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PreprintCC BY-NC-NDbioRxiv

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

  • S. Davila
  • C. Starocelsky
  • C. Pino
  • F. Codocedo
  • C. Guzman-Munoz
  • B. Bossel
  • F. Novoa
  • M. Gonzalez
  • M. E. Andres
  • R. I. Gatica1
  1. 1Universidad Arturo Prat
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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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Cite

BibTeXRIS
BibTeX
@misc{davila2026individual,
  title = {{Individual differences in novelty-seeking behavior are modulated by GRK2/3 inhibition in rats}},
  author = {S. Davila and C. Starocelsky and C. Pino and F. Codocedo and C. Guzman-Munoz and B. Bossel and F. Novoa and M. Gonzalez and M. E. Andres and R. I. Gatica},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.25.753780},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.25.753780v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Individual differences in novelty-seeking behavior are modulated by GRK2/3 inhibition in rats
AU  - S. Davila
AU  - C. Starocelsky
AU  - C. Pino
AU  - F. Codocedo
AU  - C. Guzman-Munoz
AU  - B. Bossel
AU  - F. Novoa
AU  - M. Gonzalez
AU  - M. E. Andres
AU  - R. I. Gatica
PY  - 2026
DA  - 2026/09/25
PB  - bioRxiv
DO  - 10.64898/2026.09.25.753780
UR  - https://www.biorxiv.org/content/10.64898/2026.09.25.753780v1
AB  - 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.
ER  -