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.
David Fiorella, Scott Helsley, D S Lorrain, R A Rabin, Jerrold C Winter
Psychopharmacology October 1995 DOI: 10.1007/bf02246076 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Rats (LSD-trained rats; rat brain tissue) |
| Interventions | p-chlorophenylalanine (PCPA) p-chloroamphetamine (PCA) |
| Topics | LSD Serotonin |
| Key findings | PCPA and PCA both depleted brain serotonin and 5-HIAA, but only PCPA caused supersensitivity to LSD's discriminative stimulus and a 46% increase in maximal 5-HT2C receptor-mediated phosphoinositide hydrolysis. The authors suggest this 5-HT2C upregulation mediates the supersensitivity to LSD's stimulus effects after serotonin depletion. |
Abstract
The present study was designed to determine the effects of p-chlorophenylalanine (PCPA) and p-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-HT2A and 5-HT2C 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-HT2A 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-HT2C receptor mediated PI hydrolysis. These data suggest that upregulation of the 5-HT2C receptor mediates the supersensitivity to LSD discriminative stimulus which follows the depletion of central nervous system serotonin by PCPA.