The Experts below are selected from a list of 5712 Experts worldwide ranked by ideXlab platform
Eliot L Gardner - One of the best experts on this subject based on the ideXlab platform.
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blockade of d3 receptors by yqa14 inhibits cocaine s rewarding effects and relapse to Drug Seeking Behavior in rats
Neuropharmacology, 2014Co-Authors: Rui Song, Hai Ying Zhang, Ri Fang Yang, Eliot L GardnerAbstract:Preclinical studies suggest that dopamine D3 receptor (D3R) antagonists are promising for the treatment of Drug abuse and addiction. However, few D3R antagonists have potential to be tested in humans due to short half-life, toxicity or limited preclinical research into pharmacotherapeutic efficacy. Here, we report on a novel D3R antagonist YQA14, which has improved half-life and pharmacokinetic profile and which displays potent pharmacotherapeutic efficacy in attenuating cocaine reward and relapse to Drug-Seeking Behavior. Electrical brain-stimulation reward (BSR) in laboratory animals is a highly sensitive experimental approach to evaluate a Drug's rewarding effects. We found that cocaine (2 mg/kg) significantly enhanced electrical BSR in rats (i.e., decreased stimulation threshold for BSR), while YQA14 alone had no effect on BSR. Pretreatment with YQA14 significantly and dose-dependently attenuated cocaine-enhanced BSR. YQA14 also facilitated extinction from Drug-Seeking Behavior in rats during early Behavioral extinction, and attenuated cocaine- or contextual cue-induced relapse to Drug-Seeking Behavior. YQA14 alone did not maintain self-administration in either naive rats or in rats experienced at cocaine self-administration. YQA14 also inhibited expression of repeated cocaine-induced Behavioral sensitization. These findings suggest that YQA14 may have pharmacotherapeutic potential in attenuating cocaine-taking and cocaine-Seeking Behavior. Thus, YQA14 deserves further investigation as a promising agent for treatment of cocaine addiction.
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activation of mglur7s inhibits cocaine induced reinstatement of Drug Seeking Behavior by a nucleus accumbens glutamate mglur2 3 mechanism in rats
Journal of Neurochemistry, 2010Co-Authors: Eliot L GardnerAbstract:The metabotropic glutamate receptor 7 (mGluR7) has been reported to be involved in cocaine and alcohol self-administration. However, the role of mGluR7 in relapse to Drug Seeking is unknown. Using a rat relapse model, we found that systemic administration of AMN082, a selective mGluR7 allosteric agonist, dose-dependently inhibits cocaine-induced reinstatement of Drug-Seeking Behavior. Intracranial microinjections of AMN082 into the nucleus accumbens (NAc) or ventral pallidum, but not the dorsal striatum, also inhibited cocaine-primed reinstatement, an effect that was blocked by local co-administration of MMPIP, a selective mGluR7 antagonist. In vivo microdialysis demonstrated that cocaine priming significantly increased extracellular dopamine in the NAc, ventral pallidum and dorsal striatum, while increasing extracellular glutamate in the NAc only. AMN082 alone failed to alter extracellular dopamine, but produced a slow-onset long-lasting increase in extracellular glutamate in the NAc only. Pre-treatment with AMN082 dose-dependently blocked both cocaine-enhanced NAc glutamate and cocaine-induced reinstatement, an effect that was blocked by MMPIP or LY341497 (a selective mGluR2/3 antagonist). These data suggest that mGluR7 activation inhibits cocaine-induced reinstatement of Drug-Seeking Behavior by a glutamate-mGluR2/3 mechanism in the NAc. The present findings support the potential use of mGluR7 agonists for the treatment of cocaine addiction.
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oral administration of the naaladase inhibitor gpi 5693 attenuates cocaine induced reinstatement of Drug Seeking Behavior in rats
European Journal of Pharmacology, 2010Co-Authors: Xiao Qing Peng, Eliot L Gardner, Charles R Ashby, Ajit G Thomas, Krystyna M Wozniak, Barbara S SlusherAbstract:Abstract We have recently reported that the endogenous mGlu2/3 agonist N -acetylaspartylglutamate (NAAG) and the N -acetylated-α-linked-acidic dipeptidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of Drug-Seeking Behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-Seeking behaviours. We found that oral administration of GPI-5693 (15, 30, 60 mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished Drug-Seeking Behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60 mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-Seeking Behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction.
