Biosynthesis of tetrahydroisoquinoline alkaloids in brain and other tissues of ethanol-intoxicated rats.

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This paper summarizes some of our studies on the interactions of alcohol or amine-derived aldehydes with the catecholamines (CAs). There has been increasing research interest and speculation since 1968 in the potential formation of tetrahydroisoquinoline (TIQ) alkaloids in mammalian cells via such interactions, and in the role such TIQs may have in alcohol dependence. Reviewing, two principal TIQ theories related to alcoholism have been elaborated. (1) The initial suggestion is that ethanol (EtOH)-derived acetaldehyde (AcH) may produce “simple” (1-alkyl) TIQs from its bimolecular cyclization or condensation with CAs (Collins and Cohen, 1968; Robbins, 1968; Cohen and Collins, 1970; Yamanaka et al., 1970). The major products of these cyclizations, shown in Figure 1, are salsolinol derived from dopamine (DA), and the corresponding 4, 6, 7-trihydroxy-TIQ alkaloids derived from epinephrine (E) and nor-epinephrine (NE). For simplicity, the minor isomeric TIQs resulting from neutral aqueous cyclizations and stereochemical isomers of all products (Cohen and Collins, 1970; King et al., 1974) are not considered. (2) The second postulate depends upon the fact that EtOH-derived AcH, as a substrate for aldehyde dehydrogenase, may inhibit the oxidation and thereby elevate concentrations of endogenous phenylacetaldehydes which normally arise from DA and 3-methoxy-DA deaminations. Davis and Walsh (1970) suggested the EtOH-dependent augmentation of a TIQ formation route demonstrated in vitro a decade ago (Holtz et al., 1964), involving cyclization of the phenylacetal-dehydes with DA to give 1-benzyl-substituted-TIQs related or identical to tetrahydropapaveroline (Figure 1). Both theories suggest the alkaloids or their metabolites have neurophysiological actions that would persist after EtOH depressant effects had dissipated. These actions may be manifested in and underlie part of the alcohol withdrawal syndrome.