BACKGROUND:Substance use disorders and social stress are currently associated with changes in the immune system response by which they induce a proinflammatory state in neurons and glial cells that eventually modulates the reward system.AIMS:The aim of the present work was to assess the role of the immune TLR4 (Toll-like receptors 4) and its signaling response in the increased contextual reinforcing effects of cocaine and reinforcing effects of ethanol (EtOH) induced by social defeat (SD) stress.METHODS:Adult male C57BL/6 J wild-type (WT) mice and mice deficient in TLR4 (TLR4-KO) were assigned to experimental groups according to stress condition (exploration or SD). Three weeks after the last SD, conditioned place preference (CPP) was induced by a subthreshold cocaine dose (1 mg/kg), while another set underwent EtOH 6% operant self-administration (SA). Several inflammatory molecules were analyzed in the hippocampus and the striatum.RESULTS:SD induced higher vulnerability to the conditioned rewarding effects of cocaine only in defeated WT mice. Similarly, defeated WT mice exhibited higher 6% EtOH consumption, an effect that was not observed in the defeated TLR4-KO group. However, the motivation to obtain the drug was observed in both genotypes of defeated animals. Notably, a significant upregulation of the protein proinflammatory markers NFkBp-p65, IL-1β, IL-17 A and COX-2 were observed only in the defeated WT mice, but not in their defeated TLR4-KO counterparts.CONCLUSIONS:These results suggest that TLR4 receptors mediate the neuroinflammatory response underlying the increase in the rewarding effects of cocaine and EtOH induced by social stress.

Alcohol induces cell damage and can lead to neurodegeneration. Ethanol is capable of activating TLR4 receptors which, in turn, elicit a signaling cascade that leads to the generation of an inflammatory environment that is detrimental for cell survival. Autophagy has emerged as a protective cellular mechanism, triggered in the presence of toxic stimuli. However, its dysregulation is also involved in the pathogenesis of neurodegenerative and inflammatory diseases. By activating the TLR4 immune response, chronic ethanol consumption induces neuroinflammation and neuropathological changes, impairing the autophagic pathway by altering its main molecular switch, mTOR, which might contribute to neurodegeneration. Conversely, acute ethanol treatment is capable of eliciting a rapid autophagy response in glial cells, which is absent in neurons, to alleviate ethanol toxicity through mTOR inhibition and beclin-1 activation by innate immunity receptor TLR4. These findings could provide new insight into the mechanisms that underlie ethanol-induced brain damage.

Numerous studies report that social defeat stress alters dopamine (DA) neurotransmission in several areas of the brain. Alterations of the mesolimbic dopaminergic pathway are believed to be responsible for the increased vulnerability to drug use observed as a result of social stress. In the present study, we evaluated the influence of DA receptors on the long-term effect of repeated social defeat (RSD) on the conditioned rewarding and reinstating effects of cocaine. For this purpose, the D1R antagonist SCH 23390 and the D1R antagonist raclopride were administered 30min before each social defeat and a cocaine-induced CPP procedure was initiated three weeks later. The expression of the D1R and D2R was also measured in the cortex and hippocampus throughout the entire procedure. Mice exposed to RSD showed an increase in the conditioned rewarding effects of cocaine that was blocked by both DA receptors antagonists when a subthreshold dose of cocaine was employed. However, while the vulnerability to reinstatement of the preference induced by 25mg/kg cocaine-induced CPP was abolished by the D1R antagonist, it was practically unaffected by raclopride. Increases in D2R receptor levels were observed in the cortex of defeated animals after the first and fourth social defeats and in the hippocampus 3weeks later. Nevertheless, D1R receptor levels in the hippocampus decreased only after the last social defeat. Our results confirm that RSD enhances the conditioned rewarding effects of cocaine and that both DA receptors are involved in this enduring effect of social stress.

Social defeat (SD) induces a long-lasting increase in the rewarding effects of psychostimulants measured using the self-administration and conditioned place procedures (CPP). However, little is known about the epigenetic changes induced by social stress and about their role in the increased response to the rewarding effects of psychostimulants. Considering that histone acetylation regulates transcriptional activity and contributes to drug-induced behavioral changes, we addressed the hypothesis that SD induces transcriptional changes by histone modifications associated with the acquisition of place conditioning. After a fourth defeat, H3(K9) acetylation was decreased in the hippocampus, while there was an increase of HAT and a decrease of HDAC levels in the cortex. Three weeks after the last defeat, mice displayed an increase in histone H4(K12) acetylation and an upregulation of histone acetyl transferase (HAT) activity in the hippocampus. In addition, H3(K4)me3, which is closely associated with transcriptional initiation, was also augmented in the hippocampus three weeks after the last defeat. Inhibition of HAT by curcumin (100mg/kg) before each SD blocked the increase in the conditioned reinforcing effects of 1mg/kg of cocaine, while inhibition of HDAC by valproic acid (500mg/kg) before social stress potentiated cocaine-induced CPP. Preference was reinstated when animals received a priming dose of 0.5mg/kg of cocaine, an effect that was absent in untreated defeated mice. These results suggest that the experience of SD induces chromatin remodeling, alters histone acetylation and methylation, and modifies the effects of cocaine on place conditioning. They also point to epigenetic mechanisms as potential avenues leading to new treatments for the long-term effects of social stress on drug addiction.

Inflammation during brain development is involved in the pathogenesis of early brain injury and cognitive dysfunctions. We reported that ethanol can activate the TLR4 immune receptors causing neuroinflammation, myelin dysfunction, brain damage and cognitive effects in adults and adolescents. However, it is presently unknown the potential role of neuroimmune-TLR4 response in the …

Our previous studies demonstrated that ethanol (EtOH), by activating the innate immune receptors toll-like 2 (TLR2) and 4 (TLR4) signaling in glial cells, promotes the production of inflammatory mediators and cytokines, leading to neural death. Elimination of TLR4 prevents the neuroinflammatory processes along with the myelin and behavioral impairments …

We have previously reported that ethanol, by activating the innate immune receptors TLR4, triggers signalling inflammatory response, causing gliosis, neuroinflammation and brain damage. Ethanol can also activate other immune receptors, as NOD-like-receptors (NLRs), in particular the NLRP3-inflammasome in astroglial cells, stimulating the caspase-1 activation that allows …