Reduction of cocaine self-administration and D3 receptor-mediated behavior by two novel dopamine D3 receptor-selective partial agonists, OS-3-106 and WW-III-55

Abstract

Dopamine D3 receptor (D3R)-selective compounds may be useful medications for cocaine dependence. In this study, we identified two novel arylamide phenylpiperazines, OS-3-106 and WW-III-55, as partial agonists at the D3R in the adenylyl cyclase inhibition assay. OS-3-106 and WW-III-55 have 115- and 862-fold D3R:D2 receptor (D2R) binding selectivity, respectively. We investigated their effects (0, 3, 5.6, or 10 mg/kg) on operant responding by using a multiple variable-interval (VI) 60-second schedule that alternated components with sucrose reinforcement and components with intravenous cocaine reinforcement (0.375 mg/kg). Additionally, we evaluated the effect of OS-3-106 (10 mg/kg) on the dose-response function of cocaine self-administration and the effect of WW-III-55 (0-5.6 mg/kg) on a progressive ratio schedule with either cocaine or sucrose reinforcement. Both compounds were also examined for effects on locomotion and yawning induced by a D3R agonist. OS-3-106 decreased cocaine and sucrose reinforcement rates, increased latency to first response for cocaine but not sucrose, and downshifted the cocaine self-administration dose-response function. WW-III-55 did not affect cocaine self-administration on the multiple-variable interval schedule, but it reduced cocaine and sucrose intake on the progressive ratio schedule. Both compounds reduced locomotion at doses that reduced responding, and both compounds attenuated yawning induced by low doses of 7-OH-DPAT (a D3R-mediated behavior), but neither affected yawning on the descending limb of the 7-OH-DPAT dose-response function (a D2R-mediated behavior). Therefore, both compounds blocked a D3R-mediated behavior. However, OS-3-106 was more effective in reducing cocaine self-administration. These findings support D3Rs, and possibly D2Rs, as targets for medications aimed at reducing the motivation to seek cocaine.

Fig. 1.

Structure of OS-3-106 and WW-III-55.

Fig. 2.

Effect of OS-3-106 and WW-III-55 on operant responding (±S.E.M.) for sucrose and cocaine (0.375 mg/kg per infusion) on a multiple VI 60-second schedule. Doses of OS-3-106 (top row, n = 9) and WW-III-55 (bottom row, n = 10) were given in randomized order with additional stabilization sessions between tests. The number of reinforcers (A and E), active lever presses (B and F), and inactive lever presses (C and G) were totaled across the two 15-minute components for sucrose (gray squares) or cocaine (black circles) components. Response latency (D and H) was averaged between the two 15-minute components for each reinforcer type. Note that the ordinate for response latency is on a log scale. V, Vehicle. *Difference compared with vehicle pretreatment for sucrose (gray) or cocaine (black) components, P < 0.05. #, Difference between sucrose and cocaine at a given D3R compound dose, P < 0.05. ‡, Main effect of reinforcer type, P < 0.05.

Fig. 3.

Effect of OS-3-106 on response latency (±S.E.M.) in the first component on a multiple VI 60-second schedule for sucrose (gray squares) and cocaine (0.375 mg/kg per infusion, black circles). Data were treated as between-subject (n = 4 to 5) because OS-3-106 doses and the reinforcer type available were counterbalanced between-subject within a component. Note that the ordinate for response latency is on a log scale. V, Vehicle. #, Difference between sucrose and cocaine at a given D3R compound dose, P < 0.05. †, Significant linear trend of OS-3-106 on cocaine response latency, P < 0.05.

Fig. 4.

Effect of 10 mg/kg OS-3-106 (±S.E.M.) on the number of reinforcers (A), cocaine intake (B), and active lever presses (C) for different doses of cocaine on a VI 60-second schedule (n = 8). Available cocaine doses were tested in an ascending dose order, whereas the order of vehicle and OS-3-106 pretreatment were counterbalanced between rats. Additional stabilization sessions were given between tests. ^*Difference compared with 0 mg/kg per infusion of cocaine dose after vehicle (gray) or OS-3-106 (black) pretreatment, P < 0.05. #, Difference between vehicle and OS-3-106 at a given cocaine dose, P < 0.05.

Fig. 5.

Effect of WW-III-55 on progressive ratio responding (±S.E.M.) for cocaine (0.375 mg/kg per infusion). Animals (n = 8) received doses of WW-III-55 in randomized order with additional stabilization sessions between tests. †, Significant linear trend of WW-III-55, P < 0.05. *Difference compared with vehicle pretreatment, P < 0.05.

Fig. 6.

Effect of WW-III-55 on progressive ratio responding (±S.E.M.) for sucrose. Animals (n = 10) received 5.6 mg/kg WW-III-55 or its vehicle in randomized order with additional stabilization sessions between tests. *Difference compared with vehicle pretreatment, P < 0.05.

Fig. 7.

Effects of 10 mg/kg OS-3-106 (A and B) and 5.6 mg/kg WW-III-55 (C and D) on yawning and locomotor activity induced by 7-OH-DPAT. Graphs show the number of yawns (A and C) and the distance traveled (B and D) in 30 minutes (±S.E.M.). In the OS-3-106 experiment, separate groups of rats (n = 8) were used to test each dose of 7-OH-DPAT. In the WW-III-55 experiment, separate groups of rats (n = 11) were used to test WW-III-55 versus its vehicle. Rats received pretreatment with 10 mg/kg OS-3-106 or 5.6 mg/kg WW-III-55 (black circles) or their vehicle (gray squares) 5 minutes before 30-minute tests, in randomized order. 7-OH-DPAT was given immediately before each test. Tests were separated by ≥48 hours. *Difference from 0 mg/kg 7-OH-DPAT after pretreatment with OS-3-106 or WW-III-55 (black) or their vehicle (gray), P < 0.05. #, Difference between OS-3-106 or WW-III-55 and their vehicle at a given 7-OH-DPAT dose, P < 0.05.

Fig. 8.

Effects of OS-3-106 (A) and WW-III-55 (B) on locomotor activity. Graphs show the distance traveled (centimeters + S.E.M.) in 1 hour. (A) Effects of OS-3-106 (10 mg/kg) on spontaneous and cocaine-induced (15 mg/kg i.p.) locomotion. Rats (n = 9) were tested four times, receiving one of each of the following treatments before the 1-hour test session: vehicle + vehicle (veh), OS-3-106 + vehicle (OS), vehicle + cocaine (Coc), OS-3-106 + cocaine (OS + Coc). Test order was randomized with 1 day off between test sessions. +Main effect of OS-3-106, P < 0.05. *Main effect of cocaine, P < 0.05. (B) Effects of WW-III-55 (vehicle, 3, 5.6, 10 mg/kg) on spontaneous locomotor activity. Separate groups of rats were used for each dose of WW-III-55 (n = 8, 7, 7, and 7, respectively). *Difference compared with vehicle pretreatment, P < 0.05.