Translational study of the whole transcriptome inrats and genetic polymorphisms in humansidentifiesLRP1BandVPS13Aas key genes involvedin tolerance to cocaine-induced motordisturbances

Abstract :

Motor disturbances strongly increase the burden of cocaine use disorder (CUDs). The objective of our translationalstudy was to identify the genes and biological pathways underlying the tolerance to cocaine-induced motor effects. Ina 5-day protocol measuring motor tolerance to cocaine in rats (N=40), modeling the motor response to cocaine inpatients, whole-genome RNA sequencing was conducted on the ventral and dorsal striatum to prioritize a geneticassociation study in 225 patients with severe CUD who underwent thorough phenotypic (cocaine-inducedhyperlocomotion, 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 ourparadigm. Repeated vs. acute cocaine binge administration elicited 27 differentially expressed genes in the ventralstriatum and two in the dorsal striatum. One gene,Lrp1b, was differentially expressed in both regions. In patients,LRP1Bwas significantly associated with both CIS and CIH. CIH was also associated withVPS13A, a gene involved in asevere neurological disorder characterized by hyperkinetic movements. TheLRP1Bminor allele rs7568970 had asignificant protective effect against CIS (558 SNPs, Bonferroni-correctedp=0.02) that resisted adjustment forconfounding factors, including the amount of cocaine use (adjusted beta=0.965 and2.35 for heterozygotes andhomozygotes, respectively,p< 0.01). Using hypothesis-free prioritization of candidate genes along with thoroughmethodology in both the preclinical and human analysis pipelines, we provide reliable evidence thatLRP1BandVPS13Aare involved in the motor tolerance to cocaine in CUD patients, in line with their known pathophysiology


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