Medication discovery for addiction: Translating the dopamine D3 receptor hypothesis

Abstract

The dopamine D3 receptor (D3R) has been investigated as a potential target for medication development to treat substance use disorders (SUDs) with a particular focus on cocaine and methamphetamine. Currently, there are no approved medications to treat cocaine and methamphetamine addiction and thus developing pharmacotherapeutics to compliment existing behavioral strategies is a fundamental goal. Novel compounds with high affinity and D3R selectivity have been evaluated in numerous animal models of drug abuse and favorable outcomes in nonhuman primate models of self-administration and relapse have provided compelling evidence to advance these agents into the clinic. One approach is to repurpose drugs that share the D3R mechanism and already have clinical utility, and to this end buspirone has been identified as a viable candidate for clinical trials. A second, but substantially more resource intensive and risky approach involves the development of compounds that exclusively target D3R, such as GSK598809 and PG 619. Clinical investigation of these drugs or other novel D3R-selective agents will provide a better understanding of the role D3R plays in addiction and whether or not antagonists or partial agonists that are D3R selective are effective in achieving abstinence in this patient population.

Further Characterization of Quinpirole-Elicited Yawning as a Model of Dopamine D3 Receptor Activation in Male and Female Monkeys

“…There is evidence supporting the use of D3R antagonists and partial agonists for the treatment of cocaine and MA abuse as well as accompanying symptoms such as cognitive dysfunction (Newman et al, 2012;Mugnaini et al, 2013;Nakajima et al, 2013). Considering female rhesus monkeys in the current study were less sensitive to the behavioral effects of quinpirole, it is likely that drug potency will be a critical variable in future studies investigating D3R compounds as a treatment option.…”

“…In 2011, the United Nations Office on Drugs and Crime estimated 14 to 21 million people worldwide used cocaine at least once in 2009, with 20% of users in the United States meeting the criteria of drug dependence (Degenhardt and Hall, 2012). Despite the array of negative health and societal consequences, a successful pharmacotherapy for psychostimulant addiction has remained elusive (Newman et al, , 2012. There is evidence that dopamine (DA) D 3 receptors (D3R), a subtype of the D2-like family of DA receptors, mediate many of the effects of psychostimulants associated with high abuse potential (Heidbreder and Newman, 2010;Heidbreder, 2013), including the role of conditioned stimuli (Neisewander et al, 2004;Achat-Mendes et al, 2009;Orio et al, 2010;Yan et al, 2013), discriminative stimulus effects (Martelle et al, 2007;Achat-Mendes et al, 2009;Collins and Woods, 2009), and cue conditioning (Le Foll et al, 2002).…”

The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

“…Buspirone was initially marketed as an anxiolytic, but more recently has been identified as a potential candidate to treat drug addiction and compulsive behavior disorders based on its high affinity for D3 receptors (as well as 5-HT1A and D2 receptors) [125]. In addition, a study of non human primates indicates that buspirone attenuates drug-taking relapse in abstinent animals [126]. Other general examples of repurposed drugs include sildenafil for erectile dysfunction (developed as an anti-hypertensive) [127], thalidomide (original indication: nonbarbiturate sedative-hypnotic), finasteride (original indication: prostatic hyperplasia) and chlorpromazine (original indication: antihistamine) that are also effective treatments for erectile dysfunction, leprosy, hair loss and psychosis, respectively [128][129][130].…”

A Single Glycine in Extracellular Loop 1 Is the Critical Determinant for Pharmacological Specificity of Dopamine D2 and D3 Receptors

“…The dopamine D3 receptor (D3R), a member of the dopamine D2-like receptor subfamily, is a potential therapeutic target for drug abuse and other neuropsychiatric disorders (Heidbreder and Newman, 2010;Newman et al, 2012b). Developing potent and selective D3R ligands is critical to understanding and dissecting their downstream signaling pathways and functional specificity (Holmes et al, 2004).…”