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Fetal yawning assessed by 3D and 4D sonography
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mise à jour du
21 mai 2013
Biochem Pharmacol.
2012;84(7):882-90.
Medication discovery for addiction:
translating the dopamine D3 receptor hypothesis
Newman AH, Blaylock BL, Nader MA, Bergman J,
Sibley DR, Skolnick P

Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, USA. 

Chat-logomini

 
1. Overview of the challenge in medications development for substance use disorders: focus on cocaine and methamphetamine
 
Major challenges exist for developing medications to treat substance use disorders (SUDs) in general, and psychostimulant addiction, in particular. Despite a considerable global burden [1], the negative health and societal consequences of cocaine and methamphetamine abuse have continued unabated. Based on decades of research, it is clear that therapeutic strategies that include medications are necessary to reduce, and ultimately, eliminate illicit drug taking. Nevertheless, translation from mechanistic target identification to preclinical testing in animal models of self-administration and relapse through clinical evaluation of novel or repurposed molecules has progressed at a snail's pace. The reasons for failure to deliver effective medications to treat psychostimulant addictions have been described and debated (e.g., [2]). The lack of consistent efforts in drug development for this patient population in the private sector has historically been a barrier to success. Further, the multi-billion dollar price tag [3] coupled with the high risk of developing psychiatric medications has contributed to the recent exodus of big pharma from development of drugs that act on the central nervous system (CNS). This disengagement from psychiatric drug development will undoubtedly further slow this process because of downstream effects on smaller pharmaceutical and biotech firms that have traditionally relied on the resources of big pharma in the latter stages of drug development [4]. Translation from animal to clinical studies, low medication compliance during the conduct of clinical trials, placebo effects, and the current FDA perspective to demonstrate complete abstinence, as opposed to reduction in drug use [5], all provide formidable challenges to the successful development of medications to treat SUDs [2,6].
 
Nevertheless, scientific advances have led to the identification of ''druggable'' targets, and medicinal chemistry efforts have, in turn, resulted in the development of small molecules that show promise in preclinical models of addiction. In this commentary, we present the dopamine D3 receptor (D3R) as a uniquely suited target for drug development, with D3R antagonists and partial agonists showing promise in models of cocaine and methamphetamine abuse. We briefly summarize recent advances in the discovery of small molecules that bind with high affinity and selectivity to D3R and have properties in preclinical models that forecast successful translation to the clinic. We highlight selected novel agents and in addition, present promising data on a repurposed molecule, buspirone, as a candidate for clinical trials.
 
2. Why the dopamine D3 receptor (D3R) may be a uniquely suited target for psychostimulant abuse and addiction
 
Although both cocaine and methamphetamine are psychostimulants and bind to all three monoamine transporters (norepinephrine, dopamine, serotonin), their mechanisms of action differ. Cocaine blocks neurotransmitter transport into the cell, but cannot be transported itself, whereas methamphetamine serves as a substrate, competing for the neurotransmitter both at the membrane and vesicular transporters, ultimately facilitating the release of neurotransmitter into the synapse. Although all three transporters are affected by chronic use of these drugs and the neurotoxicity associated with methamphetamine is certainly one consequence of this, it is the dopamine transporter that appears to be most closely linked to the psychomotor stimulant Chronic exposure to cocaine and/or methamphetamine causes long lasting molecular and cellular neuroadaptations of the mesencephalic dopaminergic system that may ultimately contribute to the addict's inability to stop taking drugs, despite serious negative consequences [7&endash;10]. Indeed, an increased extracellular concentration of dopamine has been implicated as a critical factor in morphological changes that can lead to changes in neural plasticity and behavior.
 
