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

Abstract

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.

Unraveling the Spatiotemporal Distribution of VPS13A in the Mouse Brain

“…While VPS13A seems not to be a core synaptic protein, previous studies suggested that VPS13A was modulated by the dopaminergic system [ 25 ]. Thus, we explored if VPS13A expression was modulated by the manipulation of specific neurotransmitter systems.…”

Individual differences in oxycodone addiction-like behaviors in a large cohort of heterogeneous stock (HS) rats

“…Previous studies have employed smaller numbers of animals, used inbred strains that were selectively bred to be high or low responders (52) and used the BXD recombinant inbred mouse panel (53) or Hybrid Mouse Diversity Panel (HMDP) (54). Moreover, several of these studies also used other proxies for addiction-like behaviors, like exploratory locomotion (52) or drug-induced motor effects (55) following passive drug injections.…”

“…The results from these studies might provide valuable information on the genetic behind individual differences in the vulnerability and resilience to oxycodone abuse and might also provide several addiction-like traits to be used for personalized diagnoses and/or novel treatment approaches. Finally, to facilitate investigating the biological origins of the difference in oxycodone addiction-like behaviors through epigenetic, transcriptomic (55), microbiome, neurobiological, or other mechanisms in HS rats beyond genetic factors, samples of these behavioral and genetically characterized animals were collected and made available free of charge through the oxycodone biobank (32).…”

“…Previous studies have employed smaller numbers of animals, used inbred strains that were selectively bred to be high or low responders (52) and used the BXD recombinant inbred mouse panel (53) or Hybrid Mouse Diversity Panel (HMDP) (54). Moreover, several of these studies also used other proxies for addiction-like behaviors, like exploratory locomotion (52) or drug-induced motor effects (55) following passive drug injections. This behavioral screening is the first high-throughput intravenous oxycodone self-administration study in HS rats, a genetically diverse population that self-administers oxycodone with high inter-individual variability and low intra-individual variability.…”

Drug addiction: from bench to bedside

“…As an experimental model, locomotor sensitisation is linked with increased tendency to self-administer psychostimulants [ 92 , 93 ] and with reinstatement of previously extinguished self-administration [ 94 , 95 ]. Whereas the existence of psychomotor sensitisation in humans is discussed [ 96 , 97 ], it is a key aspect of vulnerability to drug addiction and relapse, specifically drug craving or compulsive drug-seeking behaviour [ 91 , 98 , 99 ]. Still, locomotor sensitisation can be dissociated from the rewarding effect of a drug of abuse and conditioned place preference or self-administration are more appropriate experimental paradigms to test this aspect [ 100 – 102 ].…”