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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.

The arcuate nucleus of the hypothalamus (ARC) is a critical nexus of neuron populations that interpret peripheral signals of energy status and deliver diverse efferent outputs to metabolically active tissues. These neurons are critical to maintaining energy homeostasis, and disruption of their complex neurocircuitry results in metabolic disease phenotypes. The goals of this dissertation were to investigate the novel role for the circulating [alpha]-klotho protein to regulate neurons within the ARC to modulate peripheral metabolism. Intracerebroventricular administration of a recombinant [alpha]-klotho in lean, obese, and type I diabetic mice for 1-12 days revealed a novel role for [alpha]-klotho to regulate whole body energy and glucose metabolism. [alpha]-Klotho-treated mice experienced suppressed food intake, increased energy expenditure, and improved glucose clearance. Central [alpha]-klotho-mediated regulation of peripheral glucose metabolism was determined to be independent from body weight and insulin sensitivity but may be due to reduced hepatic gluconeogenic gene expression and improved insulin secretion. Furthermore, cerebrospinal fluid collected from humans demonstrated body weight is strongly and negatively correlated to [alpha]-klotho concentrations, suggesting central [alpha]-klotho is also important to energy homeostasis in humans. Experiments utilizing ex vivo patch clamp electrophysiology, immunohistochemical detection of the neuronal activation marker cFOS, and the immortal GT1-7 hypothalamic cell line demonstrated a novel role for [alpha]-klotho to regulate neurons in the ARC. [alpha]-Klotho decreased activity of the orexigenic neuropeptide Y/agouti-related peptide neuron population and increased activity of a subset of the anorexigenic proopiomelanocortin neuron population. [alpha]-Klotho was also shown to regulate the non-neuronal ARC astrocytes, which are involved in hormonal transport, nutrient-sensing, and neuronal health. Mechanistically, ICV pretreatment with inhibitors of fibroblast ...

Development of brain synaptosomal uptakes of 3H-norepinephrine and 3H-dopamine in pups whose mothers received ethanol were nearly normal. However, development of synaptosomal uptake of 3H-serotonin was significantly lower than in controls, while uptake of 3H-norepinephrine into synaptic storage vesicles was increased.

Long Sleep (LS) and Short Sleep (SS) mice differ in duration of ethanol-induced sleep time because of differences in brain sensitivity to the depressant effects of alcohols. These lines of mice also differ in their sensitivity to salsolinol, the condensation product of acetaldehyde with dopamine. Some of ethanol's acute effects may be due to salsolinol interactions with catecholamine systems. In the present study, the half-lives of salsolinol were found to be 12.8 min (LS) and 12.3 min (SS). Salsolinol administration resulted in a decrease in brain norepinephrine content in LS but not SS mice. Dopamine levels were not altered by salsolinol. Ethanol or salsolinol, in vitro, inhibited dopamine uptake by striatal synaptosomes. The IC50 values for ethanol were 491 mM (LS) and 514 mM (SS), and for salsolinol, 300 microM (SS). Thus, the mouse line which is most sensitive to the behavioral effects of salsolinol is also most sensitive to salsolinol's effects on norepinephrine levels and inhibition of dopamine uptake. However, much higher concentrations are required to alter dopamine uptake in vitro than are required to alter behavior in vivo.

Both marijuana and alcohol have effects on sleep which can be clinically important if either drug is used heavily. A number of polygraphic studies of both drugs' effect on sleep demonstrate that both are rapid eye movement (REM) sleep suppressors and that both effect the REM sleep deprivation response for days after the acute effects have ceased. Marijuana also increases slow wave sleep compared to alcohol which decreases it. The studies reviewed indicate that marijuana, like alcohol, has persisting effects on neuronal activity and presumably on its underlying neurochemical regulation. Also, the studies suggest that caution should be employed in advising the public about the use of marijuana.

AbstractTwenty patients with tongue tremor associated with essential tremor are reported. Patients were unaware of the tongue tremor, and voice disturbance was a complaint in only one patient. Three patients had an isolated tongue tremor. Hand tremor was present in 16 patients. Dystonia, myoclonus, and tremor of other body parts were present in some patients. Three patients had a mild‐to‐moderate dysarthria. The frequency of tongue tremor (4–8 Hz) was identical to hand tremor. The intravenous infusion of ethanol suppressed tongue tremor. Therapy with propranolol, primidone, or clonazepam also reduced tongue tremor amplitude. Tongue tremor is a common finding in some essential tremor patients but often there are no symptoms.

