LSD AND STRUCTURAL ANALOGS - PHARMACOLOGICAL EVALUATION AT D-1 DOPAMINE-RECEPTORS

The hallucinogenic effects of lysergic acid diethylamide (LSD) have be en attributed primarily to actions at serotonin receptors. A number of studies conducted in the 1970s indicated that LSD also has activity a t dopamine (DA) receptors, These latter studies are difficult to inter pret, however, because they were completed before the recognition of t wo pharmacologically distinct DA receptor subtypes, D-1 and D-2. The a vailability of subtype-selective ligands (e.g., the D-1 antagonist SCH 23390) and clonal cell lines expressing a homogeneous receptor populat ion now permits an assessment of the contributions of DA receptor subt ypes to the DA-mediated effects of LSD, The present study investigated the binding and functional properties of LSD and several lysergamide analogs at dopamine D-1 and D-2 receptors. Several of these compounds have been reported previously to bind with high affinity to serotonin 5HT(2) (i.e., H-3-ketanserin) sites in the rat frontal cortex (K-0.5 5 -30 nM). All tested compounds also competed for both D-1-like (H-3-SCH and D-2-like (H-3-spiperone plus unlabeled ketanserin) DA receptors i n rat striatum, with profiles indicative of agonists (n(H)<1.0). The a ffinity of LSD and analogs for D-2 like receptors was similar to their affinity for 5HT(2) sites. The affinity for D-1 like receptors was sl ightly lower (2- to 3-fold), although LSD and several analogs bound to D-1 receptors with affinity similar to the prototypical D-1 partial a gonist SKF38393 (K-0.5 ca. 25 nM). A second series of experiments test ed the binding and functional properties of LSD and selected analogs i n C-6 glioma cells expressing the rhesus macaque D-1A receptor. LSD an d the analogs tested bound to C-6 mD(1A) cells with affinity and kinet ics similar to those obtained in rat straitum. Additionally, LSD and s elected analogs were able to increase cAMP accumulation, albeit only a s partial agonists. Similar to the actions of SKF38393, they could sti mulate, as well as block, DA-stimulated cAMP synthesis. These results represent the first clear demonstration of the interaction of LSD with DA D-1 receptors, and provide a basis for evaluating the contribution of D-1 receptors to the biobehavioral actions of LSD.