Development Of Tolerance To Alcohol Research Articles

Computational Screening of Phytochemicals against Munc13-1, a Promising target to treat Alcoholism

In silico analysis and characterization has revolutionized target and drug discovery significantly. Alcohol abuse is a big threat to society, economy and wellbeing of people. It has increased the overall disease and injury burden, globally. Recently, a study revealed a brain protein, Munc13-1 C1 domain to play a significant role in development of alcohol tolerance, by binding to alcohol molecules, eventually leading to Alcohol Use Disorder. The aim of this study was to discover a phytochemical that would attach to our target protein, Munc13-1 C1 domain so that it cannot bind with the alcohol molecules. Munc13-1 3D structure obtained from PDB was docked against a library of compounds by MOE software. Ten phytochemicals based on their binding affinity with the target protein were shortlisted i.e. Tannic Acid, Anemone blue anthocyanin 1, Oolonghomobisflavan B, Diosmin, Oolonghomobisflavan A, Neodiosmin, Blepharocalyxin B, 8-Hydroxyhesperetin, Eupatorin and Monotesone A. However, only 8-Hydroxyhesperetin, Eupatorin and Monotesone A followed Lipinski rules. They were non-toxic and non-carcinogenic according to SwissADME. Moreover, have a good drug-like model score as analysed by Molsoft. Further, in-vivo and invitro examinations are required to inspect their role in reducing alcohol tolerance.

Sir2/Sirt1 Links Acute Inebriation to Presynaptic Changes and the Development of Alcohol Tolerance, Preference, and Reward.

Acute ethanol inebriation causes neuroadaptive changes in behavior that favor increased intake. Ethanol-induced alterations in gene expression, through epigenetic and other means, are likely to change cellular and neural circuit function. Ethanol markedly changes histone acetylation, and the sirtuin Sir2/SIRT1 that deacetylates histones and transcription factors is essential for the rewarding effects of long-term drug use. The molecular transformations leading from short-term to long-term ethanol responses mostly remain to be discovered. We find that Sir2 in the mushroom bodies of the fruit fly Drosophila promotes short-term ethanol-induced behavioral plasticity by allowing changes in the expression of presynaptic molecules. Acute inebriation strongly reduces Sir2 levels and increases histone H3 acetylation in the brain. Flies lacking Sir2 globally, in the adult nervous system, or specifically in the mushroom body α/β-lobes show reduced ethanol sensitivity and tolerance. Sir2-dependent ethanol reward is also localized to the mushroom bodies, and Sir2 mutants prefer ethanol even without a priming ethanol pre-exposure. Transcriptomic analysis reveals that specific presynaptic molecules, including the synaptic vesicle pool regulator Synapsin, depend on Sir2 to be regulated by ethanol. Synapsin is required for ethanol sensitivity and tolerance. We propose that the regulation of Sir2/SIRT1 by acute inebriation forms part of a transcriptional program in mushroom body neurons to alter presynaptic properties and neural responses to favor the development of ethanol tolerance, preference, and reward. We identify a mechanism by which acute ethanol inebriation leads to changes in nervous system function that may be an important basis for increasing ethanol intake and addiction liability. The findings are significant because they identify ethanol-driven transcriptional events that target presynaptic properties and direct behavioral plasticity. They also demonstrate that multiple forms of ethanol behavioral plasticity that are relevant to alcoholism are initiated by a shared mechanism. Finally, they link these events to the Drosophila brain region that associates context with innate approach and avoidance responses to code for reward and other higher-order behavior, similar in aspects to the role of the vertebrate mesolimbic system.

