Individual differences in novelty-seeking behavior are modulated by GRK2/3 inhibition in rats

Davila, S.; Starocelsky, C.; Pino, C.; Codocedo, F.; Guzman-Munoz, C.; Bossel, B.; Novoa, F.; Gonzalez, M.; Andres, M. E.; Gatica, R. I.

doi:10.64898/2026.09.25.753780

bioRxiv · 10.64898/2026.09.25.753780

Individual differences in novelty-seeking behavior are modulated by GRK2/3 inhibition in rats

Davila, S.·Starocelsky, C.·Pino, C.·Codocedo, F.·Guzman-Munoz, C.·Bossel, B.·Novoa, F.·Gonzalez, M.·Andres, M. E.·Gatica, R. I.

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Abstract

Background and Purpose High novelty-seeking is an endophenotype associated with greater vulnerability to drug addiction, marked by a hyperdopaminergic state and reduced dopamine D2 receptor (D2R) levels in the dorsal striatum (DS). G protein-coupled receptor kinases (GRKs) regulate desensitization, internalization, and recycling of these receptors, including the D2R. This study investigated the relevance of GRK2 and 3 (GRK2/3) in novelty-seeking behavior and striatal dopamine dynamics. Experimental Approach Individual novelty-seeking trait was assessed in Sprague Dawley rats using an open-field test. D2R, GRK2, and GRK5 protein levels were measured in synaptosomal DS samples using Western Blot. Pharmacological inhibition of GRK2/3 was assessed using Cmpd101. We tested the effect of systemic Cmpd101 administration on contextual novelty discrimination and local Cmpd101 perfusion on baseline and stimulus-evoked extracellular dopamine (DA) levels in the DS. Key Results Locomotor activity in a novel environment inversely correlated with the synaptosomal GRK2 and D2R protein levels in the DS. Systemic Cmpd101 treatment modulated the locomotor discrimination index in a novelty phenotype-dependent manner. Moreover, local Cmpd101 perfusion in the DS elicited a sustained elevation in basal extracellular dopamine levels and significantly blunted subsequent stimulus-evoked DA release, both effects independent of novelty-seeking phenotype. Conclusion and Implications Together, our findings link GRK2/3 signaling to individual differences in novelty-seeking and striatal dopaminergic function. These results suggest a potential relevance to drug addiction vulnerability.

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Davila, S., Starocelsky, C., Pino, C., Codocedo, F., Guzman-Munoz, C., Bossel, B., Novoa, F., Gonzalez, M., Andres, M. E., Gatica, R. I.. 2026-10-01. Individual differences in novelty-seeking behavior are modulated by GRK2/3 inhibition in rats. https://doi.org/10.64898/2026.09.25.753780

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