Background: Endogenous κ‐opioid receptor (KOPR) systems modulate the actions of several drugs of abuse. Their role in modulating the effects of ethanol is unknown. An increase in nucleus accumbens extracellular dopamine (DA) has been implicated in mediating the rewarding and locomotor‐activating effects of ethanol and virtually all drugs of abuse. The present microdialysis studies were conducted to determine whether the lack of KOPR alters ethanol‐evoked DA levels in the nucleus accumbens of naïve mice and whether a similar effect is observed in mice repeatedly exposed to ethanol.Methods: Gene deletion techniques were used in conjunction with in vivo microdialysis to examine the influence of lack of KOPR on ethanol‐evoked DA in the nucleus accumbens. To determine whether pharmacological inactivation of KOPR produces similar effects in naïve mice and those repeatedly exposed to ethanol, the KOPR antagonist norbinaltorphimine (n‐BNI) was administered in wild‐type mice before repeated air or ethanol vapor inhalation. Microdialysis was conducted 24 hours later.Results: Acute ethanol administration increased DA levels in the nucleus accumbens of wild‐type mice. In littermates lacking the KOPR gene, ethanol‐evoked DA levels were enhanced. Prior ethanol exposure reduced ethanol‐evoked DA levels in vehicle‐treated and n‐BNI–treated mice. Statistical analysis, however, revealed a significant main effect of n‐BNI, indicating that KOPR blockade increased ethanol‐evoked DA levels in naïve mice and repeated ethanol exposure attenuated, but did not abolish, this effect.Conclusions: These findings demonstrate that inhibition of KOPR leads to increased sensitivity to the DA‐releasing effects of ethanol in the nucleus accumbens.

Chronic alcohol consumption predisposes susceptible individuals to both acute and chronic pancreatitis.Our hypothesis was that alcohol increases the risk of pancreatitis by disrupting defense mechanisms and/or enhancing injury-associated pathways through altered gene expression. Hence, we studied the expression of pancreatic genes in rats chronically exposed to ethanol.Male Wistar rats were pair-fed liquid diets without and with ethanol for 4 weeks. Total RNA was extracted from rat pancreas and other organs. The mRNA expression patterns among pancreatic samples from ethanol-fed rats and controls were compared with use of mRNA differential display. The differentially expressed cDNA tags were isolated, cloned, and sequenced.One cDNA tag that was overexpressed in the pancreas showed 99% sequence homology to a rat pancreatic cholesterol esterase mRNA (CEL; Enzyme Commission number [EC] 3.1.1.13). The differential expression was confirmed by realtime PCR. Gene expression was also increased in the liver but not in the heart or brain of the alcohol-fed rats. Because CEL has fatty acid ethyl ester (FAEE)-generating activity and FAEEs play a major role in acute alcoholic pancreatitis, we determined the expression of other genes encoding for FAEE-generating enzymes and showed similar organ-specific expression patterns.Our results demonstrate that chronic ethanol consumption induced expression of FAEE-related genes in the pancreas and liver. This upregulation may be a central mechanism leading to acinar cell injury.

N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels essential for glutamatergic transmission and plasticity. NMDARs are inhibited by acute ethanol and undergo brain region-specific adaptations after chronic alcohol exposure. In previous studies, we reported that knock-in mice expressing ethanol-insensitive GluN1 or GluN2A NMDAR subunits display altered behavioral responses to acute ethanol and genotype-dependent changes in drinking using protocols that do not produce dependence. A key unanswered question is whether the intrinsic ethanol sensitivity of NMDARs also plays a role in determining behavioral adaptations that accompany the development of dependence. To test this, we exposed mice to repeated cycles of chronic intermittent ethanol (CIE) vapor known to produce a robust escalation in ethanol consumption and preference. As expected, wild-type mice showed a significant increase from baseline in ethanol consumption and preference after each of the four weekly CIE cycles. In contrast, ethanol consumption in male GluN2A(A825W) mice was unchanged following cycles 1, 2, and 4 of CIE with a modest increase appearing after cycle 3. Wild-type and GluN2A(A825W) female mice did not show a clear or consistent escalation in ethanol consumption or preference following CIE treatment. In male GluN1(F639A) mice, the increase in ethanol consumption observed with their wild-type littermates was delayed until later cycles of exposure. These results suggest that the acute ethanol sensitivity of NMDARs especially those containing the GluN2A subunit may be a critical factor in the escalation of ethanol intake in alcohol dependence.