Three drug classes—dopaminergic agonists (e.g., D-amphetamine), serotonergic agonists (e.g., LSD), and glutamatergic antagonists (e.g., PCP)—produce schizophrenia-like effects in animals. A common signaling pathway involving the protein DARPP-32 mediates these effects. DARPP-32 is phosphorylated or dephosphorylated at three sites, leading to synergistic inhibition of protein phosphatase-1 and regulation of downstream effectors GSK-3, CREB, and c-Fos. In mice lacking DARPP-32 or with point mutations at its phosphorylation sites, the drugs' effects on sensorimotor gating and repetitive movements were strongly reduced, indicating DARPP-32's essential role in these psychotomimetic actions.
An enzyme called adenylate cyclase, found in the thoracic ganglia of an insect nervous system, is specifically activated by low concentrations of serotonin. This activation is selectively blocked by very low concentrations of D-lysergic acid diethylamide (LSD), 2-bromo-LSD, and cyproheptadine, substances known to block certain serotonin receptors in living organisms. The inhibition is competitive with respect to serotonin, and the inhibitory constant of LSD for this serotonin-sensitive adenylate cyclase is 5 nM. These findings suggest that the serotonin receptor in neural tissue is closely linked to this enzyme, which may mediate serotonergic neurotransmission, and that some physiological effects of LSD might occur through interaction with this enzyme.