Alpha 2 adrenergic receptors play an important role in regulating the neuronal release of norepinephrine through presynaptic feedback inhibition in the locus ceruleus. Therefore, alpha 2 adrenergic autoreceptors may underlie some aspects of the pathogenesis and symptomatic expression of depressive illness. We studied two brain-expressed alpha 2 adrenergic receptor genes as genetic markers in linkage analyses in 17 multiplex pedigrees of unipolar depression. Neither of the genes was supportive of linkage to depression. Lod scores of less than -2 were found in both familial pure depressive disease pedigrees and in depression spectrum disease pedigrees. Therefore, we conclude that depression in our pedigrees is not related to mutations in the two alpha 2 adrenergic receptor genes tested.