Methamphetamine Blocks Adenosine A Receptor Activation via Sigma 1 and Cannabinoid CB Receptors.

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 A receptor (AR). First, we noticed that methamphetamine does not affect A functionality if the receptor is expressed in a heterologous system. However, AR becomes sensitive to the drug upon complexes formation with the cannabinoid CB receptor (CBR) and the sigma 1 receptor (σR). Signaling via both adenosine AR and cannabinoid CBR was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the AR-CBR heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the AR- and the CBR-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σR, alters the expression and function of two interacting receptors, AR, which is a therapeutic target for neuroprotection, and CBR, which is the most abundant G protein-coupled receptor (GPCR) in the brain.