Victoria Gómez Murcia¹, Aurelio Franco García¹, Juana María Hidalgo Céspedes¹, M. VICTORIA MILANÉS MAQUILÓN¹, María Cristina Núñez Parra¹

(1) FARMACOLOGÍA CELULAR Y MOLECULAR, IMIB-Arrixaca, España

Adenosine is an endogenous purine nucleoside that neuromodulates the Central Nervous System through the activation of different receptors types. The purinergic system, through the A2A adenosine receptor (A2AR), is involved in addiction induced by different drugs of abuse. Particularly, it has been previously demonstrated that A2A gene deletion in mice modifies some of the behavioral effects of morphine (1). To investigate the specific role of this receptor in the acquisition of the behavioral responses induced by morphine withdrawal, we have used the condition place aversion (CPA) paradigm and administered an A2AR antagonist to morphine-dependent and control mice prior the conditioning sessions with naloxone.

The aversive emotional aspects of naloxone-precipitated morphine withdrawal were evaluated by the CPA paradigm. After a pre-conditioning test, to induce opiates dependence the mice that did not show a natural preference for any chamber of the CPA apparatus were subcutaneously implanted with one morphine (75 mg) (MOR) or placebo (PLA; control) pellet. An A2RA antagonist (sch58261; 1mg/kg) or its vehicle (CTL; 10 ml/kg) was administered intraperitoneally 15 min before the conditioning sessions with naloxone (NX; 0.1 mg/kg, s.c.). Data are presented as the mean ± S.E.M. of the time that mice spent in the naloxone-paired chamber and the statistical analysis was performed using a Student’s t test. P values < 0.05 were considered significant.

As expected, opiate dependent animals injected with vehicle before the naloxone conditioning session spent significantly (p < 0.01) less time in the morphine withdrawal-paired chamber during the CPA test when compared with the pre-conditioning test. In contrast, when vehicle was administered prior the naloxone conditioning session no differences were found in the time spent by control animals in the naloxone-associated chamber during the CPA and the pre-conditioning tests. The administration of the A2A antagonist to the placebo group before naloxone conditioning did not induce any changes in the time spent by these animals in the naloxone-paired compartment during the CPA and pre-conditioning test. Nonetheless, when sch58261 was injected 15 min before naloxone conditioning to morphine dependent mice they did not decrease the time spent in compartment associated with withdrawal during the CPA test in comparison with the preconditioning test, which indicates that these animals did not showed aversion for the abstinence syndrome-associated environment. (&& p<0.01 vs preconditioning test).

Our results revealing that the blockade of A2AR in morphine dependent mice before conditioning to the abstinence syndrome prevented the aversion to the withdrawal paired-compartment indicates that this receptor is essential for the acquisition of morphine withdrawal-induced behaviors. Given that the CPA paradigm is considered as a measure for drug-seeking behavior, our results point out that A2AR antagonists might be effective pharmacological tools to treat addiction to opiates. 1. A Castañé et al. Br J Pharmacol 2008 Nov;155(5):757-66. Funding: Seneca (21133/SF/19 Fundación Séneca. Región de Murcia (Spain)); MICIN (SAF2017-85679-R; PID2020-113557RB-I00; FPU/01722).