THE MGLU7 RECEPTOR: A NEW TARGET IN THE THERAPY OF OPIATES ADDICTION?

Zuzana Hajasova, Corinne Canestrelli, Delphine Rigault, Isabelle Brabet, Francine Acher, Florence Noble and Nicolas Marie

Neuroplasticité et thérapies des addictions » / Inserm UMR‐S 1124 /, Université Paris Descartes, 75006 Paris France

Abstract

Addiction to drugs such as opiates (morphine and its derivatives), is a chronic psychiatric illness mainly characterized by seeking and compulsive consumption of psychoactive substances. It is a major health issue since it results in high morbidity and mortality. The opiate addicts can benefit from opioid replacement therapy but its use does not fully prevent relapse which remains the main problem in the treatment of addiction. There is therefore a need to find new therapeutic targets to prevent relapse. Accumulating evidences showed that the glutamatergic system is involved in drug addiction. Indeed, relapse is accompanied by an increase in glutamate release in brain structures involved in drug addiction, suggesting that inhibiting this release could block relapse. This could be achieved by stimulating group III metabotropic glutamate receptor. The purpose of this work was to show that the group III metabotropic glutamate receptors could be a valuable target in the treatment of opiate addiction. To achieve this goal we used LSP2‐9166 (a new mixed mGlu4/mGlu7 orthosteric agonist) in two models of drug addiction in mice: behavioral sensitization (by measuring locomotor activity) and conditioned place preference. Since comorbidities such as anxiety or depression are common among addicts, we tested the effect of LSP2‐9166 on these two behaviors with the light/dark box test and the forced swimming test, respectively. We also measured the effect of LSP2‐9166 on spontaneous locomotor activity, hedonic state by measuring preference for sucrose and memory using the Y maze. We showed that LSP2‐9166 blocks the expression and the reinstatement of an extinguished conditioned place preference to morphine but has no effect on expression and induction of behavioral sensitization. These effects are not due to a blockade of spontaneous locomotor activity, anhedonia or memory deficit and might involve the mGlu7 receptor. Indeed, the effects of LSP2‐9166 in morphine reinforcing effects are blocked by the XAP044, a mGlu7 antagonist. Whereas LSP2‐9166 has an anxiolytic effect at low dose, an anxiogenic effect is observed at high doses. Finally, the LSP2‐9166 has no effects in the forced swim test. All these results suggest that mGlu7 might a valuable target in the treatment of opiate addiction. However, its role needs to be confirmed especially by delineating the respective role of mGlu4 and mGlu7 in the effects of LSP2‐9166 using selective antagonists.

Keywords: Drug addiction, cocaine, morphine, glutamate, mGlu receptors.