Gatica, R. I. | bioRxiv Science

bioRxiv2026

Dissociation of Molecular and Behavioral Neuroadaptations Following Acute GRK2/3 Inhibition in Amphetamine-Treated Rats

BackgroundIndividual vulnerability to addiction is driven by neuroadaptations within dopaminergic circuits. G protein-coupled receptor kinases (GRKs), specifically GRK2 and GRK3 regulate D2 receptor (D2R) signaling and trafficking, but their role in amphetamine (AMPH)-induced locomotor sensitization remains unclear. This study aimed to determine whether GRK2/3 inhibition alters locomotor sensitization, and its associated molecular correlates across striatal regions. MethodsAdult rats (n = 39) were assigned to saline, acute AMPH, or repeated AMPH groups and received intraperitoneal administration of vehicle or the GRK2/3 inhibitor Cmpd101 (1.0 mg/kg intraperitoneally, i.p.). Locomotor activity was assessed under basal and injection conditions to evaluate sensitization. Protein levels of D2R, GRK2, and GRK5 were quantified across striatal regions using Western blot and analyzed with linear mixed models. ResultsCmpd101 did not significantly affect the acute hyperlocomotor effects of AMPH or the expression of AMPH sensitization. At the molecular level, Cmpd101 had no effect on D2R levels and produced selective, region-dependent changes in GRK2 and GRK5. Notably, GRK2/3 inhibition altered the relationship between protein expression and the degree of locomotor sensitization in a region-specific manner, rather than inducing consistent changes in absolute protein levels. ConclusionsGRK2/3 inhibition by Cmpd101 produces region-specific molecular effects and reshapes protein-behavior relationships without significantly altering locomotor sensitization. These findings support a model in which GRKs act as context-dependent modulators of dopaminergic signaling rather than direct drivers of behavioral output.

neuroscience↗

bioRxiv2022

Geometrical factors determining dendritic domain intersection between neurons: a modeling study

Overlap between dendritic trees of neighboring neurons is a feature of nervous systems. Overlap allows neurons to share common afferences and defines the topography of the circuit they belong to. Proximity is also a requirement for dendritic communication, including dendro-dendritic synaptic contacts. We simulated overlap dynamics between pairs of ventral tegmental area dopamine neurons, a population characterized by diverse and extensive dendritic domains. Using each neurons 3D convex hull (CH) as a proxy for dendritic domain size and shape, we examined intersection versus cell-to-cell distance curves for 210 pairs of neurons, and found that decay dynamics were diverse and complex, indicating that intersection between real dendritic domains does not comply with spherical or isotropic shape assumptions. We re-examined intersection dynamics for the same 210 pairs, but this time with either: a) a normalized volume corresponding to the average volume of all CHs, b) normalized shapes, using an average CH shape, or CHs from neurons exhibiting average dendritic distribution, isotropy or morphology, or c) a normalized cell body position, which we artificially placed in each CHs centroid. All three interventions significantly increased pair intersection and simplified decay dynamics, yet shape normalization had the strongest influence. Critically, shape uniformity was also the most relevant factor for increased dendritic domain pair intersection using the neurons original brain position and distances. We applied this experimental approach to other populations using reconstructions from neuromorpho.org database and found that shape and intersection dynamics were cell-type dependent. We conclude that intersection between neurons is not only maximized by proximity, but that individual-specific dendritic domain geometries have a profound impact too. The results predict that one biological solution for circuits requiring selective connectivity is to exhibit greater heterogeneity in size, cell body location, and especially shape, among their constituent neuronal elements.

neuroscience↗