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Perturbation of Rat Brain Serotonergic Systems Results in an Inverse Relation Between Substance P and Serotonin Concentrations Measured in Discrete Nuclei

Abstract: Since substance P (SP) has been demonstrated to coexist with serotonin (5‐HT) in the same population of neurons in the descending raphe system, we have studied the possibility of interactions between these neu‐rotransmitters in other brain areas. Brain nuclei were punched from frozen 300–μm slices of rat brain and extracted with 0.1 M HCIO4 or 2 M acetic acid prior to assay, respectively, of 5‐HT content by HPLC with electrochemical detection or SP content by specific radioimmunoassay. Ten days after injection of rats with the 5‐HT neurotoxin P‐chloroamphetamine (PCA, 10 mg/kg, B.W., i.p.) or 3 days after 5‐HT synthesis blockade with p‐chlorophenylalanine (PCPA, 300 mg/kg, B.W., i.p.), the 5‐HT content of all brain nuclei studied was reduced by means of, respectively, 50% and 81%. In PCA‐treated animals, the SP content of the periaqueductal grey matter was significantly increased; PCPA treatment caused, in addition, large increases in the SP content of five other brain nuclei. Blockade of 5‐HT receptors by methysergide (15 mg/kg for 5 days) did not significantly change 5‐HT levels or turnover, but resulted in 50–200% increases in the SP content of 10 of the 28 brain nuclei studied. Significant decreases in the SP content of numerous areas were seen following treatments (pargyline 30 mg/kg, alone or in combination with 5‐hydroxytryptophan, 60 mg/kg) that simultaneously increased 5‐HT levels. These results illustrate the modulation of distinct SP‐containing systems of the rat brain by perturbation of central serotoninergic pathways and indicate a reciprocal relationship between the SP and 5‐HT concentrations of numerous brain nuclei, in particular n. striae terminalis, n. raphe dorsalis, n. accumbens, n. septi, substantia grisea centralis, and n. raphes medianus.