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The Growth Hormone Secretagogue Receptor Inverse Agonist/Antagonist PF‐5190457 Suppresses Oxycodone Seeking
Author(s) -
Garcia Erik,
Kasper James,
Chapman Holly,
Stutz Sonja,
Fox Robert,
Anastasio Noelle,
Moeller Frederick,
Cunningham Kathryn
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03708
Subject(s) - oxycodone , inverse agonist , agonist , medicine , pharmacology , self administration , polysubstance dependence , antagonist , opioid , craving , fentanyl , psychology , anesthesia , substance abuse , addiction , receptor , psychiatry
Aims The rise in opioid overdose deaths and opioid use disorder patents ( OUD ) have reached crisis levels in the United States. Medication‐assisted treatment mitigates withdrawal, reduces mortality, and reduces intake of abused opioids (e.g., oxycodone, fentanyl). Nevertheless, 50% of OUD patients exhibit recurring relapse episodes, signifying the need to identify novel therapeutics to further reduce recidivism rates. The gut‐brain peptide ghrelin modulates hedonic motivation for food and abused drugs via actions at the growth hormone secretagogue 1α receptor ( GHS1 αR ). The GHS1αR inverse agonist/antagonist PF‐5190457 ( ‘457 ) has been shown to reduce cue‐evoked alcohol craving and cue reactivity in human psychopharmacology studies. The current experiments were designed to test the efficacy of ‘457 in a preclinical model of relapse‐like behavior following a brief abstinence interval from intravenous oxycodone self‐administration ( SA ). Methods Male Sprague‐Dawley rats (n=60) were implanted with indwelling jugular catheters and allowed to acquire stable oxycodone SA (0.1 mg/kg/inf) in daily 180‐min sessions. After the final SA session, rats remained in the home cage for 72 hours prior to the drug‐seeking cue test. Rats were pretreated with ‘457 (20 or 30 mg/kg, i.p.) or vehicle before saline or oxycodone (0.5 mg/kg, s.c.) and the start of the 60‐min cue test. Previously active lever presses resulted in the presentation of the discrete cues associated with oxycodone infusions and inactive lever presses had no consequence. Results Pretreatment with ‘457 suppressed previously active lever presses in rats abstinent from oxycodone SA when compared to vehicle ( p = 0.04). ‘457 did not alter inactive lever presses in oxycodone or saline‐trained rats. Oxycodone priming elevated drug‐seeking which was suppressed by ‘457 (F 2,23 =6.23, p = 0.007). Inactive lever presses were not affected by ‘457 or oxycodone pretreatment (F 2,23 =0.97, p = 0.39). Conclusions The efficacy of the GHS1αR inverse agonist/antagonist ‘457 to suppress relapse‐like behaviors in a rodent SA assay suggests the possibility that ‘457 is a viable non‐opioid therapeutic strategy to mitigate opioid relapse vulnerability.