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BackgroundHigh-Runner (HR) mice, selectively bred for increased voluntary wheel running behavior, exhibit heightened motivation to run. Exercise has been shown to influence hippocampal long-term potentiation (LTP) and memory, and is neuroprotective in several neurodegenerative diseases. ObjectiveThis study aimed to determine the impact of intense running in HR mice with wheel access on hippocampal LTP, compared to HR mice without wheels and non-selected control (C) mice with/without wheels. Additionally, we investigated the involvement of D1/D5 receptors and the dopamine transporter (DAT) in LTP modulation and examined levels of these proteins in HR and C mice. MethodsAdult female HR and C mice were individually housed with/without running wheels for at least two weeks. Hippocampal LTP of extracellular field excitatory postsynaptic potentials (fEPSPs) was measured in area CA1, and SKF-38393 (D1/D5 receptor agonist) and GBR 12909 (DAT inhibitor) were used to probe the role of D1/D5 receptors and DAT in LTP differences. Western blot analyses assessed D1/D5 receptor and DAT expression in the hippocampus, prefrontal cortex, and cerebellum. ResultsHR mice with wheel access showed significantly increased hippocampal LTP compared to those without wheels and to C mice with/without wheels. Treatment with SKF-38393 or GBR 12909 prevented the heightened LTP in HR mice with wheels, aligning it with levels in C mice. Hippocampal D1/D5 receptor levels were lower, and DAT levels were higher in HR mice compared to C mice. No significant changes were observed in other brain regions. ConclusionsThe increased hippocampal LTP seen in HR mice with wheel access may be related to alterations in dopaminergic synaptic transmission that underlie the neurophysiological basis of hyperactivity, motor disorders, and/or motivation.