Hallucinogens recruit specific cortical 5-HT (2A) receptor-mediated signaling pathways to affect behavior?

GONZÁLEZ-MAESO J; WEISSTAUB NV; ZHOU M,; CHAN P; IVIC L; ANG R; LIRA A; BRADLEY-MOORE M; GE Y; ZHOU Q; SEALFON SC; GINGRICH JA.

NEURON

CELL PRESS

Año: 2007 p. 439 - 452

0896-6273

Hallucinogens, including mescaline, psilocybin,and lysergic acid diethylamide (LSD), profoundlyaffect perception, cognition, and mood. Allknown drugs of this class are 5-HT2A receptor(2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactiveproperties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediatetheir effects are poorly understood. By genetically expressing 2AR only in cortex, we showthat 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling patternand behavioral response to hallucinogens.Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same2AR-expressing cortical neurons. However, the signaling and behavioral responses to thehallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortexneurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitiveheterotrimeric Gi/o proteins and Src. These studies identify the long-elusive neural and signalingmechanisms responsible for the unique effects of hallucinogens