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the preferential dopamine d3 receptor antagonist s33138 inhibits cocaine reward and cocaine triggered relapse to Drug Seeking Behavior in rats
Neuropharmacology, 2009Co-Authors: Xiao Qing Peng, Charles R Ashby, Krista Spiller, Nitza Thomasson, Millan Mark, Elisabeth Mocaer, Carmen Munoz, Eliot L GardnerAbstract:Abstract We have previously reported that selective dopamine (DA) D3 receptor antagonists are effective in a number of animal models of Drug addiction, but not in intravenous Drug self-administration, suggesting a limited ability to modify Drug reward. In the present study, we evaluated the actions of S33138, a novel partially selective D3 receptor antagonist, in animal models relevant to Drug addiction. S33138, at doses of 0.156 or 0.625 mg/kg (i.p.), attenuated cocaine-enhanced brain-stimulation reward (BSR), and the highest dose tested (2.5 mg/kg) produced a significant aversive-like rightward shift in BSR rate-frequency reward functions. Further, S33138 produced biphasic effects on cocaine self-administration, i.e., a moderate dose (2.5 mg/kg, p.o.) increased, while a higher dose (5 mg/kg, p.o.) inhibited, cocaine self-administration. The increase in cocaine self-administration likely reflects a compensatory response to a partial reduction in Drug reward after S33138. In addition, S33138 (0.156–2.5 mg/kg, p.o.) also dose-dependently inhibited cocaine-induced reinstatement of Drug-Seeking Behavior. The reduction in cocaine-enhanced BSR and cocaine-triggered reinstatement produced by lower effective doses (e.g., 0.156 or 0.625 mg/kg) of S33138 is unlikely due to impaired locomotion, as lower effective doses of S33138 decreased neither Ymax levels in the BSR paradigm, rotarod performance, nor locomotion. However, the higher doses (2.5 or 5 mg/kg) of S33138 also significantly inhibited sucrose self-administration and rotarod performance, suggesting non-D3 receptor-mediated effects on non-Drug reward and locomotion. These data suggest that lower doses of S33138 interacting essentially with D3 receptors have pharmacotherapeutic potential in treatment of cocaine addiction, while higher doses occupying D2 receptors may influence locomotion and non-Drug reward.
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gamma vinyl gaba inhibits cocaine triggered reinstatement of Drug Seeking Behavior in rats by a non dopaminergic mechanism
Drug and Alcohol Dependence, 2008Co-Authors: Xiao Qing Peng, Charles R Ashby, Jeremy G Gilbert, Arlene C Pak, Jonathan D Brodie, Stephen L Dewey, Eliot L GardnerAbstract:Relapse to Drug use is a core feature of addiction. Previous studies demonstrate that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, attenuates the acute rewarding effects of cocaine and other addictive Drugs. We here report that systemic administration of GVG (25-300 mg/kg) dose-dependently inhibits cocaine- or sucrose-induced reinstatement of reward-Seeking Behavior in rats. In vivo microdialysis data indicated that the same doses of GVG dose-dependently elevate extracellular GABA levels in the nucleus accumbens (NAc). However, GVG, when administered systemically or locally into the NAc, failed to inhibit either basal or cocaine-priming enhanced NAc dopamine in either naive rats or cocaine extinction rats. These data suggest that: (1) GVG significantly inhibits cocaine- or sucrose-triggered reinstatement of reward-Seeking Behavior; and (2) a GABAergic-, but not dopaminergic-, dependent mechanism may underlie the antagonism by GVG of cocaine-triggered reinstatement of Drug-Seeking Behavior, at least with respect to GVG's action on the NAc.
Christian Heidbreder - One of the best experts on this subject based on the ideXlab platform.
