The impact of psychostimulants on central and peripheral neuro-immune regulation: a scoping review of cytokine profiles and their implications for addiction.

It is now well-accepted that psychostimulants act on glial cells causing neuroinflammation and adding to the neurotoxic effects of such substances. Neuroinflammation can be described as an inflammatory response, within the CNS, mediated through several cytokines, reactive oxygen species, chemokines and other inflammatory markers. These inflammatory players, in particular cytokines, play important roles. Several studies have demonstrated that psychostimulants impact on cytokine production and release, both centrally and at the peripheral level. Nevertheless, the available data is often contradictory. Because understanding how cytokines are modulated by psychoactive substances seems crucial to perspective successful therapeutic interventions, here, we conducted a scoping review of the available literature. We have focused on how different psychostimulants impact on the cytokine profile. Publications were grouped according to the substance addressed (methamphetamine, cocaine, methylphenidate, MDMA or other amphetamines), the type of exposure and period of evaluation (acute, short- or long-term exposure, withdrawal, and reinstatement). Studies were further divided in those addressing central cytokines, circulating (peripheral) levels, or both. Our analysis showed that the classical pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß were those more investigated. The majority of studies have reported increased levels of these cytokines in the central nervous system after acute or repeated drug. However, studies investigating cytokine levels during withdrawal or reinstatement have shown higher variability in their findings. Although we have identified fewer studies addressing circulating cytokines in humans, the available data suggest that the results may be more robust in animal models than in patients with problematic drug use. As a major conclusion, an extensive use of arrays for relevant cytokines should be considered to better determine which cytokines, upon the classical ones, may be involved in the progression from episodic use to the development of addiction. A concerted effort is still necessary to address the link between peripheral and central immune players, including from a longitudinal perspective. Until there, the identification of new biomarkers and therapeutic targets to envision personalized immune-based therapeutics will continue to be unlikely.

Neuron-Microglia Contact-Dependent Mechanisms Attenuate Methamphetamine-Induced Microglia Reactivity and Enhance Neuronal Plasticity.

Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP3R2-Ca2+-dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation.

TLR2-induced IL-10 production impairs neutrophil recruitment to infected tissues during neonatal bacterial sepsis.

Sepsis is the third most common cause of neonatal death, with Group B Streptococcus (GBS) being the leading bacterial agent. The pathogenesis of neonatal septicemia is still unsolved. We described previously that host susceptibility to GBS infection is due to early IL-10 production. In this study, we investigated whether triggering TLR2 to produce IL-10 is a risk factor for neonatal bacterial sepsis. We observed that, in contrast to wild-type (WT) pups, neonatal TLR2-deficient mice were resistant to GBS-induced sepsis. Moreover, if IL-10 signaling were blocked in WT mice, they also were resistant to sepsis. This increased survival rate was due to an efficient recruitment of neutrophils to infected tissues that leads to bacterial clearance, thus preventing the development of sepsis. To confirm that IL-10 produced through TLR2 activation prevents neutrophil recruitment, WT pups were treated with the TLR2 agonist Pam3CSK4 prior to nebulization with the neutrophil chemotactic agent LTB4. Neutrophil recruitment into the neonatal lungs was inhibited in pups treated with Pam3CSK4. However, the migration was restored in Pam3CSK4-treated pups when IL-10 signaling was blocked (either by anti-IL-10R mAb treatment or by using IL-10-deficient mice). Our findings highlight that TLR2-induced IL-10 production is a key event in neonatal susceptibility to bacterial sepsis.