Figure 3.

Efavirenz has discriminative stimulus effects that are similar to lysergic acid diethylamine (LSD) and consistent with serotonin 2A (5-HT_2A) receptor activity. (a) The data represent mean (±SEM) percent drug-appropriate responding (DAR) for eight rats discriminating 0.1 mg/kg LSD. Control data for vehicle and the training dose are shown to the left of the axis break, whereas substitution data for different doses of efavirenz alone and in combination with MDL100 907 are shown to the right. Drug-appropriate responding by efavirenz (30 mg/kg intraperitoneally) in rats discriminating LSD was fully blocked following pretreatment with a low dose of the 5-HT_2A-selective antagonist MDL100  907 (0.1 mg/kg intraperitoneally). The value n=5 indicates that three of the eight rats tested following 30 mg/kg efavirenz failed to complete the drug discrimination test. The asterisks (*) indicate the absence of a significant difference from the LSD control at P=0.05. Although rates of responding (responses per s) significantly decreased at all doses of efavirenz tested, a 58% decrease in rate of responses occurred at the 30 mg/kg dose (0.29±0.11 compared with 0.70±0.12 for the 0.1 mg/kg intraperitoneal training dose of LSD, P<0.05). The almost undetectable rates of responding at doses of efavirenz higher than 30 mg/kg precluded interpretation of the outcome of discrimination tests. MDL100 907 alone (0.1 mg/kg intraperitoneally) did not influence the rate of responding. (b) The graph shows efavirenz-appropriate lever responding as a function of discrimination training sessions in the presence of efavirenz (open squares) vs sessions with vehicle. With an 18 mg/kg intraperitoneal training dose, rats (n=6) reliably discriminated efavirenz from vehicle (⩾80% correct responding) within 20 training sessions, whereas a training dose of 10 mg/kg (the initial training dose) failed to yield evidence of stimulus control. *P<0.05, DAR is statistically different for vehicle vs efavirenz sessions. (c) LSD (0.1 mg/kg) occasioned drug-lever responding in rats discriminating efavirenz. *P<0.05, not statistically different from the training drug. All rats completed the first fixed ratio and there were no significant differences in the rates of responding (0.34±0.05 compared with 0.37±0.06 for the 18 mg/kg intraperitoneal training dose of efavirenz, P>0.05). (d) Efavirenz (15 mg/kg intraperitoneally) induces head-twitch in wild-type 129S6/SvEv mice, but not in 5-HT_2A-knockout (KO) littermates. Mice were injected with vehicle or efavirenz (15 mg/kg), and the head-twitch response was scored immediately after injection for 15 min. ***P<0.001; Bonferroni's post hoc test within two-way analysis of variance (ANOVA).