Involvement of 5-hydroxytryptamine 2A (5-HT2A) receptors in the mediation of the discriminative stimulus properties of (+/-)DOI in rats.

Rats were trained to discriminate between the 5-HT2A/2C receptor agonist (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)DOI, 0.35 mg/kg] and saline using a two-lever drug discrimination procedure; afterwards, the effects of different 5-HT agonists and antagonists on the discriminative stimulus properties induced by (+/-)DOI were studied. In substitution tests, D-lysergic acid diethylamide (LSD, 0.02 and 0.04 mg/kg) and quipazine (0.5, 1.5 and 3 mg/kg), 5-HT2A/2C agonists, evoked dose-related responses to the (+/-)DOI-appropriate lever, while the non-selective 5-HT agonist 1-(3-chlorophenyl)piperazine (m-CPP, 0.1, 0.5 and 1 mg/kg), which has the highest binding affinity for 5-HT2C receptors, failed to show substitution. In antagonist studies, the discriminative stimulus effect of (+/-)DOI was completely antagonized by ketanserin (0.5 mg/kg) and cyproheptadine (0.5 mg/kg), preferential 5-HT2A receptor antagonists, and partially by the 5-HT2A/2C receptor antagonist mesulergine (0.25, 0.5 and 1.0 mg/kg) and the 5-HT2A/D2 antagonist spiperone (0.025, 0.05 and 0.1 mg/kg). The above data suggest that the discriminative stimulus effects of (+/-)DOI are predominantly mediated by 5-HT2A receptors.