Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and σ receptors

Abstract

Sigma receptor (σR) antagonists attenuate many behavioral effects of cocaine but typically not its reinforcing effects in self-administration procedures. However, the σR antagonist rimcazole and its N-propylphenyl analogs, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (SH 3-28), dose-dependently decreased the maximal rates of cocaine self-administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of σR antagonists [N-phenethylpiperidine oxalate (AC927), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD 1047), N-[2-(3,4-dichlorophenyl) ethyl]-4-methylpiperazine dihydrochloride (BD 1063), and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100)] had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective σR antagonists in their dual affinities for σRs and the dopamine transporter (DAT) assessed with radioligand binding. Selective DAT inhibitors and σR antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both σRs and the DAT were sufficient to reproduce the effects of rimcazole analogs. Typical DAT inhibitors [2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), methylphenidate, and nomifensine] dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT inhibitor and σR antagonist doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. In addition, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither rimcazole analogs nor typical σR antagonists (NE-100 and AC927) maintained responding above control levels across a wide range of doses. These findings suggest that the unique effects of rimcazole analogs are due to dual actions at the DAT and σRs and that a combined target approach may have utility in development of medical treatments for cocaine abuse.

Fig. 1.

Displacement of radioligands for the DAT and σRs by various ligands for the binding sites. Ordinates, percentage of specific radiotracer bound to membrane preparations as described under Materials and Methods; abscissae, concentration of each competing compound. Top panel, binding to the DAT as labeled with [³H]WIN 35,428. Middle panel, binding to σ₁Rs as labeled with [³H]pentazocine. Bottom panel, binding to σ₂Rs as labeled with [³H]DTG. The curves represent the results of a single experiment with vertical bars representing S.E.M.s from averages of results from three samples. The results were selected from at least three replications as representative of the binding parameters resulting from global modeling of all of the data.

Fig. 2.

Substitution of saline, dopamine uptake inhibitors (WIN 35,428, methylphenidate, and nomifensine), rimcazole and its analogs (SH 3-24 and SH 3-28), and σR antagonists (AC927 and NE-100) in rats trained to self-administer cocaine. A–C, ordinates, responses per second; abscissae, dose of each substituted drug in milligrams per kilogram per injection. Each point represents the mean ± S.E.M. (n = 6–19). A, cocaine (●) and saline (○). B, cocaine replication (●), WIN 35,428 (○), methylphenidate (▵), and nomifensine (▿). C, cocaine replication (●), rimcazole (○), SH 3-24 (▵), SH 3-28 (▿), AC927 (♢), and NE-100 (□). D, representative cumulative records showing patterns of self-administration in real time maintained by intravenous cocaine injection under the fixed-ratio 5 response schedule, and those obtained when saline, WIN 35,428, or the σR antagonist, rimcazole, was substituted for cocaine. Ordinates, cumulative responses; abscissae, time. The five 20-min self-administration components of each session are indicated by the lower event line displaced down. The preceding 2-min TO periods are indicated by the lower event line displaced up. In the first component, each fifth response turned off the LEDs for 20 s but did not activate the infusion pump (EXT), whereas in subsequent components injections were also delivered with each fifth response (diagonal marks on the cumulative record) with doses (in milligrams per kilogram per injection) indicated. Vertical marks on the line below the cumulative curve indicate responses on the left (inactive) lever. The cumulative curve reset to the baseline at the end of the 20-min component.

Fig. 3.

Effects of presession treatments with rimcazole and its analogs on responding maintained by cocaine injection or food presentation. Each point represents the mean ± S.E.M. (n = 6). Rimcazole and its analogs were administered intraperitoneally at 5 min before sessions. A–C, effects of presession treatments with rimcazole and its analogs on cocaine self-administration. Ordinates, responses per second; abscissae, cocaine injection dose in milligrams per kilogram. A, effects of rimcazole (3.2, 10, and 32 mg/kg) on cocaine self-administration. B, effects of SH 3-24 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. C, effects of SH 3-28 (3.2, 10, and 32 mg/kg) on cocaine self-administration. D–F, effects of presession treatments with rimcazole and its analogs on responding maintained by cocaine injection (0.32 mg/kg per inj) or food presentation (fourth component, each). Ordinates, response rates as percentage of control response rates (sessions before drug tests), which averaged 0.40 (±0.13), and 0.91 (±0.10) response/s, respectively, for cocaine- and food-maintained responding; abscissae, milligrams per kilogram of test compounds administered intraperitoneally, log scale. ●, behavior maintained by cocaine (0.32 mg/kg per inj i.v.); ○, behavior maintained by food presentation.

