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

Abstract

Methamphetamine abuse imposes a significant burden on individuals and society worldwide, and an effective therapy of methamphetamine addiction would provide distinguished social benefits. Ghrelin significantly participates in reinforcing neurobiological mechanisms of stimulants, including amphetamines; thus, ghrelin antagonism is proposed as a promising addiction treatment. The aim of our study was to elucidate whether the pretreatment with growth hormone secretagogue receptor (GHS-R1A) antagonist, substance JMV2959, could reduce the methamphetamine intravenous self-administration (IVSA) and the tendency to relapse, and whether JMV2959 could reduce or prevent methamphetamine-induced conditioned place preference (CPP) in rats. Following an adequate maintenance period, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 180 min sessions of methamphetamine IVSA under a fixed ratio FR1, which significantly reduced the number of active lever-pressings, the number of infusions, and the amount of the consumed methamphetamine dose. Pretreatment with JMV2959 also reduced or prevented relapse-like behavior tested in rats on the 12th day of the abstinence period. Pretreatment with JMV2959 significantly reduced the expression of methamphetamine-induced CPP. Simultaneous administration of JMV2959 with methamphetamine during the conditioning period significantly reduced the methamphetamine-CPP. Our results encourage further research of the ghrelin antagonism as a potential new pharmacological tool for methamphetamine addiction treatment.

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

“…After the experiments, the rats were placed back to their home cages and immediately started eating regardless of the treatments; during the IVSA study, food was always fully consumed by all rats. In our IVSA study, the JMV2959 treatments did not affect the rat's body mass, in accordance with the literature 22,39 . The JMV2959 pretreatment significantly attenuated the 30 μg/kg s.c. fentanyl‐induced locomotor stimulation, stereotypical sniffing, and confined gnawing during the rat accumbens‐microdialysis 16 …”

“…36,37 Thus, the differ- antagonism in alcohol and sucrose models 36,38,39 and recently with methamphetamine. 22 Similarly to our results, no tolerance effect has been found after repeated administration of JMV2959 in mice. 40 Studies with various GHS-R1A agonists/antagonists/inverse agonists reflected the participation of more complex mechanisms indicating the involvement of different receptor subtypes or various coupled G-proteins which diversely influence multiple signalling pathways mediating feeding, metabolism, and behaviour.…”

“…In our IVSA study, the JMV2959 treatments did not affect the rat's body mass, in accordance with the literature. 22,39 The JMV2959 pretreatment significantly attenuated the 30 μg/kg s.c. fentanyl-induced locomotor stimulation, stereotypical sniffing, and confined gnawing during the rat accumbens-microdialysis. 16 Fentanyl is highly lipophilic, crosses rapidly through biological membranes, and uses passive and active transport mechanisms to pass through the blood-brain barrier.…”

“…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…”

“…doses were based on our previous studies 13,16,22 and had no significant effect on rat locomotor behaviour 14 (see details in Supporting Information).…”