LSD and structural analogs: pharmacological evaluation at D1 dopamine receptors

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Abstract
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 (K0.5 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 (nH2 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 (K0.5 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 D1A receptor. LSD and the analogs tested bound to C-6 mD1A 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.