Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats
Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%–10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and a...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-01-01
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| Series: | Frontiers in Behavioral Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnbeh.2019.00292/full |
| _version_ | 1819059439628451840 |
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| author | Giordano de Guglielmo Marsida Kallupi Sharona Sedighim Amy H. Newman Olivier George |
| author_facet | Giordano de Guglielmo Marsida Kallupi Sharona Sedighim Amy H. Newman Olivier George |
| author_sort | Giordano de Guglielmo |
| collection | DOAJ |
| description | Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%–10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D3 receptor antagonist VK4-116 ([R]-N-[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1H-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5–25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D3 receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D3 receptor antagonism may be a viable therapeutic approach for the treatment of OUD. |
| first_indexed | 2024-12-21T14:11:07Z |
| format | Article |
| id | doaj.art-16f9e227ccc945bfa59b9a44b7b04584 |
| institution | Directory Open Access Journal |
| issn | 1662-5153 |
| language | English |
| last_indexed | 2024-12-21T14:11:07Z |
| publishDate | 2020-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Behavioral Neuroscience |
| spelling | doaj.art-16f9e227ccc945bfa59b9a44b7b045842022-12-21T19:01:03ZengFrontiers Media S.A.Frontiers in Behavioral Neuroscience1662-51532020-01-011310.3389/fnbeh.2019.00292502436Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock RatsGiordano de Guglielmo0Marsida Kallupi1Sharona Sedighim2Amy H. Newman3Olivier George4Department of Psychiatry, University of California, San Diego, La Jolla, CA, United StatesDepartment of Psychiatry, University of California, San Diego, La Jolla, CA, United StatesDepartment of Psychiatry, University of California, San Diego, La Jolla, CA, United StatesMolecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, United StatesDepartment of Psychiatry, University of California, San Diego, La Jolla, CA, United StatesPrescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%–10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D3 receptor antagonist VK4-116 ([R]-N-[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1H-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5–25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D3 receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D3 receptor antagonism may be a viable therapeutic approach for the treatment of OUD.https://www.frontiersin.org/article/10.3389/fnbeh.2019.00292/fullVK4-116escalationopioiddependancewithdrawal |
| spellingShingle | Giordano de Guglielmo Marsida Kallupi Sharona Sedighim Amy H. Newman Olivier George Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats Frontiers in Behavioral Neuroscience VK4-116 escalation opioid dependance withdrawal |
| title | Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats |
| title_full | Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats |
| title_fullStr | Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats |
| title_full_unstemmed | Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats |
| title_short | Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats |
| title_sort | dopamine d3 receptor antagonism reverses the escalation of oxycodone self administration and decreases withdrawal induced hyperalgesia and irritability like behavior in oxycodone dependent heterogeneous stock rats |
| topic | VK4-116 escalation opioid dependance withdrawal |
| url | https://www.frontiersin.org/article/10.3389/fnbeh.2019.00292/full |
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