Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances

Florence Vorspan (1, 2, 3) , Romain Icick (2, 4) , Nawel Mekdad (2) , Cindie Courtin (2) , Vanessa Bloch (1, 2, 3) , Frank Bellivier (2, 4) , Jean-Louis Laplanche (3) , Nathalie Prince (2) , Dmitry Pishalin (2) , Cyril Firmo (5) , Corinne Blugeon (5) , Bruno Mégarbane (2) , Cynthia Marie-Claire (2) , Nadia Benturquia (6)

1 UPCité - Université Paris Cité
2 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
3 Hôpital Lariboisière-Fernand-Widal [APHP]
4 Service de Psychiatrie et de Médecine Addictologique [AP-HP, GH Saint-Louis-Lariboisière-F.Widal]
5 Genomique ENS - GenomiqueENS
6 NAVVEC - UM 81 (UMR 8206/ U705) - Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique

Motor disturbances strongly increase the burden of cocaine use disorder (CUDs). The objective of our translational study was to identify the genes and biological pathways underlying the tolerance to cocaine-induced motor effects. In a 5-day protocol measuring motor tolerance to cocaine in rats (N = 40), modeling the motor response to cocaine in patients, whole-genome RNA sequencing was conducted on the ventral and dorsal striatum to prioritize a genetic association study in 225 patients with severe CUD who underwent thorough phenotypic (cocaine-induced hyperlocomotion, CIH; and cocaine-induced stereotypies, CIS) and genotypic [571,000 polymorphisms (SNPs)] characterization. We provide a comprehensive description of the rat striatal transcriptomic response to cocaine in our paradigm. Repeated vs. acute cocaine binge administration elicited 27 differentially expressed genes in the ventral striatum and two in the dorsal striatum. One gene, Lrp1b, was differentially expressed in both regions. In patients, LRP1B was significantly associated with both CIS and CIH. CIH was also associated with VPS13A, a gene involved in a severe neurological disorder characterized by hyperkinetic movements. The LRP1B minor allele rs7568970 had a significant protective effect against CIS (558 SNPs, Bonferroni-corrected p = 0.02) that resisted adjustment for confounding factors, including the amount of cocaine use (adjusted beta = −0.965 and −2.35 for heterozygotes and homozygotes, respectively, p < 0.01). Using hypothesis-free prioritization of candidate genes along with thorough methodology in both the preclinical and human analysis pipelines, we provide reliable evidence that LRP1B and VPS13A are involved in the motor tolerance to cocaine in CUD patients, in line with their known pathophysiology.

Domaines: Sciences du Vivant [q-bio]

Florence Vorspan, Romain Icick, Nawel Mekdad, Cindie Courtin, Vanessa Bloch, et al.. Translational study of the whole transcriptome in rats and genetic polymorphisms in humans identifies LRP1B and VPS13A as key genes involved in tolerance to cocaine-induced motor disturbances. Translational Psychiatry, 2020, 10 (1), pp.381. ⟨10.1038/s41398-020-01050-7⟩. ⟨hal-03893616⟩