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Alcohol
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
According to this theory, acetaldhyde, which results from the metabolism of ethanol, primarily in the liver, but possibly also in the brain183 interferes with the biological disposition of a biogenic amine, namely dopamine. Normally, as shown in Figure 4, dopamine is converted to 3, 4-dihydroxyphenyl acetaldehyde which is oxidized to its corresponding acid. Acetaldehyde, however, is a known inhibitor of the oxidation of aromatic aldehydes. Excess acetaldehyde originating from the ethanol may decrease the normal pathway of dopamine metabolism, thereby enhancing the condensation of 3, 4-diphydroxy-phenyl acetaldehyde with dopamine to form tetrahydropapaveroline. Indeed both ethanol and acetaldehyde significantly enhance tetrahydropapaveroline synthesis in brain stem homo-genates.184 In plants, tetrahydropapaveroline is a natural biosynthetic precursor of a vast complex of alkaloids which include morphine type compounds. It is conceivable that tetrahydropapaveroline could be formed as a consequence of alcohol abuse and then undergo similar biotransformation in mammalian systems, as illustrated in Figure 4. In summary, it has been postulated by Davis et al.184 that diversion of neuroamine metabolism with formation of biologically active alkaloid derivatives may then be involved in alcoholism. This theory has been the subject of vigorous criticism but thus far it has been neither conclusively proven nor disproven. An important objection raised was the striking clinical difference in the features of ethanol and morphine physical dependence,185 but the hypothesis does not need to be relevant to all aspects of tolerance and physical dependence in alcoholism. Some of these could well be more directly related to other pharmacological actions of ethanol rather than to the proposed hypothesis. Other objections focused on the lack of direct evidence that tetrahydro-papaveroline is formed in vivo.186 It was also found that ethanol-dependent mice, when challenged with an opiate antagonist, do not develop opiate-dependent behavior.187 Again, this latter criticism does not fully disprove the proposed theory, but indicates that the aspects of physical dependence in question are based on some different mechanism.
Aldehyde dehydrogenase-2 as a therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2019
Mitsuru Kimura, Akira Yokoyama, Susumu Higuchi
Disulfiram has also been reported to be effective in the treatment of cocaine addiction. Several clinical trials have demonstrated that disulfiram treatment reduces cocaine use in patients with cocaine addiction regardless of alcohol abuse [107–110]. A possible mechanism for this effect is that disulfiram inhibits the activity of dopamine β-hydroxylase (DBH), an enzyme that converts dopamine to norepinephrine [111,112]. The decreased levels of norepinephrine by the inhibition of DBH reduces attenuates α1-adrenergic receptor signaling and results in dopamine release in the nucleus accumbens, which is essential for cocaine-primed reinstatement [112]. However, Yao et al. reported the effect may be via ALDH2 inhibition [113]. To examine their hypothesis, the group used a selective ALDH2 inhibitor (ALDHi) in rats. ALDH2 inhibition by ALDHi increased the DOPAL concentration and tetrahydropapaveroline (THP) formation, the product formed by the condensation of dopamine and DOPAL. THP inhibits tyrosine hydroxylase selectively and results in the suppression of dopamine production in the ventral tegmental area neurons, which is thought to suppress the reinforcing effect of cocaine.