5-HT2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat

The possible effect of 5-HT2A/2C receptor agonists on an amphetamine-induced behavioral response was examined using the two-lever drug discrimination paradigm. The experiments were designed to investigate an interaction of the hallucinogenic 5-HT2A/2C agonists lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI), with the discriminative stimulus elicited by a relatively low dose of (+)-amphetamine (1.35 micromol/kg, 0.25 mg/kg, which produced approximately 50% selection of the drug lever). DOI and LSD did not produce amphetamine-like responding at any dose tested or time of administration. However, LSD alone was able to induce a drug-appropriate response in two of nine amphetamine-trained rats. Simultaneous administration of DOI or LSD with amphetamine was not significantly different from the response produced by amphetamine alone. Pre-administration of DOI (3 hr) or of LSD (2 hr) before amphetamine, however, evoked significant enhancement of the amphetamine cue. The results suggest that the enhanced behavioral response to amphetamine may be due either to an increased sensitivity of dopaminergic neurons in the mesolimbic area, or to an enhanced release of dopamine by amphetamine.