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 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.
Fiorella
D
D
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University, New York, USA.
Helsley
S
S
Lorrain
D S
DS
Rabin
R A
RA
Winter
J C
JC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011985:Receptors, Serotonin / Q000145:classification* / Q000187:drug effects*; D012680:Sensitivity and Specificity; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology
D006213:Hallucinogens; D011985:Receptors, Serotonin; D012701:Serotonin; D008238:Lysergic Acid Diethylamide