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We investigated the effect of pretreatment with a prostaglandin synthetase inhibitor, ibuprofen, on the pharmacokinetics and pharmacodynamics of ethanol in six fasting subjects. Ibuprofen caused a 10% decrease in the maximum rate of elimination of ethanol. Visual memory, which is a function primarily mediated by the right cerebral hemisphere, was measured by the Benton Visual Retention test and was more impaired during combined ibuprofen and ethanol dosing than during ethanol dosing alone (P = 0.05). The auditory-verbal memory of the subjects, which is primarily a function of the left cerebral hemisphere, was assessed by the Selective Reminding Test and showed decreased impairment during combined ibuprofen and ethanol dosing as compared with ethanol dosing alone (P = 0.04). The opposite effect of ibuprofen on ethanol-induced cognitive impairment as measured by two lateralized functions is consistent with the reports in tissue and animal models that central nervous system effects of ethanol may be mediated at least in part by prostaglandins.

Microglia undergo maturation during the third trimester of human development (equivalent to the first 1-2 weeks of postnatal life in rodents), during which these cells may be particularly sensitive to insult. Alcohol exposure during this period can activate the neuroimmune system, an effect that may contribute to the pathophysiology of fetal alcohol spectrum disorders. Here, we investigated whether repeated alcohol exposure during the third trimester-equivalent in rats has a priming effect on the neuroimmune response to injection of bacterial lipopolysaccharide (LPS). Pups were exposed to alcohol in vapor chambers for 4 h daily from postnatal day (PD)2 to PD16 (peak blood alcohol concentrations ∼150 mg/dL). On PD17, rats were injected with either saline or LPS (50 μg/kg) and the frontal cortex, cerebellar vermis, and dentate gyrus were collected 2 h later. Messenger RNA (mRNA) levels for the pro-inflammatory agents interleukin 1β (IL-1β) and chemokine (C-C) motif ligand 2 (CCL2), as well as levels of the anti-inflammatory cytokine interleukin 10 (IL-10), were measured using reverse transcriptase polymerase chain reaction. LPS consistently increased IL-1β and CCL2 mRNA levels in the dentate gyrus, frontal cortex, and cerebellum of both male and female rats. Furthermore, the LPS-induced increase of IL-1β mRNA levels was significantly blunted in the frontal cortex of alcohol-exposed female rats. Conversely, LPS only minimally affected IL-10 mRNA expression and there were no significant differences between air- and alcohol-exposed rats. Taken together with the literature regarding the effect of third-trimester alcohol exposure on the neuroimmune system, our findings suggest that chronic exposure to lower levels is less disruptive to the neuroimmune system than binge-like exposure to high doses of alcohol.

Abstract When acetyl ethyl tetramethyl tetralin (AETT), at 10–50 μg/ml, was added to rat liver mitochondria respiring with succinate or with glutamate plus malate as substrate, the rate of mitochondrial respiration increased significantly after an initial lag period, of 2–3 min. AETT also stimulated respiration in the presence of oligomycin, and at higher concentrations of AETT a phase of strongly inhibited respiration followed an initial stimulatory phase. These observations suggest that AETT uncouples oxidative phosphorylation. A diketo derivative (DK) of tetramethyl tetralin also appears to be an uncoupling agent, according to those criteria, and both compounds uncoupled mitochondria from brain as well as liver. DK and many other uncoupling agents, such as hexachlorophene (HCP), produced an immediate burst of respiration, whereas the brief lag after addition of AETT was similar to that seen after addition of triethyltin (TET).

Background and ObjectivesThe study examined the effects of an alcohol challenge on naturalistic drinking among alcohol‐dependent individuals and explored brief motivational interviewing (MI) as a potential intervention for these participants.MethodAlcohol‐dependent individuals (n = 32, eight females) completed the intake assessment, alcohol challenge, one MI session, and 1‐month follow‐up (87.5% retention) where they completed measures of drinking and motivation for change.ResultsAs expected, multilevel mixed models revealed that drinking did not increase post‐alcohol challenge. Participants reported a reduction in ambivalence, drinking days, and a trend towards fewer total drinks between the MI and 1‐month follow‐up.ConclusionsConsistent with other studies, the alcohol challenge did not worsen alcohol use. Results support further investigation of brief MI for alcohol‐dependent participants in alcohol challenges.Scientific SignificanceAlcohol administration to alcohol‐dependent participants appears to not exacerbate naturalistic drinking. MI may be a feasible intervention for non‐treatment seeking alcohol‐dependent participants in alcohol challenge studies. (Am J Addict 2014;23:96–101)

