The effects of a tyrosine hydroxylase activator on the monoamine metabolism in rabbits exposed to tobacco smoke
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Nicotine is the most commonly used drug in the world today, with over 1.1 billion users worldwide, while smoking remains the single largest preventable cause of disease and premature death. Being the prime cause of cancer and heart disease, smoking also causes many other fatal conditions and chronic illnesses among adults. Of the 17 million smokers that try to quit smoking each year, fewer than one out of ten actually succeed. The success rate is only in the order of 2.5 % (WHO, 2002). Cigarette smokers have been shown to have lower platelet MAO levels than non-smokers because of possible decreased MAO synthesis, the presence of MAO inhibitory compounds in smoke or the fact that low MA0 individuals are more vulnerable to smoking (Oreland, 1981). Through positron emission tomography (PET) it was discovered that MAO-A levels are reduced by 30 %, and MAO-B levels by 40 % in smokers compared to non-smokers and ex-smokers (Fowler et al., 1996). Nicotine only inhibits MAO at levels 200 times higher than those found in smokers. Thus, smoking addiction is not induced by nicotine alone but also by other compounds in cigarette smoke that increase neurotransmitter amine concentrations (Fowler et al., 1998). Nicotine and MAO inhibition increase dopamine (DA) levels in several areas of the brain. The continuous increases in DA causes shifts from pleasure towards a wanting process such as drug cravings. Thus, the motivation for smoking may be directed to either restoring a homeostatic imbalance, or the enjoyment of behaviour associated with DA release (Nestler, 2004b). A direct link to serotonin (5-HT) involvement in the regulation of drug intake is provided by findings showing that manipulations which decrease brain 5-HT neurotransmission elevate self administration of several different drugs. An increase in 5-HT neurotransmission could reduce drug consumption by strengthening inhibitory control (Opitz & Weischer, 1988). Bupropion (BUP) (zybanB) is a phenylaminoketone, atypical anti-depressant in sustained release formulation, approved by the Food and Drug Administration (FDA) as the first non-nicotine pharmacotherapy for smoking cessation. The mechanism of action is not yet proven, but is likely to involve the modest blockade of DA and norepinephrine (NA) reuptake (Butz et a/., 1982), and the antagonism of high-affinity nicotinic acetylcholine receptors (Slemmer et a/., 2000). Bupropion was found to have a modulating effect on MAO, DA, NA and 5-HT and thus helps with smoking cessation (Xi-Ming Li et a/., 2001). A potential tyrosine hydroxylase activator (THA), nicotinamide adenine dinucleotide (NAD), has already been used successfully since 1939 for the shortterm treatment of alcoholism and various types of substance dependencies (Cleary, 1986). A THA will hypothetically terminate tobacco cravings due to its activation of tyrosine hydroxylase, which is important in the synthesis of DA. Recently, research confirmed that NAD had a normalizing effect on the neurotransmitters which causes the homeostatic imbalance to return to normal. NAD also plays a role in the production of 5-HT in the brain (South, 1997). We hypothesised that NAD will terminate the craving effects of tobacco addiction, having the same normalising effect as bupropion on DA and 5-HT levels and that it may be a MAO-B inhibitor. The rabbit was used as animal model for nicotine withdrawal. Rabbits were divided into four groups (n=8) and implanted subcutaneously with two AlzetB osmotic pumps, three groups containing smoke extract and one vehicle (propylene glycol). After twenty-seven days the pumps were removed and the three smoke groups (group 1, 2 and 3) treated with saline, NAD and bupropion respectively for four days and the control group (group 4) with NAD for four days. Blood samples were taken three times a day during the four days of treatment. The rabbits were decapitated on day five and the nucleus accumbens removed and frozen at -86 "C until analysed. MA0 activity as well as DA and 5-HT levels, including their metabolites, were determined in plasma and brain tissue. Groups receiving NAD and bupropion had higher DA and DOPAC blood levels compared to the control group 1, suggesting that NAD increases the DA levels to avoid a decrease of DA during withdrawel that leads to craving. Thus, NAD could have the same normalizing effects as bupropion, thereby identifying it as a potential drug for the treatment of smoke addiction. In the nucleus accumbens (NAc) no significant difference could be detected in the DA, 5-hydroxyindoleacetic acid (5-HIAA) or 5-HT concentrations between group 1, 2, 3 and 4 after four days of treatment, indicating that mono-amine levels have normalised after 4 days of treatment. DOPAC concentrations, however, were significantly lower on day 32 in the NAD treated group (group 2) and the bupropion treated group (group 3) compared to the control group. This decrease in DOPAC concentration was probably due to downregulation in an attempt to normalize DA levels. The weight of each rabbit was determined on day 1, 27 and 31 to determine the effect of NAD and bupropion 011 the weight of the rabbits. The two groups treated with NAD gained less weight than the saline- and bupropion-treated group, indicating that NAD might be valuable in the prevention of disproportionate amount of weight gain during smoking cessation. NAD did not inhibit either bovine or baboon MAO-6. Inhibition of MAO-6 can thus be eliminated as the possible mechanism by which NAD elevated DA levels. The results of Nel (2003) measuring withdrawl symptoms (e.g. locomotor activity, acoustic startle) in smoking rats treated with NAD , clearly indicated that NAD do reduce withdrawl symptoms in rats. Above results indicate that NAD has the same effect on monoamine levels as bupropion, preventing DA levels to fall below normal levels - the cause for craving and withdrawl symptoms. NAD treatment shows promising results and potential in the treatment of tobacco addiction and further research into its mechanism of action is paramount.
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