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dopamine d3 receptor antagonists a patent review 2007 2012
Expert Opinion on Therapeutic Patents, 2013Co-Authors: Fabrizio Micheli, Christian HeidbrederAbstract:Introduction: The synthesis and characterization of new highly potent and selective dopamine (DA) D3 receptor antagonists has permitted to characterize the role of the DA D3 receptor in the control of Drug-Seeking Behavior and in the pathophysiology of impulse control disorders and schizophrenia. Areas covered: In the present review, the authors will first describe most recent classes of DA D3 receptor antagonists by reviewing about 43 patent applications during the 2007 – 2012 period; they will then outline the biological rationale in support of the use of selective DA D3 receptor antagonists in the treatment of Drug addiction, impulse control disorders and schizophrenia. Expert opinion: The strongest clinical application and potential for selective DA D3 receptor antagonists lies in the reduction of Drug-induced incentive motivation, the attenuation of Drug's rewarding efficacy and the reduction in reinstatement of Drug-Seeking Behavior triggered either by re-exposure to the Drug itself, re-exposure to ...
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rationale in support of the use of selective dopamine d3 receptor antagonists for the pharmacotherapeutic management of substance use disorders
Naunyn-schmiedebergs Archives of Pharmacology, 2013Co-Authors: Christian HeidbrederAbstract:Growing evidence indicates that dopamine (DA) D3 receptors are involved in the control of Drug-Seeking Behavior and may play an important role in the pathophysiology of substance use disorders. First, DA D3 receptors are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and pallidum, which have been associated with Behaviors controlled by the presentation of Drug-associated cues. Second, repeated exposure to Drugs of abuse has been shown to produce neuroadaptations in the DA D3 system. Third, the synthesis and characterization of highly potent and selective DA D3 receptor antagonists has permitted to further define the role of the DA D3 receptor in Drug addiction. Provided that the available preclinical and preliminary clinical evidence can be translated into clinical proof of concept in human, selective DA D3 receptor antagonists show promise for the treatment of substance use disorders as reflected by their potential to (1) regulate the motivation to self-administered Drugs under schedules of reinforcement that require an increase in work demand and (2) disrupt the responsiveness to Drug-associated stimuli that play a key role in the reinstatement of Drug-Seeking Behavior triggered by re-exposure to the Drug itself, re-exposure to environmental cues that had been previously associated with Drug-taking Behavior, or stress.
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acute administration of sb 277011a ngb 2904 or bp 897 inhibits cocaine cue induced reinstatement of Drug Seeking Behavior in rats role of dopamine d3 receptors
Synapse, 2005Co-Authors: Jeremy G Gilbert, Eliot L Gardner, Charles R Ashby, Amy Hauck Newman, Christian Heidbreder, Arlene C Pak, Xiao Qing PengAbstract:Recent studies have shown that the novel dopamine (DA) D3 receptor antagonists SB-277011A and NGB 2904 inhibit cocaine- and/or stress-induced reinstatement of Drug-Seeking Behavior. The present study sought to determine if SB-277011A, NGB 2904, or BP-897 (a mixed D3 agonist/antagonist) similarly inhibit cocaine-associated cue-induced reinstatement of Drug-Seeking Behavior. Long-Evans rats were allowed to self-administer cocaine. Each cocaine infusion was paired with discrete conditioned cue-light and tone. Subsequently, Drug-Seeking (i.e., lever-pressing) Behavior was extinguished in the absence of cocaine and cocaine-associated cues. Rats were then tested for cue-induced reinstatement of Drug-Seeking. We found that cocaine-associated cues evoked robust reinstatement of lever-pressing. Acute intraperitoneal (i.p.) administration of SB-277011A (6, 12, or 24 mg/kg) produced a dose-dependent inhibition of cue-induced reinstatement of Drug-Seeking Behavior by 35, 65, and 85%, respectively, compared to vehicle-treated animals. Acute i.p. administration of NGB 2904 (0.1, 1.0, or 5.0 mg/kg) produced a 45, 30, and 70% inhibition of cue-induced reinstatement, respectively, compared to vehicle-treated animals. Acute i.p. administration of either 0.1 or 1 mg/kg of BP 897 did not produce a significant effect on cue-induced reinstatement, whereas a dose of 3 mg/kg produced a 70% inhibition of cue-induced reinstatement. These findings, combined with previous data, suggest that DA D3 receptor antagonism may underlie the inhibitory effects of SB-277011A and NGB 2904 on cocaine cue-induced reinstatement, while the effects of BP 897 may involve D3 and non-D3 receptor mechanisms.
