Netrin G1: its downregulation in the nucleus accumbens of cocaine‐conditioned mice and genetic association in human cocaine dependence

Abstract

Netrin G1 is a presynaptic ligand involved in axonal projection. Although molecular mechanisms underlying cocaine addiction are still poorly understood, Netrin G1 might have a role as a regulator of anxiety, fear and spatial memory, behavioural traits impaired in the context of cocaine exposure. In this study, the Netrin G1 (Ntng1) expression was investigated in the nucleus accumbens of mice primarily conditioned to cocaine using a place preference paradigm. A genetic association study was then conducted on 146 multiplex families of the Collaborative study on Genetics of Alcoholism, in which seven single nucleotide polymorphisms located in the NTNG1 gene were genotyped. NTNG1 expression levels were also quantified in BA10, BA46 and the cerebellum of healthy controls (with no Axis 1 psychopathology). Decreased Ntng1 expression was initially observed in the nucleus accumbens of mice conditioned to cocaine. Significant genetic family-based associations were detected between NTNG1 polymorphisms and cocaine dependence. NTNG1 expression in BA10, BA46 and the cerebellum, however, were not significantly associated with any allele or haplotype of this gene. These results confirm that Ntng1 expression is disturbed in the nucleus accumbens of mice, after cocaine conditioning. A haplotype of NTNG1 was found to constitute a vulnerability factor for cocaine use disorder in patients, although none of its single nucleotide polymorphisms were associated with a differential expression pattern in healthy controls. The data suggest that change in the Ntng1 expression is a consequence of cocaine exposure, and that some of its genetic markers are associated with a greater risk for cocaine use disorder.

Association of the Plcb1 Gene With Drug Dependence

“…Together with previous results, this study highlights PLCB1 as a gene that may contribute to drug dependence. Finally, these findings and previous results from our and other groups on NFAT5 and NTNG1 11,12 suggest that genes which expression is altered by the effect of drugs of abuse may play an important role in the susceptibility to drug dependence.…”

“…Previous studies had reported that two genes (NFAT5 and NTNG1) with altered expression under cocaine also bear variants that confer susceptibility to cocaine dependence as shown by association studies 11,12 . Since we have shown that PLCB1 is involved in the vulnerability to cocaine dependence, we explored the possibility that its expression is altered by the action of cocaine.…”

MiR-9, miR-153 and miR-124 are down-regulated by acute exposure to cocaine in a dopaminergic cell model and may contribute to cocaine dependence

“…Interestingly, three of the genes encoding differentially expressed mature miRNAs (hsa-miR-9-1, hsa-miR-153-1 and hsa-miR-124-3) were found to be nominally associated with cocaine dependence in this study. Previous studies had reported genes which expression is altered by cocaine and that also carry risk variants for cocaine dependence, or viceversa ( NFAT5, PLCB1 and NTNG1 ) 27 , 62 , 63 . The findings in the present study, together with the previous ones, support the hypothesis that genes up-regulated or down-regulated by cocaine may also contribute to the susceptibility to cocaine dependence.…”

Regulation of Synaptic Development by Astrocyte Signaling Factors and Their Emerging Roles in Substance Abuse

“…The impact of alcohol on netrins in the CNS has yet to be thoroughly investigated. However, a recent study of cocaine dependency in a young adult male mouse (18-20 g) model (induced by daily intraperitoneal injections of cocaine [15 mg/kg]) revealed the downregulation of netrins and the impairment of netrin1-dependent axonal guidance signaling [37], thus disrupting the formation of synapses. A subsequent study using human brain samples from 34 to 54 year-old adults also showed downregulation of netrins in response to cocaine dependency [37].…”

“…However, a recent study of cocaine dependency in a young adult male mouse (18-20 g) model (induced by daily intraperitoneal injections of cocaine [15 mg/kg]) revealed the downregulation of netrins and the impairment of netrin1-dependent axonal guidance signaling [37], thus disrupting the formation of synapses. A subsequent study using human brain samples from 34 to 54 year-old adults also showed downregulation of netrins in response to cocaine dependency [37]. In developmental rodent studies, loss-of-function or mutations of netrin1 or its receptors produced pups with impaired motor function; these pups would not suckle and died within a few days [32,38].…”