modeling parkinsons disease genetics altered function of the dopamine system in adh4 knockout mice class iv alcohol dehydrogenase adh4 efficiently reduces aldehydes produced during lipid peroxidation and may thus serve to protect from toxic effects of aldehydes eg on neurons we hypothesized that adh4 dysfunction may increase risk for parkinsons disease pd and previously reported association of an adh4 allele with pd we found that a promoter polymorphism in this allele induced a 2530 reduction of transcriptional activity based on these findings we have now investigated whether adh4 homo adh4 or heterozygous adh4 knockout mice display any dopamine systemrelated changes in behavior biochemical parameters or olfaction compared to wildtype mice the spontaneous locomotor activity was found to be similar in the three groups whereas administration of damphetamine or apomorphine induced a significant increase in horizontal activity in the adh4 mice compared to wildtype mice we measured levels of monoamines and their metabolites in striatum frontal cortex and substantia nigra and found increased levels of dopamine and dopac in substantia nigra of adh4 mice investigation of olfactory function revealed a reduced sense of smell in adh4 mice accompanied by alterations in dopamine metabolite levels in the olfactory bulb taken together our results suggest that lack of adh4 gene activity induces changes in the function of the dopamine system findings which are compatible with a role of lossoffunction mutations in adh4 as possible risk factors for pd