Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis

Abstract

The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy.

Chart 1. Chemical Structures of Highlighted D3R-Selective Partial Agonists and Antagonists

Chart 2. Recently Reported D3R-Preferential Ligands with Novel Structural Templates

Chart 3. Behaviorally Tested D3R-Preferential Ligands

Figure 1

Concentration profiles for 10 mg/kg (±)-1 in mouse plasma following i.v. (○) or p.o. (■) administration. Data are presented as mean ± SEM; n = 3 mice per time point.

Figure 2

Effects of i.p. vehicle or 1 (racemic and enantiomers) on PR self-administration of METH. Data are presented as mean ± SEM; * p < 0.05, ** p < 0.01, *** p < 0.001. Statistics in panel A refer to number of METH injections (right axis) compared to vehicle; statistics in panel B refer to break point values (last ratio completed), normalized to baseline responding, compared to vehicle.

Figure 3

(A) Acquisition of METH self-administration and extinction of self-administration. (B) Effects of i.p. vehicle or (±)-1 on METH-primed reinstatement of METH-seeking behavior. Data are presented as mean ± SEM; * p < 0.05 compared to vehicle.

Figure 4

Effects of i.v. vehicle or (±)-1 on cocaine choice in seven monkeys individually and as a group (lower right panel). Ordinates, percent of total reinforcers earned that resulted in cocaine injections. Abscissae, dose of cocaine (mg/kg) available as an alternative to a food pellet. Data in lower right panel represent mean ± SEM.

Figure 5

Effects of acute and chronic administration of (±)-1 (i.v.) on METH choice in three rhesus monkeys (mean ± SEM of days 3–5 of daily treatment). Ordinates, percent of total reinforcers earned that resulted in METH injections. Abscissae, dose of METH (mg/kg) available as an alternative to a food pellet.