Alcohol dependence mechanisms

Littleton J, Zieglgansberger W Pharmacological mechanisms of naltrexone and acamprosate in the prevention of relapse in alcohol dependence. Am J Addict 12 (suppl 1) S3-S11,2003... 

Lerman, C.R.D., Kaufmann, V., Audrain, J., Hawk, L., Liu, A., Niaura, R., Epstein, L. Mediating mechanisms for the impact of bupropion in smoking cessation treatment. Drug Alcohol Depend. 67 219, 2002. 

Self, D.W. and Nestler, E.J. Relapse to drug-seeking neural and molecular mechanisms. Drug Alcohol Depend. 51 49, 1998. 

Morgenstern J and Longabaugh R (2000). Cognitive behavioural treatment for alcohol dependence A review of evidence for its hypothesized mechanisms of action. Addiction, 95, 1475-1490. 

Spyridopoulos, I., Wischhusen, J., Rabenstein, B., Mayer, P., Axel, D.L, Frohheh, K.U., and Karsch, K.R., 2001, Alcohol Errhances Oxysterol-lnduced Apoptosis in Human Endothelial Cells by a Caldum-Dependent Mechanism, Arterioscler. Thromb. Vase. Biol. 21 439 144. 

Mechanism of Action An alcohol abuse deterrent that appears to interact with glutamate and gamma-aminobutyric acid neurotransmitter systems centrally, restoring their balance. Therapeutic Effect Reduces alcohol dependence. Pharmacokinetics Slowly absorbed from the G1 tract. Steady-state plasma concentrations are reached within 5 days. Does not undergo metabolism. Excreted in urine. Half-life 20-33 hr. 

Although the mechanism of action of SSRIs in treating alcohol dependence remains unclear, Gorelick and Paredes ( 432) postulate that it is not due to motor inhibition or general sedation. Rather, they believe it may be related to decreased appetite and food intake or a conditioned taste aversion mediated by increased brain serotonin activity. Other competing theories have been summarized by Thomas ( 433) ... 

Heilig M, Egli M Pharmacologic treatment of alcohol dependence Target symptoms and target mechanisms. Pharmacol Ther 2006 111 855. 

A somewhat similar oxidation of terminal alkenes to methyl ketone and alcohol by 02 in the presence of Co(salMDPT) [salMDPT = bis(salicylideneiminopropyl)methylamine] and in ethanol solvent has recently been reported by Drago and coworkers (equation 244).560 Only terminal alkenes were found to be reactive with this catalytic system. The reaction is alcohol dependent and occurs in ethanol and methanol but not in t-butyl or isopropyl alcohols. The alcohol is concomitantly oxidized during the reaction, and may act as a coreducing agent and/or favor the formation of cobalt hydride. This oxidation might occur according to the mechanism of equation (243). 

The mechanism of the aerobic oxidation of alcohols depends on the particular catalyst used. Two general mechanisms can be considered (1) the direct oxygenation of alcohols by 02 through a free-radical chain process initiated by the catalyst, and (2) the direct oxidation of the alcohol by the catalyst, which is then regenerated by 02. Both mechanisms are well illustrated [6] by the aerobic oxidations catalyzed by the persistent tetramethylpiperidine-N-oxyl (TEMPO) radical 1 and the nonpersis-tent phthalimide-N-oxyl (PINO) radical 2. 

This Fischer esterification reaction reaches equilibrium after a few hours of refluxing. The position of the equilibrium can be shifted by adding more of the acid or of the alcohol, depending on cost or availability. The mechanism of the reaction involves initial protonation of the carboxyl group, attack by the nucleophilic hydroxyl, a proton transfer, and loss of water followed by loss of the catalyzing proton to give the ester. Because each of these steps is completely reversible, this process is also, in reverse, the mechanism for the hydrolysis of an ester ... 

Acamprosate (calcium acetylhomotaurinate) has been postulated to act by restoring the alcohol-induced neurotransmission imbalance of inhibition-excitation inputs believed to underlie alcohol dependence (1,2). The molecular structure of acamprosate explains its specificity toward the basic molecular mechanisms involved in the pathophysiology of alcohol dependence. A competitive interaction has been described between spermidine and acamprosate, suggesting a specific binding site for acamprosate on A-methyl-D-aspartate receptors (3). 

The rate of the reaction of MeOH with CO catalyzed by NaOMe depends on the concentration of the MeO ion and on the pressure of CO to the first power. The rates are higher for secondary and tertiary than for primary alcohols. The mechanism is ... 

Topiramate, a drug used for treating seizure disorders, appears useful for treating alcohol dependence. Compared with the placebo group, patients taking topiramate achieved more abstinent days and a lower craving for alcohol. The mechanism of action of topiramate is not well understood but is distinct from that of other drugs used for the treatment... 

Both acute and chronic alcohol use can lead to impotency in men. Increased blood alcohol concentrations lead to decreased sexual arousal, increased ejaculatory latency, and decreased orgasmic pleasure. Additionally, many chronic alcoholics develop testicular atrophy and decreased fertility the mechanisms are complex and likely involve altered hypothalamic function and a direct toxic effect of alcohol on Leydig cells. Testosterone levels may be depressed, but many men who are alcohol-dependent have normal testosterone and estrogen levels. Gynecomastia is associated with alcoholic liver disease and is related to increased cellular response to estrogen and to accelerated metabolism of testosterone. 

There is extensive history on the use of stoichiometric and catalytic organic nitroxyls for alcohol oxidation, wherein the key step involves a reaction between the alcohol and an JV-oxoammonium salt (Scheme 15.5, featuring TEMPO) [18, 20]. The JV-oxoammonium salt can be formed in situ from the corresponding nitroxyl radical using various oxidants, such as NaOCl or NO2 (Scheme 15.5, top left), or by acid-induced disproportionation of the nitroxyl into N-oxoammonium and hydroxylamine species (Scheme 15.5, bottom left) [21]. Stable Af-oxoammonium salts have also been isolated and used directly as reagents or catalysts for alcohol oxidation [22]. The pH-dependent mechanism of the reaction of the Af-oxoammonium salt with alcohols has been studied... 

Scheme 15.5 Generation of A/-oxoammonium salts from nitroxyl radicals, and the pH-dependent mechanism of oxoammonium reactivity ith alcohols hydride transfer at pH < 5 (Path A) and adduct formation/Cope-type elimination at pH > 5 (Path B).

---