Repeated Lipopolysaccharide (LPS) or Cytokine Treatments Sensitize Ethanol Withdrawal-Induced Anxiety-Like Behavior

Abstract

Previous investigations demonstrated that repeated stresses before an ethanol exposure sensitize ethanol withdrawal-induced anxietylike behavior ('anxiety'). In addition to activating the hypothalamic-pituitary-adrenal axis, acute stress also elevates cytokines in brain. Initially, to test possible cytokine involvement in this stress/withdrawal protocol, cytokines were increased in brain with 2 weekly repeated lipopolysaccharide (LPS) administrations (1000 m/kg) (LPS/withdrawal protocol) or with twice weekly intracerebroventricular (i.c.v.) administrations of the cytokines IL-1b, CCL2 (MCP-1) or TNFa (cytokine/withdrawal protocol) before exposure and withdrawal from a 5-day cycle of chronic ethanol diet. Both protocols sensitized withdrawal-induced anxiety and confirm cytokine involvement in the sensitized anxiety response. Testing of various doses of LPS (16-1000 mg/kg) and TNFa (3-100 ng, i.c.v.) demonstrated the dose-related nature of these protocols to sensitize withdrawal-induced anxiety. The sensitized anxiety was not produced by a single 5-day ethanol diet cycle or by repeated LPS or cytokine treatments alone. Likewise, sensitized anxiety in these protocols could not be attributed to differences in ethanol ingestion. When challenged with a subsequent re-exposure to a 5-day ethanol diet cycle 16 days after completion of the LPS/withdrawal or cytokine/withdrawal protocols, an increase in withdrawal-induced anxiety was observedFan indication of induction of an underlying persistent adaptive change. Finally, just as found previously with the stress/withdrawal protocol, administration of the benzodiazepine receptor antagonist flumazenil before the LPS or TNF treatments prevented anxiety sensitization. Together, these findings indicate that increased cytokine activity induces adaptive change that supports sensitization of ethanol withdrawal-induced anxiety that may be linked to GABA A -receptor function.

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

“…Further, immune signaling molecules are increased in postmortem human alcoholic brain (Crews et al., 2017) and regulate preference for alcohol drinking in animal studies (Mayfield et al., 2013). Cytokines also enhance stressful emotional states following alcohol withdrawal (Breese et al., 2008). These data, taken together with our findings reported here that combined acute EtOH and stress enhance endotoxin and brain microglial CD11B + IR in the PFC, NAc, and CeA, are consistent with microglia within these brain regions contributing to the interaction of EtOH exposure with stress that impact alcohol drinking and increase risks for AUD.…”

“…Innate immune signaling cytokines also alter EtOH consumption (Marshall et al., 2016, 2017), and the cytokine receptors IL1R1 and TNFR1 contribute to stress‐induced EtOH consumption (Karlsson et al., 2017), suggesting the neuroimmune system may contribute to addiction. Cytokines also enhance stressful emotional states following alcohol withdrawal (Breese et al., 2008). Although alcohol and stress both induce stress hormones and innate immune signaling, the mechanisms of interaction of these 2 responses and how they contribute to AUDs are poorly understood.…”

Changes in Severity of Allergy and Anxiety Symptoms Are Positively Correlated in Patients with Recurrent Mood Disorders Who Are Exposed to Seasonal Peaks of Aeroallergens

“…The protocol has been approved by the Institutional Review Board at the University of Maryland School of Medicine. We recruited 51 A pre-screening interview was performed by telephone for all subjects in order to exclude those with any major medical illness, previous psychotic disorder, winter-type seasonal affective disorder, drug or alcohol dependence, or current or intended pregnancy during the course of the study.…”

Neonatal Phencyclidine Treatment in Mice Induces Behavioral, Histological and Neurochemical Abnormalities in Adulthood

“…30 min before the test. The doses of flumazenil and SCH50911 were chosen according to the previous reports by Breese et al 15) and Frankowska et al, 16) respectively.…”

“…Spontaneous Locomotor Activity PCP-treated mice were subjected to the behavioral experiment at postnatal weeks [15][16][17][18][19]. The animals were housed individually in plastic cages (W-D-H: 215ϫ320ϫ140 mm) and acclimatized for 3 d before the measurement of spontaneous locomotor activity.…”