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

Abstract

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-1β 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.

Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine

“…To assess inflammatory effects, we measured immune factors with evidence for a role in methamphetamine-induced CNS effects or CD74 signaling. Although some studies show increases in pro-inflammatory cytokines such as IFN-γ and IL-1β following methamphetamine exposure [reviewed in (51,100)], we did not find significant methamphetamine-induced increases in these factors (Figures 4A,B). The timing of our sample collection and tissue type (frontal cortex) may have contributed to the different observations.…”

“…This simplified schematic illustrates several potential inflammatory pathways and the effects of DRmQ and ibudilast on these signals. Methamphetamine binds to the sigma-1 receptor (Sig-1R) (67, 68) and Toll-like receptor 4 (TLR4) complex (69), triggering signaling pathways which ultimately upregulate the expression of inflammatory cytokines including interleukins (IL-1, IL-2, IL-6, IL-8), interferons (IFNs), MCP-1, MIF, MIP-2 [recently reviewed in (51)], and other factors relevant to methamphetamine-induced pathology, such as brain derived neurotrophic factor (BDNF) (70) and intracellular adhesion molecule-1 (ICAM-1) (71) (not shown). At the Sig-1R, methamphetamine activates downstream signaling pathways, including nuclear factor kappa light chain enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways (72,73).…”

Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA

“…MDMA has been described previously as an immune system stressor ( Connor, 2004 ). Cytokines can mediate depression and anxiety behaviors ( Hu et al, 2022 ) and may even play a role in the addictive potential of stimulants ( Bravo et al, 2023 ). Notably, no such changes were observed with methylone treatment.…”

Role of Glial Cells in Neuronal Function, Mood Disorders, and Drug Addiction

“…For example, psychostimulants such as cocaine and methamphetamine, or opioids such as morphine, have been shown to increase glial cell reactivity and increase the levels of proinflammatory cytokines such as Il-1β, TNFα, and IL-6, but decrease the levels of anti-inflammatory cytokines such as IL-10 [ 138 , 239 , 240 , 241 ]. Moreover, substances of abuse may reduce astrocyte cell number, alter glutamate neurotransmission and metabolism through the specific astrocytic glutamate transporter GLT-1 [ 242 , 243 ], increase the number of reactive microglia and neuroinflammatory markers, as well as impair OLs, resulting in a decrease in myelination. Finally, glial dysfunction may affect BBB permeability and contribute to neurotoxicity, further exacerbating addictive behavior [ 138 ].…”