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].