Histidyl-proline diketopiperazine (His-Pro DKP) has been proposed as a metabolite of thyrotropin releasing hormone (TRH). Since spinal cord TRH arises from serotoninergic (5-HT) neurons in the brainstem, a 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), was injected into the lateral ventricle of 7 rats, and the levels of TRH and His-Pro DKP in the spinal cord were studied 5 weeks later. In comparison to the saline treated controls, 5,7-DHT treated animals showed marked depletion of TRH throughout the spinal cord, especially in the lumbosacral area where almost 90% disappeared, (0.28 +/- 0.02 vs. 2.46 +/- 0.01 ng/mg protein; P less than 0.0001). In contrast, His-Pro DKP showed no significant change in any region. Since 5,7-DHT lowers spinal cord TRH by destroying TRH perikarya in the medulla, we conclude that spinal cord His-Pro DKP is not derived from the same neurons as TRH.