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Review
, 75 (1), 2-16

Dopamine Transport Inhibitors Based on GBR12909 and Benztropine as Potential Medications to Treat Cocaine Addiction

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Review

Dopamine Transport Inhibitors Based on GBR12909 and Benztropine as Potential Medications to Treat Cocaine Addiction

Richard B Rothman et al. Biochem Pharmacol.

Abstract

The discovery and development of medications to treat addiction and notably, cocaine addiction, have been frustrated by both the complexity of the disorder and the lack of target validation in human subjects. The dopamine transporter has historically been a primary target for cocaine abuse medication development, but addictive liability and other confounds of such inhibitors of dopamine uptake have limited clinical evaluation and validation. Herein we describe efforts to develop analogues of the dopamine uptake inhibitors GBR 12909 and benztropine that show promising profiles in animal models of cocaine abuse that contrast to that of cocaine. Their unique pharmacological profiles have provided important insights into the reinforcing actions of cocaine and we propose that clinical investigation of novel dopamine uptake inhibitors will facilitate the discovery of cocaine-abuse medications.

Figures

Figure 1
Figure 1
Structure of GBR12909 and related compounds.
Figure 2
Figure 2
Effect of GBR12909 pretreatment on the elevation of extracellular DA by 1.0 mg/kg i.v. cocaine. DA levels are mean±SEM expressed as a percentage of three baseline samples obtained before treatment (n=6 rats/group). GBR12909 (0.3 or 1.0 mg/kg i.v.) or saline was administered 60 min before cocaine challenge given at time 0. *p<0.05 with respect to the corresponding saline pretreatment group. From: [30].
Figure 3
Figure 3
The effects of repeated administration of GBR 12909 (1.7 mg/kg, IV slow injection) on rates of responding maintained under the multiple fixed ratio (FR) food, time out (TO) 3 s (open circle), FR cocaine (10 μg/kg/inj), TO 3 (open square), TO 10-min schedule. Effects are expressed as the mean (n = 4) absolute rate of responding (resp/s) over days (indicated by numbers) of each treatment mode (control = noninjection baseline; acute = replicate single administrations; chronic = repeated daily administrations of GBR 12909; saline = repeated daily administrations of saline). □From Fig 6. in: [31].
Figure 4
Figure 4
The effects of repeated administration of GBR 12935 (3 mg/kg, IM) on rates of responding maintained under the multiple fixed ratio (FR) food, time out (TO) 3 s (open circle), FR cocaine (10 μg/kg/inj), TO 3 s (open square), TO 10-min schedule. Effects are expressed as the mean (n = 3) absolute rate of responding (resp/s) over days (indicated by numbers) of each treatment mode (control = noninjection baseline; acute = replicate single administration; chronic = repeated daily administrations of GBR 12935). □From: [31].
Figure 5
Figure 5
Reductions in DA transporter occupancy are shown in transaxial [11C]WIN-35,428 images in baboons before (left) and after (right) treatment with three different doses of GBR. Each dose was given 90 minutes before [11C]WIN-35,428 injection. Images shown are at mid-striatal level, and represent average PET images (between 70–90 minutes post-injection of the radiotracer) normalized to injected. From [52].
Figure 6
Figure 6
Effects of the 6-mL dose of GBR-decanoate on rates of responding maintained by food or cocaine, for 28 sessions following a single treatment in rhesus monkeys. Effects are expressed as the mean percent of control rates for food- or cocaine-maintained responding (n = 2). From [59].
Figure 7
Figure 7
Effects of GBR-decanoate (GBR-dec) on METH-induced DA release (left) and 5-HT release (right) in the nucleus accumbens of conscious rats: 2-week test. Rats were treated with single i.m. injections of GBR-dec (1 ml/kg of a 48% solution, or 480 mg/kg) or sesame oil vehicle. Two weeks later, acute i.v. doses of 0.3 and 1.0 mg/kg METH (bottom) were injected at 0 and 60 min, respectively. Acute i.v. saline was administered on the same schedule (top). Data are mean ± S.E.M. for n = 6 to 7 rats/group, expressed as percentage of baseline. Baseline dialysate DA levels for GBR-dec and vehicle groups were 3.95 ± 0.64 and 1.69 ± 0.17 nM. Baseline dialysate 5-HT levels for GBR-dec and vehicle groups were 0.41 ± 0.09 and 0.33 ± 0.05 nM., P < 0.05 with respect to vehicle-pretreated group that received METH. From: [59].
Figure 8
Figure 8
Chemical structures of cocaine and highlighted benztropine analogs.
Figure 9
Figure 9