Background: Short‐sleep (SS) mice exhibit higher locomotor activity than do long‐sleep (LS) mice when injected with low doses of ethanol or the noncompetitive N‐methyl‐D‐aspartate receptor (NMDAR) antagonist MK‐801 (dizocilpine). SS mice also have higher densities of brain NMDARs. However, two strains of LS X SS recombinant inbred (RI) mice also show differential activation to ethanol and MK‐801, but have similar numbers of NMDARs. Here we used inbred LS (ILS) and SS (ISS) mice to investigate further the relationship between NMDARs and sensitivity to the stimulant effects of low doses of ethanol.Methods: Open field activity and spontaneous alternations were measured after saline or drug injection. [3H]MK‐801 binding parameters were determined in hippocampus, cortex, striatum, and nucleus accumbens. Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region of hippocampal slices.Results: Systemic injection of either ethanol or MK‐801 increased locomotor activity to a greater extent in ISS mice than in ILS mice. The competitive NMDAR antagonist 2‐carboxypiperazin‐4‐yl‐propyl‐1–1phosphonic acid (±CPP) depressed activity of ILS, but not ISS, mice. No strain differences were observed in spontaneous alternations or in the number or affinity of NMDARs in the brain regions examined. Likewise, the magnitudes of hippocampal NMDAR‐mediated fEPSPs were similar in ILS and ISS mice and were inhibited to the same extent by a competitive NMDAR antagonist. However, both ethanol and the NMDAR NR2B receptor antagonist ifenprodil inhibited the late component of hippocampal NMDAR fEPSPs to a greater extent in ISS, than in ILS, mice.Conclusions: Differential ethanol‐ and MK‐801‐induced behavioral activation in ILS and ISS mice was not associated with differences in NMDAR number. Nonetheless, pharmacological differences in hippocampal NMDAR responsiveness suggest that ISS mice express NMDARs that have a greater sensitivity to noncompetitive, but not competitive, NMDAR antagonists. These differences, which may reflect differences in NMDAR subunit composition, could underlie the differential responsiveness to low doses of ethanol in ILS and ISS mice.

Acute and chronic alcohol exposure significantly affect behavior but the underlying neurobiological mechanisms are still poorly understood. Here, we used functional connectivity density (FCD) mapping to study alcohol-related changes in resting brain activity and their association with behavior. Heavy drinkers (HD, N=16, 16 males) and normal controls (NM, N=24, 14 males) were tested after placebo and after acute alcohol administration. Group comparisons showed that NM had higher FCD in visual and prefrontal cortices, default mode network regions and thalamus, while HD had higher FCD in cerebellum. Acute alcohol significantly increased FCD within the thalamus, impaired cognitive and motor functions, and affected self-reports of mood/drug effects in both groups. Partial least squares regression showed that alcohol-induced changes in mood/drug effects were associated with changes in thalamic FCD in both groups. Disruptions in motor function were associated with increases in cerebellar FCD in NM and thalamus FCD in HD. Alcohol-induced declines in cognitive performance were associated with connectivity increases in visual cortex and thalamus in NM, but in HD, increases in precuneus FCD were associated with improved cognitive performance. Acute alcohol reduced 'neurocognitive coupling', the association between behavioral performance and FCD (indexing brain activity), an effect that was accentuated in HD compared with NM. Findings suggest that reduced cortical connectivity in HD contribute to decline in cognitive abilities associated with heavy alcohol consumption, whereas increased cerebellar connectivity in HD may have compensatory effects on behavioral performance. The results reveal how drinking history alters the association between brain FCD and individual differences in behavioral performance.

Background: Diet is a modifiable behavior of interest in multiple sclerosis (MS); however, measures of diet in persons with MS have not been vetted for feasibility, acceptability, and validity. Methods: This cross-sectional study examined the Automated Self-Administered 24-H (ASA24) Dietary Assessment Tool in 30 persons with MS and 15 healthy control (HC) participants. Participants were prompted to complete six ASA24 recalls and undergo a standard doubly labeled water (DLW) protocol. Acceptability of ASA24 was assessed using an online questionnaire. Total energy expenditure (TEE) from DLW was compared with ASA24-reported energy intake for assessing validity. Results: All participants completed four or more ASA24 recalls, indicating feasibility of ASA24. Regarding acceptability, the hardest part of completing the ASA24 was remembering everything eaten the previous day. Pearson correlation coefficients between DLW TEE and ASA24 kcal/day were not significant among HC (r = 0.40; p = 0.14) or MS (r = 0.26; p = 0.16) participants. The absolute mean error between DLW TEE and ASA24 among HC participants was 694.96 ± 506.25 mean kcal/day and among MS participants was 585.37 ± 529.02 mean kcal/day; this represents a mean difference of 30 and 25%, respectively. Conclusion: This study established the feasibility and acceptability of ASA24 in persons with MS and provides a foundation regarding the need for further validation research examining appropriate outcomes for supporting dietary interventions.

AbstractChronic ethanol consumption stimulates neuroimmune signaling in the brain, and Toll‐like receptor (TLR) activation plays a key role in ethanol‐induced inflammation. However, it is unknown which of the TLR signaling pathways, the myeloid differentiation primary response gene 88 (MyD88) dependent or the TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF) dependent, is activated in response to chronic ethanol. We used voluntary (every‐other‐day) chronic ethanol consumption in adult C57BL/6J mice and measured expression of TLRs and their signaling molecules immediately following consumption and 24 hours after removing alcohol. We focused on the prefrontal cortex where neuroimmune changes are the most robust and also investigated the nucleus accumbens and amygdala. Tlr mRNA and components of the TRIF‐dependent pathway (mRNA and protein) were increased in the prefrontal cortex 24 hours after ethanol and Cxcl10 expression increased 0 hour after ethanol. Expression of Tlr3 and TRIF‐related components increased in the nucleus accumbens, but slightly decreased in the amygdala. In addition, we demonstrate that the IKKε/TBK1 inhibitor Amlexanox decreases immune activation of TRIF‐dependent pathway in the brain and reduces ethanol consumption, suggesting the TRIF‐dependent pathway regulates drinking. Our results support the importance of TLR3 and the TRIF‐dependent pathway in ethanol‐induced neuroimmune signaling and suggest that this pathway could be a target in the treatment of alcohol use disorders.