Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior.
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.
González-Maeso
Javier
J
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Weisstaub
Noelia V
NV
Zhou
Mingming
M
Chan
Pokman
P
Ivic
Lidija
L
Ang
Rosalind
R
Lira
Alena
A
Bradley-Moore
Maria
M
Ge
Yongchao
Y
Zhou
Qiang
Q
Sealfon
Stuart C
SC
Gingrich
Jay A
JA
D000662:Amphetamines; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D004594:Electrophysiology; D006213:Hallucinogens / Q000494:pharmacology*; D017404:In Situ Hybridization, Fluorescence; D007650:Ketanserin / Q000494:pharmacology; D008090:Lisuride / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D000662:Amphetamines; D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D007650:Ketanserin; D008090:Lisuride; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine