There is some evidence of substance-mediated responses in microglia. In particular, alcohol, cocaine, and methamphetamine show evidence (sometimes conflicting, however) of microglia-mediated neuroinflammation. Microglia may also have a modulatory effect on synaptic pruning in the dopaminergic circuit, which is implicated in addiction.

Scripps College

Microglial dysfunction has been implicated in psychiatric conditions, such as depression, anxiety, bipolar disorder, and schizophrenia. 
Some proposed mechanisms include:
-overexpression of inflammatory cytokines as a response to psychological stressors (may be especially important in suicidality)
-abnormal phagocytosis and synaptic pruning (too much), as well as adult neurogenesis (not enough)
-decreasing development of oligodendrocyte progenitor cells, which results in decreased myelination/white matter function (especially associated with depression)

Microglia and Psychiatric Disorders

Rahimian, R., Wakid, M., O’Leary, L.A., Mechawar, N., 2021. The emerging tale of microglia in psychiatric disorders. Neuroscience & Biobehavioral Reviews 131, 1–29.. doi:10.1016/j.neubiorev.2021.09.023

"The emerging tale of microglia in psychiatric disorders"

Stressors can induce depression and depressive-like behaviors in mouse models, and this is associated with changes in microglia, particularly in the frontal cortex and the hippocampus. Furthermore, in post-mortem analysis of suicides, imaging reveals abnormal densities (both increased and decreased) of microglia in both MDD patients and in other psychiatric patients relative to healthy controls.

Microglia in Major Depressive Disorder

There is evidence that neuroinflammation plays a role in the pathology of bipolar disorder, but further investigation is necessary to determine whether or not microglia are involved in this. However, microglia do appear to be overactive in the context of BD during both the manic and depressive phases, and they under-produce BDNF, which is involved in synaptic plasticity. There is some gene expression that differentiates the microglial function in BD patients and those with schizophrenia, as well as differences in postmortem microglia expression in BD patients who died by suicide versus those who did not, with the non-suicide group expressing lower levels of microglia density. Typical mood stabilizer treatments (lithium and valproic acid) seem to act on microglia, but the mechanism is unknown.

Microglia in Bipolar Disorder

There is evidence of increased neuroinflammation and inflammatory cytokines in the CSF of schizophrenia patients within 5 years of onset, as well as increased microglia density in the dorsolateral prefrontal cortex. Abnormal microglia density in the temporal lobe seems to be consistent across all schizophrenia patients, but there appears to be some nuanced differences among different subtypes and among the brains of patients who died by suicide versus not. Antipsychotic exposure seems to impact microglial density and inflammation, but this is not yet well understood.

Microglia in Schizophrenia

Microglia in Substance Use Disorders

SSRIs appear to regulate the activation state of microglia in addition to their effects on the serotonergic system when studied in vitro. Fluoxetine (Prozac) and its metabolite, norfluoxetine, have been shown to induce apoptosis in microglia, which limits the amounts of neuroinflammation they can cause. There appear to be both direct and indirect (modulating amount of serotonin available to microglia, or changing the extracellular environment) mechanisms by which this is done. 

Effects of SSRIs on Microglia

Both typical and atypical antipsychotics appear to inhibit the release of pro-inflammatory cytokines and potentially promote regular neurogenesis in schizophrenia patients by decreasing oxidative stress. Studies of prenatal administration of some antipsychotics in mice models have demonstrated a decrease in psychosis-like behaviors in the offspring. Given that the microglial inflammatory mechanisms are particularly pronounced in schizophrenia, this is a particular area of interest for future pharmacological research.

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