Effects of cocaine, GA 103, JHW 007, AHN 2-003, AHN 2-005 and AHN 1-055 in rats trained to discriminate 10 mg/kg cocaine from saline. Top, ordinate: percentage of responses on the cocaine-appropriate lever. Bottom ordinate: rates at which responses were emitted (as a percentage of response rate after saline administration). Abscissa: drug dose in mg/kg (log scale). Each point represents the effect in 4–16 rats.
Figure 10
Figure 10
Dose-dependent effects of cocaine, GBR 12909, AHN 1-055, AHN 2-005 and JHW 007 on locomotor activity in mice. Ordinate: horizontal locomotor activity counts after drug administration in counts/minute. Abscissa: dose of drug in μmole/kg, log scale (i.p administration). Each point represents the average effect determined in 8 mice. The data are from the 30 min period immediately after drug administration.
Figure 11
Figure 11
Place conditioning (A) and locomotor effects (B) of atropine in rats. The CPP scores represent the time spent in the drug-paired side during the postconditioning expressed as a difference from that during the last preconditioning session. The locomotor activity was expressed as the total horizontal distance traveled (centimeters) during the first exposure to drug in the first conditioning session. Data are presented as means ± S.E.M. *, p < 0.05; **, p < 0.01, as determined by the Dunnett’s test versus saline group. From [87].
Figure 12
Figure 12
Place conditioning (A–C) and locomotor effects (D) of AHN 1-055 administered to rats at different times before placement in the conditioning chamber. A to C, place conditioning effects of AHN 1-055 given 0, 45, and 90 min before conditioning sessions, respectively. For cocaine and saline treatments, animals were placed in the conditioning chamber immediately after injection. Data are presented as means ± S.E.M. Significant differences from control (p < 0.05) are indicated by *, as determined by Student’s t test versus saline group for the cocaine groups and by ANOVA followed by the Dunnett’s test versus saline group for AHN 1-055 groups. From [87].
Figure 13
Figure 13
Same as above except for AHN 2-005
Figure 14
Figure 14
Same as above except for JHW 007
Figure 15
Figure 15
A. Time course of effects of JHW007 on specific [125I]RTI-121 binding (top) and on locomotor activity in mice. x-axis, time after JHW007 injection. y-axis (top), specific [125I]RTI-121 binding expressed as a percentage of vehicle control; y-axis (bottom), horizontal activity counts per minute. Binding data are from 5–10 mice (top). B. Time course of effects of cocaine on specific [125I]RTI-121 binding (top) and locomotor activity in mice. x-axis, time after cocaine injection. Each point represents data from 5–13 (top) or 8 (bottom) mice, with error bars representing +1 SEM. From [18].
Figure 16
Figure 16
Relationship between percentage occupancy of the DA transporter in striatum and locomotor stimulant effects of cocaine, AHN 1-055, AHN 2-005 or JHW 007. Ordinates: difference between mean horizontal activity counts after drug and after saline. Abscissae: percent occupancy of DA transporter sites. For each drug, the solid line represents the linear regression of percent occupancy of the DA transporter and horizontal locomotor activity when the line is forced to intersect the origin, the point representing no occupancy and no effect. Note that the locomotor stimulant effects of cocaine are less strongly related to DA transporter occupancy than are the effects of AHN 1-055 and AHN 2-005. In contrast to each of the other drugs, the locomotor stimulant effects of JHW 007 were not related to its occupancy at the DA transporter. Modified from [18].
Figure 17
Figure 17
Interactions of cocaine and JHW 007 or AHN-2-005. A, B, y-axis, Locomotor activity counts; x-axis, treatment condition, vehicle (V), or dose of cocaine. Each point represents the average effect determined in eight mice, except n = 6 for combination of 10 mg/kg JHW 007 plus 60 mg/kg cocaine. The unconnected points above 40 mg/kg cocaine (A) show a replicate determined several months later in a separate shipment of mice. C, y-axis, Percentage of responses on the cocaine-appropriate lever after drug; x-axis, dose of cocaine. Circles, Effects of cocaine alone; squares, effects of cocaine administered 4.5 h after treatment with 10 mg/kg JHW 007; inverted triangle, effects of cocaine administered 28.5 h after treatment with JHW 007. Each cocaine point represents the average effect determined in five to six mice; for drug combinations, each point represents the effects of three to four mice. The error bars represent +1 SEM. From [18].

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