The histamine H(3) receptor is a constitutively active G protein-coupled receptor for the neurotransmitter histamine that serves a negative feedback function. A role for the histamine H(3) receptor has been suggested in neurodegenerative diseases, such as Parkinsons disease and Alzheimer's disease. Mice deficient in apolipoprotein E (apoE), a protein involved in development, regeneration, neurite outgrowth, and neuroprotection, show increased measures of anxiety and reduced sensitivity to effects of histamine H(3) receptor antagonists on measures of anxiety. In this study, we tested whether in mice lacking apoE (Apoe-/-) histamine levels and histamine release in brain areas involved in the regulation of anxiety are altered. H(3) receptor antagonist-induced histamine release was lower in the amygdala of Apoe-/- than wild-type mice. In contrast, there were no genotype differences in histamine release in the hypothalamus. Consistent with these data, histamine immunohistochemistry revealed lower total and synaptic histamine levels in the central nucleus of the amygdala of Apoe-/- than wild-type mice. Such changes were not seen in the hypothalamus, hippocampus, or cortex. In Apoe-/- mice, chronically decreased histamine levels and reduced histamine release in the amygdala might contribute to increased measures of anxiety.