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Histamine (HA) is a neurotransmitter that has been found in the brains of several species. We examined the brain of Rana pipiens using a well-characterized antibody to HA conjugated to 1-ethyl-3(3diamethylaminopropyl)-carbodiimide (EDCDI) with immunohistochemistry (IHC). Staining was enhanced by pre-treating the animals with histidine, colchicine, and quinacrine. IHC staining was done in the standard fashion using the "ABC" technique. HA-immunoreactive (HA-IR) fibers in the brain of Rana pipiens were distributed in a manner similar to that found in other species. The cerebral hemispheres were lightly labelled in nearly all regions. The hippocampus and diencephalon were labelled. The septal and nuclei and basal ganglia also contained HA-IR fibers. The optic tectum and torus semicircularis all demonstrated HA-IR fibers. In the optic tectum the HA-IR fibers were limited to the gray layers and central white layer. The brainstem contains widely distributed HA-IR fibers. The cerebellum was lightly labelled in the Purkinje and molecular cell and fibrous regions.