Increased cocaine self-administration and prefrontal cortical dysregulation of glutamatergic and GABAergic signaling in a rat model for sensory processing sensitivity

Hesen, R.; Mottarlini, F.; Caffino, L.; Fennema, S.; Parolaro, S.; Guerrin, C.; Quednow, B. B.; Fumagalli, F.; Verheij, M.; Homberg, J. R.

doi:10.1101/2025.10.28.685083

bioRxiv · 10.1101/2025.10.28.685083

Increased cocaine self-administration and prefrontal cortical dysregulation of glutamatergic and GABAergic signaling in a rat model for sensory processing sensitivity

Hesen, R.·Mottarlini, F.·Caffino, L.·Fennema, S.·Parolaro, S.·Guerrin, C.·Quednow, B. B.·Fumagalli, F.·Verheij, M.·Homberg, J. R.

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Abstract

While all organisms are tuned to the environment, some are more sensitive than others. In humans, this is reflected by the trait sensory processing sensitivity (SPS), comprising 20-30% of the population, which is characterized by heightened emotional reactivity, deeper information processing, greater awareness of their environment, and susceptibility to overstimulation. It is expected but unproven that high SPS increases the risk for psychostimulant use. To clarify this, we selected Wistar rats on behavioral extremes related to SPS and subjected them to isolation, neutral, and enriched housing conditions, followed by cocaine self-administration (S/A). Subsequently, we investigated neurobiological differences in excitatory/inhibitory neurotransmission of the low- and high SPS-like rats by evaluating key glutamatergic and GABAergic proteins in the infralimbic (ILc) and prelimbic (PLc) subregions of the prefrontal cortex. High SPS-like rats displayed higher cocaine intake during 1h S/A training sessions in isolated versus social conditions, whereas low SPS-like rats showed similar intake across housing conditions. During 6h S/A sessions, high SPS-like rats displayed a higher cocaine intake regardless of housing and greater motivation for cocaine under a progressive ratio scheme. High SPS-like cocaine-naive rats exhibited lower expression of glutamatergic and GABAergic markers in ILc and PLc compared to low SPS-like cocaine-naive rats. The opposite occurred after cocaine exposure: low and high SPS-like rats showed lower and higher expression levels, respectively, compared to naive counterparts. In conclusion, these findings suggest that a high SPS-like trait with associated glutamatergic and GABAergic alterations might be a risk factor for the development of cocaine use disorder.

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Hesen, R., Mottarlini, F., Caffino, L., Fennema, S., Parolaro, S., Guerrin, C., Quednow, B. B., Fumagalli, F., Verheij, M., Homberg, J. R.. 2025-10-29. Increased cocaine self-administration and prefrontal cortical dysregulation of glutamatergic and GABAergic signaling in a rat model for sensory processing sensitivity. https://doi.org/10.1101/2025.10.28.685083

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