The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs III: the mechanistic basis for supersensitivity to the LSD stimulus following serotonin depletion

The present study was designed to determine the effects ofp-chlorophenylalanine (PCPA) andp-chloroamphetamine (PCA) administration on (1) the levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain, (2) the sensitivity of LSD-trained rats to the stimulus effects of LSD, and (3) the maximal levels of 5-HT_2A and 5-HT_2C receptor mediated phosphoinositide (PI) hydrolysis in rat brain. PCA and PCPA both produced a significant depletion of whole brain 5-HT and 5-HIAA concentrations. The depletion of serotonin with PCPA, but not PCA, resulted in supersensitivity of LSD-trained subjects to the stimulus effects of LSD. Neither PCPA nor PCA treatment altered the maximal level of 5-HT_2A receptor-mediated PI hydrolysis. However, PCPA, but not PCA, treatment resulted in a significant upregulation (46%,P<0.05) of the maximal level of 5-HT_2C receptor mediated PI hydrolysis. These data suggest that upregulation of the 5-HT_2C receptor mediates the supersensitivity to LSD discriminative stimulus which follows the depletion of central nervous system serotonin by PCPA.This study was supported in part by US Public Health Service grant DA 03385 (J.C.W., R.A.R.), by National Research Service Award MH 10567 (D.F.), and by a fellowship from Schering-Plough Research Institute (D.F.). Animals used in these studies were maintained in accordance with the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council.