LSD and structural analogs: pharmacological evaluation at D₁ dopamine receptors

The hallucinogenic effects of lysergic acid diethylamide (LSD) have been attributed primarily to actions at serotonin receptors. A number of studies conducted in the 1970s indicated that LSD also has activity at dopamine (DA) receptors. These latter studies are difficult to interpret, however, because they were completed before the recognition of two pharmacologically distinct DA receptor subtypes, D₁ and D₂. The availability of subtype-selective ligands (e.g., the D₁ antagonist SCH23390) and clonal cell lines expressing a homogeneous receptor population now permits an assessment of the contributions of DA receptor subtypes to the DA-mediated effects of LSD. The present study investigated the binding and functional properties of LSD and several lysergamide analogs at dopamine D₁ and D₂ receptors. Several of these compounds have been reported previously to bind with high affinity to serotonin 5HT₂ (i.e.,³H-ketanserin) sites in the rat frontal cortex (K_0.5 5-30 nM). All tested compounds also competed for both D₁-like (³H-SCH 23390) and D₂-like (³H-spiperone plus unlabeled ketanserin) DA receptors in rat striatum, with profiles indicative of agonists (n_H<1.0). The affinity of LSD and analogs for D₂ like receptors was similar to their affinity for 5HT₂ sites. The affinity for D₁ like receptors was slightly lower (2- to 3-fold), although LSD and several analogs bound to D₁ receptors with affinity similar to the prototypical D₁ partial agonist SKF38393 (K_0.5 ca. 25 nM). A second series of experiments tested the binding and functional properties of LSD and selected analogs in C-6 glioma cells expressing the rhesus macaque D_1A receptor. LSD and the analogs tested bound to C-6 mD_1A cells with affinity and kinetics similar to those obtained in rat straitum. Additionally, LSD and selected analogs were able to increase cAMP accumulation, albeit only as partial agonists. Similar to the actions of SKF38393, they could stimulate, as well as block, DA-stimulated cAMP synthesis. These results represent the first clear demonstration of the interaction of LSD with DA D₁ receptors, and provide a basis for evaluating the contribution of D₁ receptors to the biobehavioral actions of LSD.