Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats

Abstract

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

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“…THC-CPP development was also reduced after the simultaneous administration of JMV2959 and THC during conditioning. JMV2959 also significantly reduced THC-induced behavioral stimulation in the LABORAS cage [ 215 ], similarly to a later experiment involving the synthetic aminoalkylindol cannabinoid WIN55,212-2-induced behavioral stimulation [ 216 ]. Furthermore, JMV2959 pretreatment significantly attenuated the WIN55,212-2 intravenous self-administration (IVSA) in rats [ 215 ].…”

“…JMV2959 also significantly reduced THC-induced behavioral stimulation in the LABORAS cage [ 215 ], similarly to a later experiment involving the synthetic aminoalkylindol cannabinoid WIN55,212-2-induced behavioral stimulation [ 216 ]. Furthermore, JMV2959 pretreatment significantly attenuated the WIN55,212-2 intravenous self-administration (IVSA) in rats [ 215 ]. Pretreatment with JMV2959 also seemed to reduce WIN55,212-2-seeking/relapse-like behavior in rats tested on the 12th day of the forced abstinence period.…”

“…A recent complex study [ 215 ] tested the effects of acyl-ghrelin and the ghrelin antagonism in several cannabinoid addiction rat models. It was found that pretreatment with the GHS-R1A antagonist JMV2959 significantly and dose-dependently reduced the manifestation of Δ-9-tetrahydrocannabinol/THC-conditioned place preference (CPP).…”

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“…Besides, JMV2959 reduces morphine-induced locomotor stimulation and stereotypic behavior in male rodents (Sustkova-Fiserova et al, 2014 ). Additionally, JMV2959 have been shown to inhibit elevated accumbal dopamine levels and CPP caused by cannabinoids in male rats (Charalambous et al, 2020 , 2021 ). Regarding chronic use and SUD, plasma ghrelin has been associated with cocaine-seeking and expectancy (Tessari et al, 2007 ; You et al, 2019 ), whereas systemic administration of JMV2959 reduces self-administration of methamphetamine in rats (Havlickova et al, 2018 ).…”

“…Similarly, JMV2959 administered peripherally or centrally into the VTA reduces drug-seeking and relapse behavior for opiates in rodents (D'cunha et al, 2020 ; Sustkova-Fiserova et al, 2020 ). Further, ghrelin increases the self-administration and seeking behavior for cannabinoids, whereas JMV2959 decreases these behaviors (Charalambous et al, 2021 ).…”