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

Abstract

Cocaine is one of the most used psychostimulant drugs worldwide. MicroRNAs are post-transcriptional regulators of gene expression that are highly expressed in brain, and several studies have shown that cocaine can alter their expression. In a previous study, we identified several protein-coding genes that are differentially expressed in a dopaminergic neuron-like model after an acute exposure to cocaine. Now, we used the prediction tool WebGestalt to identify miRNA molecules potentially involved in the regulation of these genes. Using the same cellular model, we found that seven of these miRNAs are down-regulated by cocaine: miR-124-3p, miR-124-5p, miR-137, miR-101-3p, miR-9-5p, miR-369-3p and miR-153-3p, the last three not previously related to cocaine. Furthermore, we found that three of the miRNA genes that are differentially expressed in our model (hsa-miR-9-1, hsa-miR-153-1 and hsa-miR-124-3) are nominally associated with cocaine dependence in a case–control study (2,085 cases and 4,293 controls). In summary, we highlighted novel miRNAs that may be involved in those cocaine-induced changes of gene expression that underlie addiction. Moreover, we identified genetic variants that contribute to cocaine dependence in three of these miRNA genes, supporting the idea that genes differentially expressed under cocaine may play an important role in the susceptibility to cocaine dependence.

Peripheral blood microRNA levels in females with cocaine use disorder

“…We specifically focused on miR-124, miR-181 and miR-212, given that among many potentially relevant miRNAs, these have been the most explored by pre-clinical studies, with evidence indicating that: (1) these miRNAs are dynamically affected by cocaine acute exposure in both in vivo (e.g. rodent brain) and in vitro studies with neuronal and dopaminergic cell populations (Cabana-Domínguez, Arenas, Cormand et al, 2018;Chandrasekar & Dreyer, 2009;Xu, Wang, Lv et al, 2013); (2) they are molecular markers of the effects of chronic cocaine exposure in the brain reward system (Chandrasekar & Dreyer, 2011;Eipper-Mains, Kiraly, Palakodeti et al, 2011;Quinn, James, Hawkins et al, 2018); (3) they are suitable for the identification of vulnerable/resilient subjects to cocaine dependence in behavioral animal models of drug addiction (Chandrasekar & Dreyer, 2011;Im, Hollander, Bali et al, 2010;Quinn, Brown, Goldie et al, 2015;Viola, Wearick-Silva, De Azeredo et al, 2016); and (4) the manipulation of these miRNAs in the brain resulted in altered cocaine-induced neuroplasticity and behavioral phenotypes (Doura & Unterwald, 2016).…”

Cocaine Self-administration and Extinction Inversely Alter Neuron to Glia Exosomal Dynamics in the Nucleus Accumbens

“…This process appears to be cocaine and self-administration specific, as food self-administration has no effect on the internalization of neuronal exosomes in astrocytes and cocaine extinction reversed the reduced internalization of neuronal exosomes in astrocytes. In parallel, it has been reported that several neuronal miRs, including miR-124-3p, are down-regulated by cocaine exposure (Cabana-Dominguez et al, 2018). It is thus conceivable that the reduced miR-124 signaling, including reduced transfer from neurons to astrocytes through exosomes, underlies cocaineinduced down-regulation of GLT1 expression.…”

Role of microRNAs in the pathophysiology of addiction

“…A study performed using the neuroblastoma SH‐SY5Y cell line found that 30‐min and 6‐hr cocaine treatments revealed a total of 90 differentially expressed miRNAs (Cabana‐Domínguez, Arenas, Cormand, & Fernàndez‐Castillo, 2018). The most significantly downregulated of these were miR‐9‐5p, miR‐101‐3p, miR‐124‐3p, miR‐124‐5p, miR‐137, miR‐153‐3p, and miR‐369‐3p.…”

“…Keller et al post‐validated miR‐1224 and miR‐6216 as significantly upregulated and miR‐130a‐3p and miR‐9a‐3p as significantly downregulated. While none of these miRNAs has been behaviorally confirmed to be relevant in nicotine addiction, miR‐9a‐3p has also been identified in cocaine and METH addiction, perhaps suggesting it for further nicotine addiction studies (Cabana‐Domínguez et al, 2018; Gu et al, 2020). Among the miRNAs reported by Keller et al (2018), it is important to note that, despite not being post‐validated, miR‐140‐3p, miR‐140‐5p, and miR‐125a‐5p were also seen to be significantly upregulated in their microarray data.…”