Intravenous drug self-administration in rats

Male Long-Evans rats (Charles River, Raleigh, NC, USA) were housed individually in a climate-controlled room on a reverse light–dark cycle with ad libitum access to food and water. Intravenous catheterization surgery and cocaine self-administration procedures under both fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules have been described previously [16]. After stable cocaine self-administration was achieved as defined in the SI Materials and methods, the effects of JJC8-088 or JJC8-091 on cocaine (0.5 mg/kg/infusion) self-administration under FR2 or PR were evaluated. This dose of cocaine is located in the middle of the descending limb of the self-administration dose-response curve [17, 18], which is important for evaluating whether a test compound produces an enhancement or inhibition of cocaine’s action. Additional groups were used to evaluate the reinforcing efficacy of JJC8-088 or JJC8-091 alone in drug-naive rats or in rats with a cocaine self-administration history. Between-subjects designs were used to study the dose effects of JJC8-088 or JJC8-091 on cocaine self-administration under FR2 or PR reinforcement (for all experiments shown in Fig. 1).

Evaluation of the effects of JJC8-088 and JJC8-091 on cocaine self-administration or self-administration by themselves. a JJC8-088 (3, 10, 30 mg/kg, i.p.) dose-dependently decreased cocaine self-administration under FR2 reinforcement conditions (F_3,33= 5.59, P < 0.01, one-way ANOVA). Post hoc individual group comparisons illustrated that JJC8-088 significantly decreased cocaine infusions after 10 mg/kg (q = 3.65, P < 0.05) or 30 mg/kg (q = 5.12, P < 0.01). b JJC8-091 (10, 30, 56 mg/kg, i.p.) did not produce a significant reduction in cocaine self-administration under FR2 reinforcement (F_3,42 = 1.67; P > 0.05). c JJC8-091, but not JJC8-088, significantly lowered the number of cocaine injections (and also break-point for cocaine self-administration) under the PR reinforcement schedule (left panel, F_2,27 = 0.78; P > 0.05; right panel, F_2,27 = 4.28; P < 0.05, one-way ANOVA). Post hoc individual group comparisons revealed a significant reduction in cocaine self-administration after 10 mg/kg (q = 3.143, P < 0.05) or 30 mg/kg JJC8-091 treatment (q = 4.855, P < 0.01), when compared to the vehicle control group; d JJC8-088, but not JJC8-091, substitution (initially 0.5 mg/kg/infusion for 5 days followed by 1.0 mg/kg/infusion for additional 4 days) sustained stable self-administration in rats previously self-administered cocaine. Two-way ANOVA for repeated measures over time (for the data after JJC compound substitution, highlighted in the gray box) revealed a significant drug main effect (F_1,18  =  39.09, P < 0.001), time main effect (F_8,144 = 17.82, P < 0.001) and drug × time interaction (F_8,144 = 4.69, P < 0.001). e Naive rats self-administered JJC8-088 intravenously similar to cocaine. Two-way ANOVA for repeated measures over time (for the data shown in a gray box) revealed a significant drug main effect (F_1,18 = 5.31, P < 0.05), but did not reveal a significant treatment × time interaction (F_9,162 = 0.48, P > 0.05). f Naive rats did not self-administer JJC8-091 during the initial 10 days of self-administration training. When JJC8-091 was replaced by cocaine, animals rapidly acquired self-administration behavior for cocaine. Two-way ANOVA for repeated measures over time (for the data shown in a gray box) revealed a significant cocaine vs. JJC8-091 main effect (F_1,19 = 51.56, P < 0.001), time main effect (F_9,171 = 3.93, P < 0.001) and drug × time interaction (F_9, 171 = 15.03, P < 0.001). *P < 0.05, **P < 0.01, compared to vehicle (a, c), JJC8-088 substitution (d), or cocaine group (f)