Role of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol

Abstract

Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological properties). Recent studies have shown that the direct administration of acetaldehyde, especially into the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce sedative as well as movement- and memory-impairing effects, whereas lower doses produce behavioral effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol's effects, investigators have pharmacologically manipulated alcohol metabolism and the production of acetaldehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties. However, it remains controversial whether acetaldehyde concentrations obtained under normal physiological conditions are sufficient to induce significant pharmacological effects. Current evidence suggests that the contribution of acetaldehyde to alcohol's effects is best explained by a process in which acetaldehyde modulates, rather than mediates, some of alcohol's effects.

Figure 1

Schematic representation of the metabolism of ethanol (ETOH) and the effects of aldehyde dehydrogenase (ALDH) inhibitors and catalase modulators. Under normal physiological conditions, ethanol is metabolized to acetaldehyde (ACA) through several enzymatic pathways involving alcohol dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1), or catalase. When ALDH is pharmacologically inhibited, acetaldehyde accumulates to high concentrations both in the brain and in the periphery. Catalase metabolizes about 60 percent of ethanol in the brain. Therefore, inhibition of catalase is believed to reduce brain acetaldehyde levels, whereas enhancement of catalase activity is believed to increase brain acetaldehyde levels.

Figure 2

Schematic representation of three alternative models that account for the role of acetaldehyde in ethanol’s (ETOH’s) effects. According to the ethanol model, acetaldehyde (ACA) does not contribute at all to ethanol’s overall pharmacological effects, and all effects are mediated directly by the molecular action of ethanol. The full prodrug model states that all pharmacological effects of ethanol are mediated by acetaldehyde. According to this model, ethanol would be a mere prodrug without pharmacological effect of its own. Finally, the intermediate modulation model stipulates that acetaldehyde synergistically interacts with ethanol to modulate ethanol’s pharmacological effects.