These changes may contribute to excessive activation of all dopamine receptor subtypes [11]. Specifically, increased expression and function of D3R upon exposure to psychostimulant drugs has led to further investigation into the role of D3R in cocaine and methamphetamine addiction [12&endash;14]. In addition, the restricted high density localization of D3Rs in neurocircuits that play a critical role in emotional and cognitive functions as well as increases in D3R in the ventral striatum of human cocaine fatalities [15,16] has further heightened interest in D3R. More recently, PET studies using the D3R-preferential ligand [11C]-(+)PHNO in methamphetamine polydrug abusers showed upregulation of D3R but not D2R in this subject population [17]. These studies, coupled with preclinical studies that will be briefly summarized below suggest that normalization of D3R function may reduce vulnerability to relapse in psychostimulant
 
3. D3R selective antagonists and partial agonists
 
A seminal report describing the D3R-selective partial agonist/ antagonist BP 897 (Fig. 1) (hD3R and hD2R Ki = 0.92 and 61 nM, respectively) showed inhibition of conditioned cue-controlled cocaine-seeking behavior in rats without producing rewarding effects of its own [18]. Many subsequent studies [19] expanded these results in other models of cocaine and methamphetamine abuse and laid the groundwork for establishing a role of D3R in psychomotor stimulant associated cues and drug seeking.
 
The similarly potent and D3R selective antagonists SB277011A and NGB 2904 also demonstrated efficacy in these animal models [14,20], and have provided both critical tools for further characterization of D3R in addiction and pharmacophoric templates for the evolution of subsequent generations of D3R selective agents [14,21]. Structure&endash;activity relationships have been derived through extensive medicinal chemistry efforts, resulting in highly potent and D3R selective agents with varying intrinsic activities (for review see [22,23]).
 
Recently, the human D3R was crystallized in complex with the antagonist eticlopride [24], which has further illuminated structural components of the receptor-binding domain, and will undoubtedly provide the basis for novel ligand discovery [25,26]. However, discovering small molecules that bind with high affinity and selectivity to the D3R is only the initial hurdle in drug development. The successful molecule must also possess appropriate biopharmaceutical properties (ADME) that provide adequate levels of an efficacious medication for treating addicted patients and preventing relapse. Although numerous animal models developed to mirror human addiction predict that these agents will be effective, clinical trials testing the efficacy of D3R selective antagonists and partial agonists in SUDs are still on the horizon.
 
4. Utilization of preclinical nonhuman primate models in addiction research
 
Effective preclinical models are essential toward identifying the in vivo profile of novel D3R partial agonists and antagonists as well as enhancing the field's understanding of the role of D3Rs in psychostimulant addiction. Since the cloning of D3Rs in 1990 [27], animal studies have been crucial to elucidating how these receptors function in situ. Over the past 15 years, a number of factors influencing the in vivo selectivity and efficacy of D3R selective compounds have been elucidated through employing various behavioral pharmacology assays in both rodents and nonhuman primates. While rodents offer beneficial characteristics such as the ability to make genetic modifications (e.g., knock-out mice) important to investigating specific roles of D3Rs in the behavioral effects of drugs of abuse [28,29], ongoing research strongly supports the use of nonhuman primates in this field of research. When considering translational research, nonhuman primates are an advantageous preclinical model due to phylogenetic similarities and 95% overall shared gene homology to humans [30]. Furthermore, the ability to conduct within-subject longitudinal assessments in monkeys with an extensive history of self-administration is an essential attribute to modeling the human condition, as addicts have typically abused cocaine for many years. With respect to dopamine D2-like receptors, nonhuman primate imaging studies show similar neurobiological changes in response to long-term drug self-administration to that of humans [31&endash;33]. Moreover, recent reports using the D3Rpreferring ligand [11C]-PHNO [34] have shown that rhesus macaques demonstrate comparable regional binding to humans [35,36] suggesting similarities in D3R distribution and availability. In addition, monkeys can self-administer cocaine for years, which provides a truly chronic model of addiction. All of these factors lend advantages toward employing nonhuman primates in preclinical behavioral pharmacology studies aimed toward evaluating potential compounds for treating drug addiction. The focus of this commentary is on the evaluation of D3R-selective agents, first with unconditioned behaviors, and then in drug self-administration and relapse models in nonhuman primates as a means to further progress candidate compounds to the clinic.
 
