Methamphetamine blocks adenosine a2a receptor activation via sigma 1 and cannabinoid cb1 receptors

Abstract

Methamphetamine is, worldwide, one of the most consumed drugs of abuse. One important side effect is neurodegeneration leading to a decrease in life expectancy. The aim of this paper was to check whether the drug affects one of the receptors involved in neurodegeneration/neuroprotection events, namely the adenosine A2A receptor (A2A R). First, we noticed that methamphetamine does not affect A2A functionality if the receptor is expressed in a heterologous system. However, A2A R becomes sensitive to the drug upon complexes formation with the cannabinoid CB1 receptor (CB1 R) and the sigma 1 receptor (σ1 R). Signaling via both adenosine A2A R and cannabinoid CB1 R was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the A2A R–CB1 R heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the A2A R-and the CB1 R-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σ1 R, alters the expression and function of two interacting receptors, A2A R, which is a therapeutic target for neuroprotection, and CB1 R, which is the most abundant G protein-coupled receptor (GPCR) in the brain.