Alterations in Rat Accumbens Endocannabinoid and GABA Content during Fentanyl Treatment: The Role of Ghrelin

Abstract

The opioid-induced rise of extracellular dopamine, endocannabinoid anandamide and γ-aminobutyric acid (GABA) concentrations triggered by opioids in the nucleus accumbens shell (NACSh) most likely participate in opioid reward. We have previously demonstrated that systemic administration of ghrelin antagonist (JMV2959) significantly decreased morphine-induced dopamine and anandamide (N-arachidonoylethanolamine, AEA) increase in the NACSh. Fentanyl is considered as a µ-receptor-selective agonist. The aim of this study was to test whether JMV2959, a growth hormone secretagogue receptor (GHS-R1A) antagonist, can influence the fentanyl-induced effects on anandamide, 2-arachidonoylglycerol (2-AG) and GABA in the NACSh and specify the involvement of GHS-R1A located in the ventral tegmental area (VTA) and nucleus accumbens (NAC). Using in vivo microdialysis in rats, we have found that pre-treatment with JMV2959 reversed dose dependently fentanyl-induced anandamide increases in the NACSh, resulting in a significant AEA decrease and intensified fentanyl-induced decreases in accumbens 2-AG levels, with both JMV2959 effects more expressed when administered into the NACSh in comparison to the VTA. JMV2959 pre-treatment significantly decreased the fentanyl-evoked accumbens GABA efflux and reduced concurrently monitored fentanyl-induced behavioural stimulation. Our current data encourage further investigation to assess if substances affecting GABA or endocannabinoid concentrations and action, such as GHS-R1A antagonists, can be used to prevent opioid-seeking behaviour.

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

“…The increase in accumbens anandamide and GABA also participate in the reinforcing effects of opioids. 16,17 Overall, these data suggest the importance of central ghrelin signalling in opioid reinforcing mechanisms. However, the only opioid intravenous self-administration (IVSA) study 18 described that when ghrelin was administered intracerebroventricularly (i.c.v.…”

“…Moreover, we wanted to determine whether JMV2959 could reduce the fentanyl-CPP and significantly influence fentanyl-induced dopamine efflux and dopamine metabolism in the NAC. In accordance with the literature 9,21 and our previous studies, 16,22 fentanyl was administered subcutaneously (20 or 30 μg/kg), intravenously (10 μg/kg into the rat tail vein), or self-administered by rats (2.5 μg/kg/infusion), and the GHS-R1A antagonist JMV2959 (1 or 3 mg/kg) was administered intraperitoneally. 11 The selected JMV2959…”

Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats

“…JMV2959 did not significantly influence the accumbens dopamine in rats, and 1, 3, and 6 mg/kg i.p. JMV2959 doses did not significantly influence rat locomotor activity [ 46 , 47 ].…”

“…Further interactions were found among ghrelin, endocannabinoid, GABA, and opioid systems in the NAC and the VTA, which might play roles in drug reinforcing properties. Namely, pretreatment with JMV2959 in rats significantly reduced/reversed the accumbens N -arachidonoylethanolamine (anandamide, AEA) increase and reduced the GABA-increase, both induced by administration of an opioid, and both being considered to participate in opioid reinforcement [ 46 ]. Thus, several neural systems, possibly within several brain structures, might cooperate or participate in the observed ghrelin antagonistic JMV2959 effects, including modulated dopamine mechanisms and/or dopamine-independent processes, so further research is necessary.…”

“…in volumes of 0.1 mL/100 g of body weight. The selected doses of JMV2959 (1, 3, and 6 mg/kg) were determined based on our previous studies in Wistar rats [ 46 , 47 , 75 , 76 ] and the literature [ 18 , 20 ]. The chosen JMV2959 doses had no significant effect on the rat locomotor behavior [ 47 ].…”