Figure 4. Blockade of the FAAH enzyme by URB597 facilitates the occurrence of cocaine-induced single trial behavioral and NAC core neurochemical sensitization in animals pretreated with a non-sensitizing dose of cocaine.

This figure shows on panel A that mice pretreated with a 10 mg/kg dose of cocaine 24 hr in advance, and then tested with a dose of cocaine, 20 mg/kg i.p., did not display behavioral sensitization, measured as increased distance traveled, as compared with mice that were pretreated with saline 24 hr before [one way ANOVA shows NS effect of sensitization treatment, F(1,14)=0.029, p=0.866]. However, increased locomotor activity, indicating behavioral sensitization, was observed in mice tested with cocaine 20 mg/kg i.p. when they received a 24 hr pretreatment with cocaine 10 mg/kg that was preceded by administration 1 hr pretreatment with either 1 or 3 mg/kg i.p. doses of URB597 (which are known to block the FAAH) [two way ANOVA shows significant main effects of URB pretreatment, F(2,52)=3.326, p<0.05, cocaine treatment, F(1,52)=7.586, p<0.01, and their interaction, F(2,52)=3.163, p<0.05]. Panel B shows dopamine microdialysis data from mice implanted with probes in the NAC core that, in agreement with locomotor activity data, display a larger DAergic response in this brain area, indicating sensitization, obtained in animals pretreated with the FAAH blocker, URB597 (URB) 3 mg/kg i.p. administered 1 hr before a non-sensitizing dose of cocaine, 24 hr before the testing dose of cocaine, 20 mg/kg i.p., compared to animals that received URB vehicle pretretments (pretreatment groups’ number of animals, n, and basal DA values, fmoles/sample ± S.E.M., were: Veh+Sal, ● filled circles, n=4, 63.18±8.6; Veh+cocaine 10 mg/kg, ○ unfilled circles, n=8, 53.2+5.0; URB+Sal, ∎filled squares, n=5, 64.7±3.9; URB+cocaine 10 mg/kg, ◻ unfilled squares, n=6, 52.4±7.9) [two way ANOVA for repeated measures shows significant main effects of URB pretreatment, F(1,27)=4.556, p<0.05, and time, F(3,81)=76.781, p<0.001, and significant URB pretreatment by time interaction, F(3,81)=2.847, p<0.05]. In microdialysis experiments, results are expressed as means with vertical bars representing S.E.M. of the amount of DA in 10 minutes dialysate samples, expressed as percentage of basal values. * = p< 0.05, Tukey’s post-hoc test.