Ghrelin receptor antagonism of fentanyl‐induced conditioned place preference, intravenous self‐administration, and dopamine release in the nucleus accumbens in rats

Abstract

The extended occurrence of fentanils abuse associated with the dramatic increase in opioid fatal overdoses and dependence strongly emphasizes insufficiencies in opioid addiction treatment. Recently, the growth hormone secretagogue receptor (GHS-R1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in opioid abuse is still unclear. Therefore, the aim of our study was to clarify whether the GHS-R1A antagonist JMV2959 could reduce the fentanyl-induced conditioned place preference (CPP), the fentanyl intravenous self-administration (IVSA), and the tendency to relapse, but also whether JMV2959 could significantly influence the fentanylinduced dopamine efflux in the nucleus accumbens (NAC) in rats, that importantly participates in opioids' reinforcing effects. Following an ongoing fentanyl selfadministration, JMV2959 3 mg/kg was administered intraperitoneally 20 minutes before three consequent daily 360-minute IVSA sessions under a fixed ratio FR1, which significantly reduced the number of active lever-pressing, the number of infusions, and the fentanyl intake. Pretreatment with JMV2959 also reduced the fentanyl-seeking/relapse-like behaviour tested in rats on the 12 th day of the forced abstinence period. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of fentanyl-CPP. The fentanyl-CPP development was reduced after the simultaneous administration of JMV2959 with fentanyl during conditioning. The JMV2959 significantly reduced the accumbens dopamine release induced by subcutaneous and intravenous fentanyl. Simultaneously, it affected the concentration of byproducts associated with dopamine metabolism in the NAC. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of fentanyl.

Growth Hormone Secretagogue Receptor 1A Antagonist JMV2959 Effectively Prevents Morphine Memory Reconsolidation and Relapse

“…We also showed that the systemic administration of JMV2959 was long-lasting and effective, which suggests a crucial role of the ghrelin-GHSR1A pathway in the regulation of drug addiction. Other studies have reported the inhibitory effect of JMV2959 on addictive drug reward memory in other drugs, such as methamphetamine, fentanyl, and cocaine ( Engel et al, 2015 ; Jerabek et al, 2017 ; Havlickova et al, 2018 ; Sustkova-Fiserova et al, 2019 ).…”

“…The disruption of drug memory reconsolidation has been suggested as a promising strategy to prevent relapse ( Lin et al, 2014 ). A number of studies have demonstrated that ghrelin and its specific receptor GHSR1A are involved in the mediation of memory reward-related neurological processes ( Havlickova et al, 2018 ; Sustkova-Fiserova et al, 2019 ). Thus, targeting these neuronal processes could disrupt memories underlying addiction behaviour ( Engel et al, 2015 ; Jerabek et al, 2017 ).…”

“…Recently, GHSR1A antagonism has been adopted as a promising anti-addiction mechanism. Studies have demonstrated that the administration of GHSR1A antagonist JMV2959 significantly inhibits fentanyl‐ and methamphetamine-induced conditioned place preference (CPP), intravenous self-administration, and dopamine release in the nucleus accumbens in rats ( Engel et al, 2015 ; Jerabek et al, 2017 ; Havlickova et al, 2018 ; Sustkova-Fiserova et al, 2019 ). However, the effect of JMV2959 on relapse to drug seeking remains unknown.…”

An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

“…Similarly, systemic or central administration of ghrelin potentiates the effects of central stimulants (e.g., amphetamine and cocaine) on locomotor stimulation and CPP (Wellman et al, 2005 ; Davis et al, 2007 ; Jang et al, 2013 ; Schuette et al, 2013 ; Dunn et al, 2019 ), whereas GHSR-1A antagonists attenuate these behavioral responses in rodents (Jerlhag et al, 2010 ; Abizaid et al, 2011 ; Clifford et al, 2012 ; Suchankova et al, 2016a ; Havlickova et al, 2018 ; Wenthur et al, 2019 ; Edvardsson et al, 2021 ). Further, the acute rewarding effect of opiates and its relationship with the GHSR-1A is evident as JMV2959 inhibits the dopaminergic release in NAc and CPP caused by morphine or fentanyl (Engel et al, 2015 ; Sustkova-Fiserova et al, 2016 , 2020 ; Jerabek et al, 2017 ). Besides, JMV2959 reduces morphine-induced locomotor stimulation and stereotypic behavior in male rodents (Sustkova-Fiserova et al, 2014 ).…”

The inhibitory effects of orexin antagonists on the reinforcing properties of amphetamine during brain self-stimulation and the development of a conditioned place preference in rats

“…В последние годы акцент в исследовании механизмов зависимости сделан на изучении аномального функционирования эмоциогенных структур мозга, активация которых во многом зависит от центральных механизмов стресса (система структур расширенной миндалины, или параамигдалярного комплекса). Особенно неясным и противоречивым является вопрос о роли нейропептидов расширенной миндалины в регуляции подкрепляющих систем мозга [16,17].…”