Interleukin-1β Causes Anxiety by Interacting with the Endocannabinoid System

Abstract

Interleukin-1␤ (IL-1␤) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1␤-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1␤-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1␤ caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1␤-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1␤-CB1R coupling, and TRPV1Ϫ/Ϫ mice were indeed insensitive to the synaptic and behavioral effects of both IL-1␤ and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1␤ on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1Ϫ/Ϫ mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.

Bioactive lipids as modulators of immunity, inflammation and emotions

“…The eCB system can also be considered as a suitable tool to shape and fine-tune diverse and complex behaviors. This is supported by the evidence that inflammation-induced anxiety is associated with inhibition of CB 1 function in GABA synapses [82], and by the demonstration that COX-2-mediated anxiety inhibition is driven by an increased eCB levels [83]. However, it should be always taken into account that AEA, 2-AG and PEA have distinct, and at times even opposite, roles in modulating inflammatory responses of specific cells and tissues.…”

Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study

“…Peripheral cytokines such as IL-6 can communicate with the brain in a number of ways (Khandaker & Dantzer, 2016). Immunoactivation in mice and healthy volunteers by injection of lipopolysaccharide has been reported to increase circulating proinflammatory cytokine levels (IL-1β, IL-6) as well as producing symptoms of anxiety and reduced cognitive performance (Reichenberg et al 2001;Rossi et al 2012). A study of human volunteers suggests inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity, which is in part mediated by peripheral IL-6 (Harrison et al 2009).…”

Endocannabinoid regulation of amyloid-induced neuroinflammation

“…First, it could be a consequence of a loss of function of TRPV1 channels, which are known to play a permissive role in the effects of IL1β both at the molecular and behavioral levels (Rossi et al, 2012). Furthermore, this TRPV1 loss of function could be exacerbated in FAAH -/-mice due to the proinflammatory millieu, a fact that is known to potentiate the actions of AEA on these channels (Singh-Tahim et al, 2005).…”