PMC

(A) Pre-treatment with Ex-4 at 10μg/kg i.p. significantly decreased the number of reinforcements earned following a chronic cocaine administration setup at cocaine doses of 0.03, 0,32, and 1.0 mg/kg/infusion ** p<0,01, * p<0.05 vs. vehicle i.p.but not (B) inactive responses.

(A) Pre-treatment with Ex-4 at 30 and 100μg/kg i.p. significantly decreased nose-poking for cocaine at the peak effective self-administration dose for cocaine (0.03 mg/kg/infusion). * p<0.05 vs. vehicle i.p./saline i.v.; ## p<0.01, # p<0.05 vs. vehicle i.p./cocaine i.v. (B) Dose-effect curves after acute cocaine self-administration: effects of Ex-4. Cocaine was self-administered i.v. according to an inverted U-shaped curve in NMRI mice. Pre-treatment with Ex-4 at 30μg/kg i.p. shifted cocaine's dose-effect curve downward. ** p<0.01, * p<0.05, vs. the corresponding saline i.v. group; # p<0.05 vs. the corresponding vehicle-pretreated group.

(A) Basal locomotion after saline or Ex-4 treatment. Locomotion was evaluated as the total beam breaks during 90 minutes. ** p<0.01, * p<0.05. vs vehicle. (B) Cocaine-induced hyperactivity after 90 minutes of basal locomotion. Locomotor activity is presented as the total beam breaks during 90-150 minutes, * p<0.05 vs. vehicle, # p<0.05 vs. COC. (C) SKF-82,958-induced hyperactivity after 90 minutes of basal locomotion. Locomotor activity is presented as the total beam breaks during 90-150 minutes, *** p<0.0001 vs. the corresponding saline group, ## p<0.001 vs. the corresponding vehicle group.

Extracellular striatal dopamine levels in response to cocaine and Ex-4. Cocaine (30 mg/kg, s.c., black circles) significantly increased dopamine levels in mice pretreated with saline. The cocaine-induced dopamine increase was attenuated when mice were pretreated with Ex-4 (30 μg/kg, i.p., black squares). ** p<0.01, * p<0.05 vs. own basal level, Bonferroni post-hoc t-test after significant one-way ANOVA ### p<0.001, # p<0.05 vs. veh-COC, Bonferroni post-hoc t-test after significant two-way ANOVA.

Ex-4 attenuates cocaine-induced c-fos expression in the striatum. (A) Optical density analysis of the autoradiograms (***p<0.0001 vs. saline/saline, ###p<0.001 vs. saline/COC, Bonferonni post-hoc t-tests after significant One-way ANOVA) (B) C-fos expression in striatum determined by radioactive in situ hybridization in brain coronal slices in saline/saline group, (C) saline/COC (D) Ex-4/COC. The grey area in (B) indicates the area measured. Diagram adopted from Franklin and Paxinos [].