3H]Ifenprodil binding in post-mortem brains of Cloninger type 1 and 2 alcoholics: A whole-hemisphere autoradiography study

The glutamate N-methyl-d-aspartate (NMDA) receptor NR2B subunits are sensitive to ethanol and are found in brain areas related to ethanol addiction, dependence, development of alcohol tolerance, and alcohol withdrawal syndrome. Previous studies indicate that early-onset Cloninger type 2 alcoholics have an intact, responsive, dopaminergic system in the nucleus accumbens (NAC), whereas type 1 alcoholics have dopaminergic defects. NR2B-containing NMDA receptors in the NAC are involved in both non-opioid and opioid receptor-mediated reward. Our aim was to evaluate the putative [3H]ifenprodil binding alterations of NR2B receptors in limbic, hippocampal, and cortical brain areas of type 1 alcoholics (n=8), type 2 alcoholics (n=8), and control subjects (n=10) by postmortem whole hemisphere autoradiography. We found significantly different binding levels among these three subject groups, and the main difference was localized in the decreased binding in type 2 alcoholics and controls in the nucleus accumbens. Although preliminary and from relatively small diagnostic groups, these results suggest pathological alterations in the NR2B-mediated reward system of type 2 alcoholics.

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish affected sib pair study of alcohol dependence (IASPSAD) sample

Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18-26%) and similarity (30-41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls. In analyses of genetically independent cases and controls, four of the seven single markers show strong evidence for association with AD (0.00003<Fisher's exact P<0.001), and the most significant single marker, rs7254880, tags an associated haplotype with frequency 0.071 in cases compared to 0.034 in controls (chi2 15.563, P<0.00008, 5000 permutation P<0.001, OR 2.17); inclusion of affected siblings gives similar results. Expression analyses conducted in independent postmortem brain samples show that expression of ZNF699 mRNA is significantly reduced in the dorsolateral prefrontal cortex of individuals carrying this haplotype compared with other observed haplotype combinations.

Gene expression in the hippocampus of inbred alcohol‐preferring and ‐nonpreferring rats

The hippocampus is sensitive to the effects of ethanol and appears to have a role in the development of alcohol tolerance. The objective of this study was to test the hypothesis that there are innate differences in gene expression in the hippocampus of inbred alcohol-preferring (iP) and -nonpreferring (iNP) rats that may contribute to differences in sensitivity to ethanol and/or in the development of tolerance. Affymetrix microarrays were used to measure gene expression in the hippocampus of alcohol-naive male iP and iNP rats in two experiments (n=4 and 6 per strain in the two experiments). Combining data from the two experiments, there were 137 probesets representing 129 genes that significantly differed (P < or = 0.01); 62 probesets differed at P < or = 0.001. Among the 36% of the genes that were expressed more in the iP than iNP rat at this level of significance, many were involved in cell growth and adhesion, cellular stress reduction and anti-oxidation, protein trafficking, regulation of gene expression, synaptic function and metabolism. Among the 64% of the genes that had lower expression in the hippocampus of iP than iNP rats were genes involved in metabolic pathways, cellular signaling systems, protein trafficking, cell death and neurotransmission. Overall, the data indicate that there are significant innate differences in gene expression in the hippocampus between iP and iNP rats, some of which might contribute to the differences observed in the development of alcohol tolerance between the selectively bred P and NP lines.

Changes in Dopamine Transporter and c‐Fos Expression in the Nucleus Accumbens of Alcohol‐Tolerant Rats

We have shown that neurochemical functions of 5-HT3 receptors in regulating dopamine (DA) release in the nucleus accumbens (ACC) after alcohol exposure compensate for the dysfunction of serotonergic activity to restore the original properties in processing alcohol tolerance, and that the development of alcohol dependence may be mediated by ACC 5-HT3 receptors. In the present study, the effects of chronic alcohol consumption on the functions of the dopamine transporter (DAT) and the expression of c-Fos proteins were investigated using in vivo brain microdialysis and immunocytochemistry. Perfusion of cocaine and 1-(2-Bis-(4-fluorophenyl) methoxy) ethyl)-4-(3-phenylpropyl) piperizine (GBR 12909) through the microdialysis probe membrane increased the extracellular levels of DA in ACC of alcohol-treated rats that had developed alcohol tolerance by drinking 10% EtOH for 30 days. The magnitudes of DA reuptake or DAT inhibitors, cocaine, and GBR 12909 that induced DA availability in the ACC were significantly higher in alcohol-treated rats than in controls. When compared with control rats, the alcohol-treated rats exhibited higher levels of DA and its metabolite, DOPAC, in the ACC. Increased expression of the c-Fos-like protein was found in the ACC of alcohol-treated rats. These results show that (1) chronic alcohol consumption desensitizes or decreases the DAT of DA terminals in the ACC and that (2) EtOH causes cellular hyperexcitability of ACC dopaminergic neurons with increased Fos expression during alcohol tolerance. The findings suggested that an abnormality of the dopaminergic neurons in the ACC that are involved with DAT dysfunction is associated with the development of alcohol tolerance.

