neonate-lesioned rats, also blocked the increased phospho-ERK. In addition, intracerebroventricular (ICV) and systemic administration of SL327 or PD98059, inhibitors of the upstream ERK activator MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2), prior to each SKF-38393 treatment eliminated mPFC phospho-ERK. Computer-monitored activity chambers and visual observation both revealed that the global MEK inhibition increased horizontal behavior and decreased certain stereotyped behaviors after an additional sensitizing dose of SKF-38393. In addition, intra-mPFC infusions with PD98059 only decreased stereotyped behaviors in primed animals. Finally, using immunohistochemistry for MAP2 combined with recombinant adenovirus (AAV) transduction of green fluorescent protein (GFP) in mPFC neurons, I found that repeated administration of SKF-38393 produces robust, long-lasting changes in the morphology of dendrites in mPFC of neonate-lesioned rats. Pretreatment with SL327 and PD98059 prevented these changes, suggesting that the alterations in dendritic morphology require ERK pathway activation. Collectively, these results demonstrate that D1 and NMDA receptors cooperatively produce prolonged ERK pathway activation in mPFC of primed neonate-lesioned rats, and suggest that persistent ERK phosphorylation in mPFC plays a pivotal role in long-lasting behavioral and structural adaptations in these animals.
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  • Breese, George R.
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  • University of North Carolina at Chapel Hill
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