PUTATIVE OXIDATIVE METABOLITES OF METHYL-6-HYDROXY-1,2,3,4-TETRAHYDRO-BETA-CARBOLINE OF POTENTIAL RELEVANCE TO THE ADDICTIVE AND NEURODEGENERATIVE CONSEQUENCES OF ETHANOL ABUSE

Ethanol is metabolized in the brain by catalase/H2O2 to yield acetalde hyde and by an ethanol-inducible form of cytochrome P450 (P450 ILE1) i n a reaction that yields oxygen radicals. Within the cytoplasm of sero tonergic axon terminals these metabolic pathways together provide cond itions for the endogenous synthesis of methyl-6-hydroxy-1,2,3,4-tetrah ydso-beta-carboline (1), by reaction of acetaldehyde with unbound 5-hy droxytryptamine (5-HT), and for the oxygen radical-mediated oxidation of this alkaloid. The major initial product of the hydroxyl radical (H O)-mediated oxidation of 1 in the presence of free glutathione (GSH), a constituent of nerve terminals and axons, is methyl-1,2,3,4-tetrahyd ro-beta-carboline-5,6-dione (6). When administered into the brains of mice, 6 is a potent toxin (LD50 = 2.9 mu g) and evokes episodes of hyp eractivity and tremor. Compound 6 binds at the GABA(B) receptor and ev okes elevated release and turnover of several neurotransmitters. Furth ermore, the GABA(B) receptor antagonist phaclofen attenuates the behav ioral response caused by intracerebral administration of 6. These obse rvations suggest that 6 might be an inverse agonist at the GABA(B) rec eptor site. Accordingly, it is speculated that ethanol drinking might potentiate formation of 6 that contributes to elevated release of seve ral neurotransmitters including dopamine (DA) and endogenous opioids i n regions of the brain innervated by serotonergic axon terminals. Subs equent interactions of DA and opioids with their receptors might be re lated to the initial development of dependence on ethanol. Redox cycli ng of 6 (and of several putative secondary metabolites) in the presenc e of intraneuronal antioxidants and molecular oxygen to produce elevat ed fluxes of cytotoxic reduced oxygen species might contribute to the degeneration of serotonergic pathways. Low levels of 5-HT in certain b rain regions of the rat predisposes these animals to drink or augments drinking. Accordingly, 6, formed as a result of ethanol metabolism in the cytoplasm of certain serotonergic axon terminals, might contribut e to the initial development of dependence on ethanol, by mediating DA and opioid release, and long-term preference and addiction to the flu id as a result of the progressive degeneration of these neurons. (C) 1 997 Elsevier Science Inc.