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      Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects

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          Abstract

          Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated—in laboratory rats—the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5–25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose–response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.

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          Most cited references42

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          Relationship between Nonmedical Prescription-Opioid Use and Heroin Use

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            Changes in Synthetic Opioid Involvement in Drug Overdose Deaths in the United States, 2010-2016

            This study uses National Vital Statistics System data to describe trends in synthetic opioid involvement in drug overdose deaths in the United States from 2010 to 2016.
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              The Neurobiology of Opioid Dependence: Implications for Treatment

              Opioid tolerance, dependence, and addiction are all manifestations of brain changes resulting from chronic opioid abuse. The opioid abuser’s struggle for recovery is in great part a struggle to overcome the effects of these changes. Medications such as methadone, LAAM, buprenorphine, and naltrexone act on the same brain structures and processes as addictive opioids, but with protective or normalizing effects. Despite the effectiveness of medications, they must be used in conjunction with appropriate psychosocial treatments.
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                Author and article information

                Journal
                Neuropsychopharmacology
                Neuropsychopharmacol
                Springer Nature
                0893-133X
                1740-634X
                November 27 2018
                Article
                10.1038/s41386-018-0284-5
                6785005
                30555159
                6d4d1c9e-269e-455e-9070-969539736e4b
                © 2018

                http://www.springer.com/tdm

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