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

Tereza Havlickova,Nina Puskina,Marek Lapka,Pavel Jerabek,Chrysostomos Charalambous,Magdalena Sustkova-Fiserova

doi:10.3390/ijms19102925

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.

Highlights

Methamphetamine is considered as a more addictive N-methylated derivate of amphetamine, developed in the 1950s [1,2]
Ghrelin significantly participates in reinforcing neurobiological mechanisms of stimulants, including amphetamines; 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

Summary

Introduction

Methamphetamine is considered as a more addictive N-methylated derivate of amphetamine, developed in the 1950s [1,2]. Unlike the restricted medical use of amphetamine, methamphetamine is usually strictly illicit across the world. Serious health and social consequences linked with methamphetamine use are well documented [3]. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) estimated 3.6% life-time prevalence and 0.5% last year use of amphetamines in Europe in 2016. Amphetamines are more prominent in northern and eastern European countries, with methamphetamine being common in the Czech Republic, Slovakia, Latvia, and Lithuania [5]. Methamphetamine injection use, which is prevalent in the Czech Republic, is the most devastating, and so far, symptomatic treatments for addiction remain insufficient. New effective methamphetamine addiction treatment strategies are currently being intensively studied

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