Background: Cocaine affects not only the central nervous system, but also systemic immunity. The role of cocaine in gut mucosal integrity is not fully understood.
Methods: Here we evaluated the effect of cocaine use on gut endothelial permeability and system inflammation in rats that self-administered cocaine or saline and in humans using immunohistochemistry, qPCR, ELISA, and Transepithelial/transendothelial electrical resistance (TEER).
Results: Cocaine administration maintained intact and undisturbed intestinal mucosal structures, increased tight junction claudin 1 and 2 mRNA expression, and decreased plasma TNF-α levels, compared to the control group, at the end of study in rats. Further, cocaine treatment decreased gut endothelial permeability in a dose-dependent manner in human epithelial Caco-2 cells in vitro. Consistently, chronic cocaine users exhibited decreased plasma levels of TNF-α compared with non-drug users in vivo. However, plasma IL-6 levels were similar between cocaine use and control groups both in humans and rats in vivo.
Conclusions: Our results from both human and rat studies in vivo and in vitro suggest that cocaine use may exert a protective effect on the integrity of gut mucosa and suppresses plasma TNF-α levels. This study may provide information on some beneficial effects of cocaine use on gut endothelial cells integrity and systemic inflammation.
Background: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler's group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during human investigations and animal self-administration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking.
Hypothesis: The hypothesis is that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression.
Discussion: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, and results in histone H3 glutamine 5 dopaminylation (H3Q5dop) and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase signaling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a "homeostatic brake."
Conclusion: The decrease in Src signaling in NAc D2-MSNs, (like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD) normalizes the NAc dopamine expression and decreases cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.
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