minocycline and Alcoholic-Intoxication

Alcohol has both acute and chronic effects on neuroimmune signaling, including triggering pro-inflammatory cytokine release by microglia. Minocycline, a second-generation tetracycline antibiotic, inhibits microglial activation and reduces neuroinflammation in preclinical studies. In mice, minocycline also reduces ethanol intake, attenuates ethanol-induced conditioned place preference, and inhibits ethanol-induced microglial activation and pro-inflammatory cytokine release.. Here, for the first time, we tested the effects of minocycline on subjective response to ethanol and acute ethanol-induced inflammation in humans.. Forty-eight heavy drinkers participated in a double-blind, placebo-controlled trial in which they were randomized to receive placebo, 100 mg, or 200 mg of minocycline for 10 days. Each subject then underwent two experimental sessions in which they were given a fixed dose of intravenous ethanol using a "clamp" procedure (100 mg%) or placebo (normal saline) on days 8 and 10 of treatment.. Minocycline was well tolerated, but there was no effect of either dose of minocycline on subjective response to ethanol or ethanol-induced craving; minocycline effects on cognitive function seem to interact with age. Minocycline treatment did not alter serum cytokine levels at baseline or during ethanol-exposure, although certain baseline cytokine levels predict sedative response to ethanol.. These findings indicate that a short-term treatment with minocycline may not alter ethanol-related inflammation or subjective response to ethanol in humans. Further research is needed to identify pharmacological agents with robust effects on ethanol-induced inflammation to determine whether neuroimmune modulation represents a viable treatment strategy for alcohol use disorder.

Topics: Adult; Alcoholic Intoxication; Alcoholism; Animals; Anti-Bacterial Agents; Cytokines; Double-Blind Method; Drug Delivery Systems; Ethanol; Humans; Infusions, Intravenous; Male; Mice; Microglia; Middle Aged; Minocycline; Young Adult

Chronic alcohol intoxication (CAI) increases both morbidity and mortality of stroke patients. Despite the high prevalence of CAI and ischemic stroke, studies addressing their comorbidity and/or protective alternatives remain scarce. Thus, the influence of CAI on both stroke outcome and minocycline treatment (recognized for its neuroprotective effect) was investigated. Female Wistar rats (35 days old) were treated with water or ethanol (6.5 g/kg/day, 22.5% w/v) for 55 days. Then, focal ischemia was induced by endothelin-1 in the motor cortex. Two hours later, four doses of 50 mg/kg of minocycline every 12 hours followed by five doses of 25 mg/kg every 24 hours were administered. Behavioral performance (open field and rotarod tests) and immunohistochemical (cellular density, neuronal death, and astrocytic activation) and biochemical (lipid peroxidation and nitrite levels) analyses were performed. CAI increased motor disruption, nitrite and lipid peroxidation levels, and neuronal loss caused by ischemia, whereas it reduced the astrogliosis. Minocycline was effective in preventing the motor and tissue damage caused by stroke. However, these effects were attenuated when CAI preceded stroke. Our data suggest that CAI beginning in adolescence contributes to a worse outcome in ischemic stroke survivors and reduces the benefits of minocycline, possibly requiring adjustments in therapy.

Topics: Alcoholic Intoxication; Animals; Behavior, Animal; Brain Ischemia; Disease Models, Animal; Endothelin-1; Female; Immunohistochemistry; Lipid Peroxidation; Minocycline; Motor Cortex; Neuroprotective Agents; Nitrites; Rats; Rats, Wistar

Evidence has emerged demonstrating that ethanol (EtOH) influences cytokine expression within the central nervous system, although most studies have examined long-term exposure. Thus, the cytokine response to an acute EtOH challenge was investigated, in order to characterize profiles of cytokine changes following acute exposure.. Rats pups were injected intraperitoneally (i.p.) with 2-g/kg EtOH, and IL-1 mRNA and protein were assessed 0, 60, 120, 180, and 240 minutes post injection (Experiment 1). In Experiments 2 to 5, the expression of several cytokines was examined in adult male rats during acute intoxication (3 hours after 4-g/kg EtOH), as well as withdrawal (18 hours post injection), after i.p. or intragastric (i.g.) EtOH administration.. Early in ontogeny, acute EtOH significantly decreased brain IL-1 mRNA and protein. Subsequently, when adult rats were examined, significant and temporally dynamic alterations in central and peripheral cytokines were observed following acute i.p. EtOH exposure (4 g/kg). Although cytokine- and region-dependent central IL-6 expression was generally increased and tumor necrosis factor alpha decreased during intoxication, IL-1 expression exhibited increases during withdrawal. In the periphery, acute i.p. EtOH elevated expression of all cytokines, with the response growing in magnitude as the time post injection increased. Following acute i.g. EtOH (4 g/kg), intoxication-related increases in IL-6 expression were again observed in the paraventricular nucleus of the hypothalamus (PVN), although to a lesser extent. Long-term, voluntary, intermittent EtOH consumption resulted in tolerance to the effects of an i.g. EtOH challenge (4 g/kg) on PVN IL-6 expression, whereas these same elevations in IL-6 expression were still seen in the amygdala in rats with a history of moderate EtOH intake. Treatment with minocycline did not significantly attenuate i.p. or i.g. EtOH-induced changes in central cytokine expression.. Together, these studies provide a foundation for understanding fluctuations in central and peripheral cytokines following acute EtOH as potential contributors to the constellation of neural and behavioral alterations observed during EtOH intoxication and withdrawal.

Topics: Age Factors; Alcoholic Intoxication; Animals; Brain; Corticosterone; Drug Tolerance; Ethanol; Interleukin-1; Interleukin-6; Liver; Male; Minocycline; Rats; Spleen; Substance Withdrawal Syndrome; Time Factors; Tumor Necrosis Factor-alpha