Current perspectives on selective dopamine D₃ receptor antagonists as pharmacotherapeutics for addictions and related disorders

Abstract

Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.

Pramipexole-Induced Increased Probabilistic Discounting: Comparison Between a Rodent Model of Parkinson's Disease and Controls

“…These outcomes guided the dosing protocol selected for the probability discounting paradigm, that is, 2 mg/kg ( ± )PPX (ie, 1 mg/kg of the active form), administered twice a day. This decision was also guided by reports that (1) 1 mg/kg of (À)PPX alters reward-mediated behavior, that is, enhances the reinforcing effects of cocaine (Caine et al, 1997) and (2) twice-daily injections of 1 mg/kg of (À)PPX in rats increases expression of forebrain D3 receptors (Maj et al, 2000), which are involved in ICDs and addictions (Heidbreder and Newman, 2010).…”

The dopamine D 3 -preferring D 2 /D 3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia

“…The D3 receptor is abundant in the ventral striatal mesolimbic system and frontal cortex but (unlike the D2 receptor) low in the dorsal striatum, which may account for the paucity of effect of D3 antagonists on locomotor activity in rodents and provides potential for few extrapyramidal symptom in clinical use in man (see reviews; (Heidbreder and Newman, 2010; Millan and Brocco, 2008). Both gene polymorphisms and increased postmortem brain D3 receptor protein levels have also been associated with patients who had schizophrenia.…”

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

“…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). In addition, D3R partial agonists and antagonists have been shown to reduce self-administration of methamphetamine (MA) in a rodent model of compulsive drug intake (Orio et al, 2010).…”