More Vasopressin mRNA in the Paraventricular Hypothalamic Nucleus of Alcohol-Preferring Rats and High Alcohol-Drinking Rats Selectively Bred for High Alcohol Preference

Both the selectively bred alcohol-preferring (P) and high alcohol-drinking (HAD) rats exhibit alcohol preference, and develop tolerance to alcohol more quickly than their counterparts, the alcohol-nonpreferring (NP) and low alcohol-drinking (LAD) rats, respectively. It has been shown that the P rats retain developed tolerance longer than do NP rats, and alcohol drinking increases concurrently with the development of tolerance. Although alcohol preference and tolerance are fundamental elements of alcoholism, the exact mechanisms underlying these two phenotypes in P and HAD rats are not well understood. Recent studies have suggested that arginine vasopressin (AVP) may be involved in modulation of alcohol tolerance. Accordingly, this study was designed to examine whether the AVP mRNA level in the hypothalamus differs in rats that have been selectively bred for alcohol preference and nonpreference. A 35S-AVP antisense oligodeoxynucleotide probe was used for in situ hybridization to localize AVP mRNA in the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus (SON), two major sites for AVP synthesis in the hypothalamus. Quantitative autoradiography demonstrated that P rats had higher levels of AVP mRNA in the PVN than NP rats. Similarly, higher levels of AVP mRNA were also found in the PVN of HAD rats, compared with LAD rats. The AVP mRNA levels in the SON were similar in the alcohol-preferring and alcohol-nonpreferring rat lines. Basal plasma AVP levels were higher in NP rats than in P rats as determined by radioimmunoassay, whereas plasma AVP levels were not significantly different between HAD and LAD rats. The results suggest that increased AVP gene expression in the PVN may contribute to alcohol preference and the development of alcohol tolerance.

More vasopressin mRNA in the paraventricular hypothalamic nucleus of alcohol-preferring rats and high alcohol-drinking rats selectively bred for high alcohol preference.

Both the selectively bred alcohol-preferring (P) and high alcohol-drinking (HAD) rats exhibit alcohol preference, and develop tolerance to alcohol more quickly than their counterparts, the alcohol-nonpreferring (NP) and low alcohol-drinking (LAD) rats, respectively. It has been shown that the P rats retain developed tolerance longer than do NP rats, and alcohol drinking increases concurrently with the development of tolerance. Although alcohol preference and tolerance are fundamental elements of alcoholism, the exact mechanisms underlying these two phenotypes in P and HAD rats are not well understood. Recent studies have suggested that arginine vasopressin (AVP) may be involved in modulation of alcohol tolerance. Accordingly, this study was designed to examine whether the AVP mRNA level in the hypothalamus differs in rats that have been selectively bred for alcohol preference and nonpreference. A 35S-AVP antisense oligodeoxynucleotide probe was used for in situ hybridization to localize AVP mRNA in the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus (SON), two major sites for AVP synthesis in the hypothalamus. Quantitative autoradiography demonstrated that P rats had higher levels of AVP mRNA in the PVN than NP rats. Similarly, higher levels of AVP mRNA were also found in the PVN of HAD rats, compared with LAD rats. The AVP mRNA levels in the SON were similar in the alcohol-preferring and alcohol-nonpreferring rat lines. Basal plasma AVP levels were higher in NP rats than in P rats as determined by radioimmunoassay, whereas plasma AVP levels were not significantly different between HAD and LAD rats. The results suggest that increased AVP gene expression in the PVN may contribute to alcohol preference and the development of alcohol tolerance.

