Alterations in Rat Accumbens Dopamine, Endocannabinoids and GABA Content During WIN55,212-2 Treatment: The Role of Ghrelin

Abstract

The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2–induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

“…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 ].…”

“…Recent microdialysis study in rats [ 216 ] found that the administration of WIN55,212-2 into the posterior VTA induced significant dopamine release in the NAC shell, which was significantly reduced by systemic JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by JMV2959 pretreament, with the monoamine oxidase (MAO) metabolism products and their turnover being the most increased (DOPAC/dopamine, HVA/dopamine).…”

“…Intracerebral WIN55,212-2 administration also increased the anandamide (AEA) and the 2-AG extracellular levels in the NAC shell, which were moderately but significantly attenuated by JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens-GABA levels was reversed by JMV2959 pretreatment [ 216 ].…”

“…The GHS-R1A antagonist JMV2959 significantly reduced several parameters of cannabinoid reward and attenuated cannabinoid intake and drug-seeking behavior. All currently available results regarding the investigation of acyl-ghrelin and its antagonist effects in cannabinoid addiction models originate from one research facility, nevertheless, they were obtained from a comprehensive dual investigation in several WIN55,212-2 and THC rat models [ 215 , 216 ]. Further preclinical and (particularly) clinical research is essential.…”

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

“…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 ).…”