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[(3)H]Lysergic acid diethylamide (LSD) in the presence of 40 nM ketanserin labeled the 5-HT(1A) receptor subtype in rat hippocampal membranes. In the presence of guanosine triphosphate (GTP), the B(max) and affinity of [(3)H]LSD binding to the 5-HT(1A) binding site were significantly decreased. [(3)H]LSD in the presence of 40 nM WB4101 labeled the 5-HT(2) receptor subtype in homogenates of rat frontal cortex. In contrast to the effect on [(3)H]LSD binding to the 5-HT(1A) binding site, GTP produced no significant effect on either the B(max) or the K(D) of [(3)H]LSD binding to the 5-HT(2) binding site. Competition of 5-HT for [(3)H]LSD binding to the 5-HT(2) binding site was best described by a computer-derived model assuming two binding sites. In the presence of GTP, the 5-HT competition curve was shifted significantly to the right with an approx. 3-fold increase in the IC(50). These binding characteristics are consistent with [(3)H]LSD acting as an antagonist at the 5-HT(2) receptor which has multiple affinity states for agonists and is coupled to a guanine nucleotide regulatory subunit. Thus, [(3)H]LSD has binding characteristics consistent with it acting as an agonist at the 5-HT(1A) receptor subtype but as an antagonist at the 5-HT(2) receptor subtype in rat brain.