Xiao Qing Peng - One of the best experts on this subject based on the ideXlab platform.
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oral administration of the naaladase inhibitor gpi 5693 attenuates cocaine induced reinstatement of Drug Seeking Behavior in rats
European Journal of Pharmacology, 2010Co-Authors: Xiao Qing Peng, Eliot L Gardner, Charles R Ashby, Ajit G Thomas, Krystyna M Wozniak, Barbara S SlusherAbstract:Abstract We have recently reported that the endogenous mGlu2/3 agonist N -acetylaspartylglutamate (NAAG) and the N -acetylated-α-linked-acidic dipeptidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of Drug-Seeking Behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-Seeking behaviours. We found that oral administration of GPI-5693 (15, 30, 60 mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished Drug-Seeking Behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60 mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-Seeking Behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction.
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the preferential dopamine d3 receptor antagonist s33138 inhibits cocaine reward and cocaine triggered relapse to Drug Seeking Behavior in rats
Neuropharmacology, 2009Co-Authors: Xiao Qing Peng, Charles R Ashby, Krista Spiller, Nitza Thomasson, Millan Mark, Elisabeth Mocaer, Carmen Munoz, Eliot L GardnerAbstract:Abstract We have previously reported that selective dopamine (DA) D3 receptor antagonists are effective in a number of animal models of Drug addiction, but not in intravenous Drug self-administration, suggesting a limited ability to modify Drug reward. In the present study, we evaluated the actions of S33138, a novel partially selective D3 receptor antagonist, in animal models relevant to Drug addiction. S33138, at doses of 0.156 or 0.625 mg/kg (i.p.), attenuated cocaine-enhanced brain-stimulation reward (BSR), and the highest dose tested (2.5 mg/kg) produced a significant aversive-like rightward shift in BSR rate-frequency reward functions. Further, S33138 produced biphasic effects on cocaine self-administration, i.e., a moderate dose (2.5 mg/kg, p.o.) increased, while a higher dose (5 mg/kg, p.o.) inhibited, cocaine self-administration. The increase in cocaine self-administration likely reflects a compensatory response to a partial reduction in Drug reward after S33138. In addition, S33138 (0.156–2.5 mg/kg, p.o.) also dose-dependently inhibited cocaine-induced reinstatement of Drug-Seeking Behavior. The reduction in cocaine-enhanced BSR and cocaine-triggered reinstatement produced by lower effective doses (e.g., 0.156 or 0.625 mg/kg) of S33138 is unlikely due to impaired locomotion, as lower effective doses of S33138 decreased neither Ymax levels in the BSR paradigm, rotarod performance, nor locomotion. However, the higher doses (2.5 or 5 mg/kg) of S33138 also significantly inhibited sucrose self-administration and rotarod performance, suggesting non-D3 receptor-mediated effects on non-Drug reward and locomotion. These data suggest that lower doses of S33138 interacting essentially with D3 receptors have pharmacotherapeutic potential in treatment of cocaine addiction, while higher doses occupying D2 receptors may influence locomotion and non-Drug reward.
