Critical role of TLR4 in uncovering the increased rewarding effects of cocaine and ethanol induced by social defeat in male mice

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. 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. 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. 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. 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. •Social defeat stress induced higher sensitivity to the reinforcing drug (cocaine and ethanol) effects.•TLR4 receptors are involved in the rewarding effects of cocaine and ethanol induced by social defeat stress.•TLR4 receptors mediate the neuroinflammatory response induced by social stress.