4.3 Cocaine
Cocaine addiction is a chronic relapsing disorder characterized by persistent perturbation of the organism’s homeostatic processes leading to maladaptive drug seeking. Although considerable attention has been paid to the consequences of neuronal changes following chronic cocaine use, few studies have demonstrated the mechanisms underlying the effects of the brain’s resident immune cells on neuroinflammation after chronic cocaine use. Cocaine self-administration increases mRNA expression of the proinflammatory cytokine IL-1ß in the VTA. Pharmacological antagonism of IL-1 receptors in the VTA reduces cocaine-induced drug seeking[77]. Cocaine abuse leads to neuroinflammation, showing the activation of the immune system, as manifested by a disrupted balance of pro- and anti-inflammatory cytokines. Several sets of clinical data have proved that the intake of cocaine can lead to the increase of IL-6 and IL-10[78-80].
Cocaine exposure has been shown to enhance neuroinflammation by upregulating glial activation in the brain, of which mitophagy has been the focus of research, but its role in this process remains a mystery. Increased autophagy contributes to cocaine-mediated activation of microglia, resulting in decreased expression and release of inflammatory factors IL-1ß, IL-6 in microglia[81]. Studies of the mechanism at the cellular level revealed that superoxide dismutase mimetics such as TEMPOL and MitoTEMPO attenuated cocaine-mediated impaired mitophagy and microglial activation[82]. Taken together, these findings suggest that cocaine exposure induces autophagy, which is intimately related to neuroinflammation. Therefore, targeting autophagy proteins can be considered as a treatment for cocaine-associated neuroinflammatory diseases. Besides, the studies on Exendin-4 (Ex4) also indicate that Ex4 reduces the expression levels of IL-1β in the hippocampus, which are up-regulated by cocaine exposure. Ex4 improves cocaine-induced behavior and is selected as a drug candidate for cocaine addiction[83]. NLRP3 has also been suggested as a potential therapeutic target for alleviating cocaine-mediated neuroinflammation. It has also been reported that the chemokine fractalkine (CX 3 CL1) modulates hippocampal-dependent neuroinflammation and synaptic plasticity through CX 3 C receptor 1 (CX 3 CR1). Further, cocaine can induce changes in CX 3 CL1 concentrations, which are highly correlated with IL1β concentrations and would activate a convergent inflammatory pathway in the hippocampus[84].