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gamma vinyl gaba inhibits cocaine triggered reinstatement of Drug Seeking Behavior in rats by a non dopaminergic mechanism
Drug and Alcohol Dependence, 2008Co-Authors: Xiao Qing Peng, Charles R Ashby, Jeremy G Gilbert, Arlene C Pak, Jonathan D Brodie, Stephen L Dewey, Eliot L GardnerAbstract:Relapse to Drug use is a core feature of addiction. Previous studies demonstrate that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, attenuates the acute rewarding effects of cocaine and other addictive Drugs. We here report that systemic administration of GVG (25-300 mg/kg) dose-dependently inhibits cocaine- or sucrose-induced reinstatement of reward-Seeking Behavior in rats. In vivo microdialysis data indicated that the same doses of GVG dose-dependently elevate extracellular GABA levels in the nucleus accumbens (NAc). However, GVG, when administered systemically or locally into the NAc, failed to inhibit either basal or cocaine-priming enhanced NAc dopamine in either naive rats or cocaine extinction rats. These data suggest that: (1) GVG significantly inhibits cocaine- or sucrose-triggered reinstatement of reward-Seeking Behavior; and (2) a GABAergic-, but not dopaminergic-, dependent mechanism may underlie the antagonism by GVG of cocaine-triggered reinstatement of Drug-Seeking Behavior, at least with respect to GVG's action on the NAc.
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the novel dopamine d3 receptor antagonist ngb 2904 inhibits cocaine s rewarding effects and cocaine induced reinstatement of Drug Seeking Behavior in rats
Neuropsychopharmacology, 2006Co-Authors: Zhengxiong Xi, Xiao Qing Peng, Charles R Ashby, Jeremy G Gilbert, Amy Hauck Newman, Leah Gitajn, Eliot L GardnerAbstract:Accumulating evidence indicates that dopamine (DA) D3 receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D3-selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of Drug-Seeking Behavior in male Long–Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1–10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration Behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished Drug-Seeking Behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-Seeking Behavior. Overall, these data show that the novel D3-selective antagonist NGB 2904 attenuates cocaine's rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-Seeking Behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during Drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.
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acute administration of sb 277011a ngb 2904 or bp 897 inhibits cocaine cue induced reinstatement of Drug Seeking Behavior in rats role of dopamine d3 receptors
Synapse, 2005Co-Authors: Jeremy G Gilbert, Eliot L Gardner, Charles R Ashby, Amy Hauck Newman, Christian Heidbreder, Arlene C Pak, Xiao Qing PengAbstract:Recent studies have shown that the novel dopamine (DA) D3 receptor antagonists SB-277011A and NGB 2904 inhibit cocaine- and/or stress-induced reinstatement of Drug-Seeking Behavior. The present study sought to determine if SB-277011A, NGB 2904, or BP-897 (a mixed D3 agonist/antagonist) similarly inhibit cocaine-associated cue-induced reinstatement of Drug-Seeking Behavior. Long-Evans rats were allowed to self-administer cocaine. Each cocaine infusion was paired with discrete conditioned cue-light and tone. Subsequently, Drug-Seeking (i.e., lever-pressing) Behavior was extinguished in the absence of cocaine and cocaine-associated cues. Rats were then tested for cue-induced reinstatement of Drug-Seeking. We found that cocaine-associated cues evoked robust reinstatement of lever-pressing. Acute intraperitoneal (i.p.) administration of SB-277011A (6, 12, or 24 mg/kg) produced a dose-dependent inhibition of cue-induced reinstatement of Drug-Seeking Behavior by 35, 65, and 85%, respectively, compared to vehicle-treated animals. Acute i.p. administration of NGB 2904 (0.1, 1.0, or 5.0 mg/kg) produced a 45, 30, and 70% inhibition of cue-induced reinstatement, respectively, compared to vehicle-treated animals. Acute i.p. administration of either 0.1 or 1 mg/kg of BP 897 did not produce a significant effect on cue-induced reinstatement, whereas a dose of 3 mg/kg produced a 70% inhibition of cue-induced reinstatement. These findings, combined with previous data, suggest that DA D3 receptor antagonism may underlie the inhibitory effects of SB-277011A and NGB 2904 on cocaine cue-induced reinstatement, while the effects of BP 897 may involve D3 and non-D3 receptor mechanisms.
Travis T. Wager - One of the best experts on this subject based on the ideXlab platform.