Genetic differences in tolerance and sensitization to the sedative/hypnotic effects of alcohol

Initial sensitivity to alcohol and the development of alcohol tolerance were examined in rats of the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines. All rats received two alcohol injections (3.0 g/kg b.wt., IP) separated by either 1 or 2 days. P rats were less sensitive to the behaviorally impairing effects of alcohol than were NP rats, as evidenced by a longer latency to lose righting reflex (RR) and a shorter time to recover RR following an initial alcohol injection. When 1 day separated the two alcohol injections, P rats recovered the RR more rapidly following a second injection compared to the first, indicating that the P rats developed tolerance to the sedative/hypnotic effects of alcohol. In contrast, the NP rats recovered the RR more slowly following the second injection compared to the first, indicating that the NP rats developed sensitization to alcohol. Tolerance in the P line and sensitization in the NP line disappeared when 2 days separated the two alcohol injections. Line differences in initial sensitivity and tolerance/sensitization to the behaviorally impairing effects of alcohol may contribute to the differences in alcohol consumption observed in the P and NP lines.

Effects of drinking history on development of alcohol-tolerance in humans: Raymond Niaura and Peter Nathan. Alcohol Behavior Research Lab, Rutgers University, NJ

Effects of drinking history on development of alcohol-tolerance in humans: Raymond Niaura and Peter Nathan. Alcohol Behavior Research Lab, Rutgers University, NJ

The development of alcohol tolerance: acute recovery as a predictor.

Two experiments examined individual differences in the rate of alcohol tolerance development as a function of acute recovery. Male social drinkers (n = 18) were trained on a complex psychomotor task and subsequently returned for four drinking sessions in which they received the same dose (0.84 ml absolute alcohol/kg) and performed the task at intervals while blood alcohol concentrations (BAC) rose and fell (peak BAC = 77.2 mg/dl). A subject's acute recovery from the impairing effect of alcohol during session 1 was measured by the difference in his performance at the same BAC on the rising and the falling limb of the curve. Rate-of-tolerance development was measured by the rate of change in the subject's average impairment under the alcohol during sessions 1-4. Acute recovery scores in both experiments significantly predicted the rate at which tolerance developed, accounting for 64% of the variance in these scores (P less than 0.0001). Subjects who displayed more acute recovery developed tolerance more quickly. The evidence was considered to imply that the same process may give rise to both acute recovery and tolerance.

Learned tolerance to the anticonvulsant effects of alcohol in rats

Ethanol (1.5 g/kg, IP) administered to kindled rats blocked the seizures normally elicited in these subjects by electrical stimulation of the amygdala. Tolerance to this anticonvulsant effect developed following a series of ethanol injections only when the amygdaloid stimulation was administered during the periods of ethanol intoxication. Control subjects stimulated each day prior to ethanol administration displayed no tolerance to ethanol's anticonvulsant effects. Such findings emphasize the important role of learning in the development of alcohol tolerance and support the view that tolerance develops more rapidly for responses that are affected by the alcohol exposure.

Learning and the development of alcohol-tolerance and dependence The role of vasopressin-like peptides

Learning and the development of alcohol-tolerance and dependence The role of vasopressin-like peptides

Learning and the development of alcohol-tolerance and dependence: The role of vasopressin-like peptides

Repeated, prolonged exposure to alcohol leads to the development of tolerance and, eventually, dependence. Daily drinking of even small amounts of alcohol will lead to a diminution of the experienced effects, or tolerance. If reasonably large amounts of alcohol are consumed for extended periods, physical dependence may develop, as measured by the occurrence of withdrawal symptoms (nausea, severe gastrointestinal upset, even convulsions) when alcohol is withheld. Tolerance and physical dependence are usually considered to be early and late manifestations, respectively, of the same or closely related physiological phenomena. More accurately, they appear to develop roughly in parallel. Recently there have been several adequate rodent models developed for the study of tolerance to and physical dependence on ethanol 2,5,6 . Application of these models may greatly increase our knowledge about the early stages of tolerance and dependence development and have considerable impact on theories of tolerance and dependence.

Cyclic nucleotides in the development of alcohol tolerance and dependence: A commentary

This paper aims to outline some of the caveats inherent in studies on first and second messengers in the central nervous system as related to tolerance and dependence. Analysis of systems based on measures of first and second messengers may be an over-simplification, since the actual molecular consequences of neurotransmission might result in a multilevel cascade of many sequential messages including protein kinase activation and protein phosphorylation and/or dephosphorylation.