Fig. 4.

Representative cumulative records showing patterns of self-administration maintained by intravenous cocaine injection under the fixed-ratio 5 response schedule with the particular treatments before sessions as indicated in each panel of the figure. All details are as in the legend to Fig. 2D.

Fig. 5.

Effects of presession treatments with σR antagonists or dopamine uptake inhibitors on cocaine self-administration in rats trained to self-administer cocaine. Ordinates, responses per second; abscissae, cocaine injection dose in milligrams per kilogram. Each point represents the mean ± S.E.M. (n = 6). AC927 was administered intraperitoneally at 15 min before sessions, whereas the other drugs were administered at 5 min before sessions. A, effects of the σR antagonist AC927 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. B, effects of NE-100 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. C, effects of WIN 35,428 (0.1, 0.32, and 1.0 mg/kg) on cocaine self-administration. D, effects of methylphenidate (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. E, effects of nomifensine (0.32, 1.0, and 3.2 mg/kg) on cocaine self-administration.

Fig. 6.

Effects of presession treatments with WIN 35,428 combined with σR antagonists on cocaine self-administration. Ordinates, responses per second; abscissae, cocaine injection dose in milligrams per kilogram. Each point represents the mean ± S.E.M. (n = 6). WIN 35,428, BD1008, BD1047, and BD1063 were administered intraperitoneally at 5, 5, 15, and 5 min before sessions, respectively. A, effects of WIN 35,428 (0.1 mg/kg) with BD 1008 (3.2 and 10 mg/kg) on cocaine self-administration. B, effects of WIN 35,428 (0.1 mg/kg) with BD 1047 (3.2 and 10 mg/kg) on cocaine self-administration. C, effects of WIN 35,428 (0.1 mg/kg) with BD 1063 (3.2 and 10 mg/kg) on cocaine self-administration. D, effects of WIN 35,428 (0.32 mg/kg) with BD 1008 (0.32, 1.0, 3.2, and 10 mg/kg) on cocaine self-administration. E, effects of WIN 35,428 (0.32 mg/kg) with BD 1047 (0.32, 1.0, 3.2, and 10 mg/kg) on cocaine self-administration. F, effects of WIN 35,428 (0.32 mg/kg) with BD 1063 (0.32, 1.0, 3.2, and 10 mg/kg) on cocaine self-administration.

Fig. 7.

Effects of presession treatments with methylphenidate (1.0 mg/kg) or nomifensine (0.32 mg/kg) combined with σR antagonists on cocaine self-administration. Ordinates, responses per second; abscissae, cocaine injection dose in milligrams per kilogram. Each point represents the mean ± S.E.M. (n = 6). Methylphenidate, BD1008, BD1047, and BD1063 were administered intraperitoneally at 5, 5, 15, and 5 min before sessions, respectively. A, effects of methylphenidate (1.0 mg/kg) with BD 1008 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. B, effects of methylphenidate with BD 1047 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. C, effects of methylphenidate with BD 1063 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. D, effects of nomifensine with BD 1008 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. E, effects of nomifensine with BD 1047 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration. F, effects of nomifensine with BD 1063 (1.0, 3.2, and 10 mg/kg) on cocaine self-administration.

Fig. 8.

Effects of presession treatments with dopamine uptake inhibitors combined with σR antagonists on responding maintained by cocaine injection or food presentation. Ordinates, response rates as percentage of control response rates (sessions before drug tests); abscissae, milligrams per kilogram σR antagonists administered intraperitoneally in combination with designated dopamine uptake inhibitors, log scale. A, effects of BD 1008 with saline. B, effects of BD 1008 with WIN 35,428 (0.1 mg/kg). C, effects of BD 1008 with methylphenidate (1.0 mg/kg). D, effects of BD 1008 with nomifensine (0.32 mg/kg). E, effects of BD 1047 with saline. F, effects of BD 1047 with WIN 35,428 (0.1 mg/kg). G, effects of BD 1047 with methylphenidate (1.0 mg/kg). H, effects of BD 1047 with nomifensine (0.32 mg/kg). J, effects of BD 1063 with saline. K, effects of BD 1063 with WIN 35,428 (0.1 mg/kg). L, effects of BD 1063 with methylphenidate (1.0 mg/kg). M, effects of BD 1063 with nomifensine (0.32 mg/kg). Dopamine uptake inhibitors and σR antagonists were administered intraperitoneally 5 min before sessions except BD 1047 (15 min). Responding was from the fourth 20-min component of the session (see Materials and Methods). All other details are as in the legend to Fig. 3, D–F.