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.
LSD reduces the binding potential of a dopamine D2/3 receptor tracer in the striatum of pigs, suggesting a direct interaction with these receptors. In a PET study, the binding potential of [11C]raclopride decreased by 19% four hours after LSD administration, without changes in cerebral blood flow. In vitro experiments showed LSD displaces the tracer from pig brain tissue with an IC50 of 275 nM, and a two-site model indicated a subnanomolar component comprising 20% of binding. Microdialysis in rats found no changes in dopamine or its metabolites. These findings indicate LSD directly occupies a portion of dopamine D2/3 receptors, which may contribute to its psychoactive effects.