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dopamine d3 d2 receptor antagonist pf 4363467 attenuates opioid Drug Seeking Behavior without concomitant d2 side effects
ACS Chemical Neuroscience, 2017Co-Authors: Travis T. Wager, Thomas Allen Chappie, David Horton, Ramalakshmi Yegna Chandrasekaran, Brian Samas, Elizabeth R Dunnsims, Cathleen Hsu, Nawshaba Nawreen, Michelle Vanasefrawley, Rebecca E OconnorAbstract:Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS Drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.1 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid Drug-Seeking Behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising ...
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Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects
2016Co-Authors: Travis T. Wager, Thomas Allen Chappie, David Horton, Brian Samas, Cathleen Hsu, Nawshaba Nawreen, Ramalakshmi Y. Chandrasekaran, Elizabeth R. Dunn-sims, Michelle A. Vanase-frawley, Rebecca E. O’connorAbstract:Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS Drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.1 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid Drug-Seeking Behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of Drug addiction
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Casein kinase 1δ/ε inhibitor PF-5006739 attenuates opioid Drug-Seeking Behavior.
ACS Chemical Neuroscience, 2014Co-Authors: Travis T. Wager, Ramalakshmi Y. Chandrasekaran, Jenifer Bradley, David M. Rubitski, Helen Berke, Scot Richard Mente, Todd William Butler, Angela C. Doran, Cheng Chang, Katherine FisherAbstract:Casein kinase 1 delta (CK1δ) and casein kinase 1 epsilon (CK1e) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing a CNS kinase inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided by structure-based Drug design, potent and selective CK1δ/e inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine derivatives. PF-5006739 (6) possesses a desirable profile, with low nanomolar in vitro potency for CK1δ/e (IC50 = 3.9 and 17.0 nM, respectively) and high kinome selectivity. In vivo, 6 demonstrated robust centrally mediated circadian rhythm phase-delaying effects in both nocturnal and diurnal animal models. Further, 6 dose-dependently attenuated opioid Drug-Seeking Behavior in a rodent operant reinstatement model in animals trained to self-administer fentanyl. Collec...
Leeyuan Liuchen - One of the best experts on this subject based on the ideXlab platform.
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dopamine d1 like receptor agonist and d2 like receptor antagonist stepholidine reduces reinstatement of Drug Seeking Behavior for 3 4 methylenedioxypyrovalerone mdpv in rats
ACS Chemical Neuroscience, 2018Co-Authors: Callum Hicks, Peng Huang, Linnet Ramos, Sunil U. Nayak, Yohanka Caro, Allen B. Reitz, Garry R. Smith, David Y.-w. Lee, Scott M. Rawls, Leeyuan LiuchenAbstract:Psychostimulant reinforcement is mediated by stimulation of both dopamine (DA) D1-like and D2-like receptors, suggesting that pharmacotherapy agents with a dual DA receptor mechanism may be useful for managing psychostimulant abuse. (-)-Stepholidine (L-SPD) is a Chinese herbal extract that functions as a D1-like receptor agonist and D2-like receptor antagonist. L-SPD has been shown to attenuate the reinforcing effects of heroin; however, its effects on the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) have not been examined. The current study determined the effects of L-SPD on reinstatement of MDPV-Seeking Behavior in the Drug intravenous self-administration (IVSA) and conditioned place preference (CPP) paradigms. To determine whether the effects of L-SPD were specific to psychostimulant reinforcement, we also examined its effects on sucrose-Seeking Behavior. Using a locomotor activity assay, we tested the locomotor effects of L-SPD, as well as its effects on MDPV-induced hyperactivity. The results of a battery of in vitro binding and functional assays confirmed that L-SPD functioned as a D1-like receptor agonist and D2-like receptor antagonist. In Behavioral experiments, L-SPD dose-dependently attenuated cue plus MDPV-primed reinstatement of MDPV-Seeking Behavior in the IVSA model. The highest dose of L-SPD also attenuated MDPV-primed reinstatement of MDPV CPP, as well as cue-induced reinstatement of sucrose-Seeking. L-SPD had no significant locomotor effects, and did not modulate the robust hyperactivity induced by MDPV. The current findings show for the first time a robust reinstatement effect with MDPV, which can be reduced by L-SPD. These results establish a role for DA receptors in Drug-Seeking Behavior for MDPV.
