d-Penicillamine, a sulfhydryl amino acid derived from penicillin, is a highly selective agent for sequestering in vivo acetaldehyde, the first metabolic product of ethanol. A substantial amount of research supports the idea that brain acetaldehyde, produced by central ethanol metabolism, plays a key role in determining some of the behavioral effects of ethanol administration. This study addressed two questions. First, we tested if d-penicillamine was able to modify the depressant effects of acetaldehyde on behavior. Second, we studied the effect of d-penicillamine on ethanol-induced behavioral stimulation.


Mice were pretreated with 75.00 mg/kg of d-penicillamine, and 30 min later, they received acetaldehyde at 0, 100, 200, or 300 mg/kg intraperitoneally. Different groups of animals were treated with 0.0, 37.5, 75, 150, or 300 mg/kg of d-penicillamine simultaneously 30, 90, 150, or 210 min before the intraperitoneal administration of saline or 1.2, 1.8, 2.4, 3.0, or 3.6 g/kg of ethanol, respectively. The specificity of d-penicillamine effects was addressed using two drugs: cocaine (4 mg/kg) and caffeine (15 mg/kg).


Our results revealed that behavioral depression caused by acetaldehyde (200 and 300 mg/kg) could be attenuated by d-penicillamine treatment. In addition, d-penicillamine was also effective in lowering behavioral locomotion induced by ethanol (1.8 and 2.4 g/kg), without altering spontaneous locomotor activity. This sulfhydryl amino acid specifically modified the effect of ethanol on locomotion because cocaine- or caffeine-induced locomotion was unaffected. In addition, blood ethanol levels were not different between d-penicillamine- and saline-pretreated mice.


Behavioral effects produced by acetaldehyde and ethanol are blocked when animals are treated with d-penicillamine, an effective sequestration agent for acetaldehyde. These results suggest that some of the psychopharmacological effects, classically attributed to ethanol, could be mediated by its first metabolite, acetaldehyde.