A BIOCHEMICAL‐BEHAVIORAL MODEL FOR STUDYING SEROTONERGIC SUPERSENSITIVITY IN BRAIN

Abstract

Abstract Chronic treatment with p ‐chlorophenylalanine methylester (PCPA) resulted in enhanced sensitivity to D,L‐5‐hydroxytryptophan (5‐HTP) induced inhibition of response rates in rats working on a Variable Interval 1 min schedule of milk reinforcement. Marked depletions of 5‐hydroxytryptamine (5‐HT) were found in the cerebral cortex, hippocampus, striatum, diencephalon, mesencephalon, and pons‐medulla oblongata. Much smaller dopamine depletions were seen in some areas, particularly the hippocampus and pons‐medulla oblongata. Analysis of the binding of [ 3 H]5‐HT to crude membrane fractions from the cerebral cortex of PCPA‐treated animals indicated a significant decrease in the apparent dissociation constant (K dAPP ) for 5‐HT, but no change in the maximum binding capacity. The increased behavioral sensitivity to 5–HTP does not seem to be due to increased conversion of 5‐HTP to 5‐HT, increased uptake of 5‐HTP, or release of 5‐HT by p ‐chlorophenylethylamine. However, the possibility that p ‐chlorophenylalanine or the metabolite p ‐chlorophenylacetic acid increased the binding of 5‐HT, thus decreasing K dAPP , cannot be ruled out. Some parallels between a recently proposed model of human depression and the observations of the present investigation are discussed.