5. Unconditioned behaviors for understanding in vivo profiles of novel D3R compounds
 
Although in vitro assays aid in identifying receptor-selectivity and efficacy to guide medicinal chemistry efforts to obtain highly selective and potent drug-like molecules, in vivo assessments are necessary to corroborate in vitro findings in order to validate structure&endash;activity relationships. Seminal reports by Collins et al. [37,38] demonstrated, in rodents, that a dopamine D2R/D3R agonist will produce an inverted-U function on drug-elicited behavior in which low-doses would elicit yawning and higher doses would produce less yawning and concomitantly induce hypothermia. Through a series of elegant antagonist studies, it was shown that D3Rs mediate the ascending limb of the drug-elicited yawning curve whereas D2Rs were implicated in the actions described on the descending limb in which yawning was lower and hypothermia was observed. While many neurotransmitter systems contribute to yawning (for review see [39]), this simple behavioral assay has been shown to be pharmacologically sensitive to D3R-selective compounds, thus making it a suitable framework for determining the selectivity and efficacy of novel compounds in vivo [37,38]. D3R- and D2R-elicited yawning and hypothermia, respectively, have recently been validated in nonhuman primates (Fig. 2) and employed to understand how a pharmacological history can functionally alter D3Rs (for methods see [40]).
 
Differential effects of the profile of D3R partial agonists in drug-naġ¨ve rhesus monkeys compared to monkeys with an extensive history of cocaine selfadministration were recently reported [40]. For these studies, monkeys were placed in primate chairs in a quiet room with a video camera. Quinpirole, PG 619 (both 0.03&endash;1.0 mg/kg) or saline (1.0 ml) was administered intravenously and yawning measured for 30 mins beginning immediately after the injection. Scoring of yawns was done by researchers blind to the drug condition. While the D3R-preferrential agonist quinpirole dose-dependently elicits yawning in a similar fashion in all age-matched monkeys irrespective of drug history, the partial agonist PG 619 (hD3R and hD2R Ki = 2.8 and 284 nM, respectively) [41] (Fig. 1) elicited yawning comparable to that of the D2R/D3R receptor agonist quinpirole only in cocaine-history monkeys [40,42] (Fig. 2A and B) suggesting functional sensitivity following cocaine self-administration. We also extended this finding to the partial agonist CJB 090 (hD3R and hD2R Ki = 0.5 and 25 nM, respectively; Fig. 1), showing that it would elicit yawns only in monkeys with an extensive cocaine history [43,44]. These findings suggest that in individuals currently abusing cocaine, a partial agonist may function as a full agonist in vivo. Interestingly, such consequences appear to be long lasting, as rhesus monkeys exposed to cocaine in utero show enhancements in quinpirole-elicited yawning some 13 years later, in adulthood [45]. An even more promising outcome was that in the same monkeys in which the D3R-partial agonist PG 619 (0.1 mg/kg) elicited yawning, it did not induce reinstatement of cocaine seeking (Fig. 2C, open triangle). When given in combination with cocaine, a range of PG 619 doses attenuated cocaine-induced reinstatement (Fig. 2C, filled triangles). There is still much research to be conducted to understand the functional role of D3R in reinstatement. All doses of PG 619 were equally effective in decreasing cocaine-elicited reinstatement to approximately 50% (Fig. 2C), while CJB 090, a drug that also elicited yawning in these monkeys, did not affect cocaine-induced reinstatement [46]. Factors such as those presented above, which more closely resemble the treatment population, are critical to comprehensively identify pharmacological mechanisms of D3R partial agonists and antagonists to facilitate a faster progression from bench to bedside. One advantageous use of a model involving unconditioned behaviors is to initially identify mechanisms of action of compounds and to determine appropriate dose ranges for selfadministration studies. For example, quinpirole robustly elicits yawning in monkeys and the shape of the quinpirole dose&endash; response curve is characterized as an inverted-U shaped function (Fig. 2A) [40]. Just as has been reported in rodents [38], the descending limb of the quinpirole dose&endash;response curve is associated with hypothermia in monkeys (see Fig. 3). Administration of the D3R-selective partial agonist PG 619 attenuated quinpirole-elicited yawning but did not affect quinpirole-induced hypothermia, suggesting a primarily D3R mediated effect.
 
 
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