Selective dopamine D3 receptor partial agonist (±)VK4-40 reduces the reinforcing strength of d-amphetamine but not cocaine in rhesus monkeys responding under a progressive-ratio schedule of reinforcement

Article

作者: Cao, Jianjing ; Allen, Mia I. ; Nader, Michael A ; Allen, Mia I ; Lewis, Emory A. ; Lewis, Emory A ; Nader, Michael A. ; Newman, Amy Hauck

BACKGROUNDAlthough countless studies have aimed to identify and test novel therapeutics for stimulant misuse, there are still no FDA-approved pharmacotherapies for stimulant use disorders. One potential treatment target is the dopamine D3 receptor (D3R) and studies in rodents have suggested that the novel D3R partial agonist (±)VK4-40 may be effective at decreasing cocaine self-administration. However, no previous studies have examined the efficacy of (±)VK4-40 in reducing cocaine self-administration in nonhuman primates nor the generality of effects by examining self-administration of other stimulants using a within-subjects design.METHODSExperiment 1 examined how acute treatment with (±)VK4-40 (1.7-3.0mg/kg, i.v.) influenced cocaine and d-amphetamine self-administration in three rhesus monkeys responding under a progressive-ratio (PR) schedule of reinforcement. In Experiment 2, the reinforcing effects of (±)VK4-40 were evaluated under a PR schedule and compared to cocaine and d-amphetamine.RESULTSWhen given as a pretreatment, (±)VK4-40 significantly reduced the reinforcing strength of d-amphetamine but not cocaine. In general, the effects of (±)VK4-40 on d-amphetamine responding were parallel downward shifts in the self-administration dose-response curve. When (±)VK4-40 was substituted for cocaine, it functioned as a reinforcer in 2 of 3 monkeys. However, the reinforcing strength of (±)VK4-40 was significantly lower than cocaine and d-amphetamine, suggesting lower potential for misuse.CONCLUSIONSOverall, these findings support further exploration of D3R partial agonists, including (±)VK4-40, for treatment of d-amphetamine misuse or potentially in combination with d-amphetamine for treatment of cocaine use disorder.

2023-11-01·Neuropsychopharmacology

Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys

Article

作者: Banks, Matthew L ; Allen, Mia I ; Newman, Amy Hauck ; Cornelissen, Jeremy C ; Nader, Michael A ; Woodlief, Kendall

Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3R partial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N = 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003-0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01-0.1 mg/kg), (±)VK4-116 (1.0-10 mg/kg), and (±)VK4-40 (1.0-10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N = 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N = 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted.

2023-03-01·Journal of Pharmacology and Experimental Therapeutics

3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder

Article

作者: Peng, Lindsey N ; Collins, Gregory T ; Cao, Jianjing ; Newman, Amy Hauck ; Doyle, Michelle R ; Rice, Kenner C

Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration procedures are widely used to screen candidate medications for stimulant use disorder, although preclinical reductions in stimulant self-administration have not translated to meaningful reductions in stimulant use in humans. One possible reason for this discordance is that most preclinical studies evaluate candidate medications under conditions that promote predictable, and well-regulated patterns of drug-taking rather than the dysregulated and/or compulsive patterns of drug-taking characteristic of a stimulant use disorder. A subset of rats ("high-responders") that self-administer 3,4-methelyendioxypyrovalerone (MDPV), a monoamine uptake inhibitor, develop high levels of dysregulated drug-taking consistent with behaviors related to stimulant use disorders. Because MDPV acts on dopamine, serotonin (5-HT), and sigma receptor systems, the current studies compared the potency and effectiveness of a dopamine D₃ receptor partial agonist (VK4-40) or antagonist (VK4-116), a sigma receptor antagonist (BD1063), a dopamine D₂/D₃/sigma receptor antagonist (haloperidol), and a 5-HT_2C receptor agonist (CP-809,101) to reduce MDPV (0.0032-0.1 mg/kg/infusion) self-administration in high- and low-responding rats as well as rats self-administering cocaine (0.032-1 mg/kg/infusion). VK4-40, VK4-116, haloperidol, and CP-809,101 were equipotent and effective at reducing drug-taking in all three groups of rats, including the high-responders; however, VK4-116 and CP-809,101 were less potent at reducing drug-taking in female compared with male rats. Together, these studies suggest that drugs targeting dopamine D₃ or 5-HT_2C receptors can effectively reduce dysregulated patterns of stimulant use, highlighting their potential utility for treating stimulant use disorders. SIGNIFICANCE STATEMENT: There are no United States Food and Drug Administration-approved treatments for stimulant use disorder, perhaps in part because candidate medications are most often evaluated in preclinical models using male subjects with well-regulated drug-taking. In an attempt to better model aberrant drug taking, this study found compounds acting at dopamine D₃ or 5-HT_2C receptors can attenuate drug-taking in male and female rats that self-administered two different stimulants and exhibited either a high or low substance use disorder-like phenotype.

100 项与 VK-440 相关的药物交易

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