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 (A2AR). First, we noticed that methamphetamine does not affect A2A functionality if the receptor is expressed in a heterologous system. However, A2AR becomes sensitive to the drug upon complexes formation with the cannabinoid CB1 receptor (CB1R) and the sigma 1 receptor (σ1R). Signaling via both adenosine A2AR and cannabinoid CB1R was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the A2AR–CB1R heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the A2AR- and the CB1R-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σ1R, alters the expression and function of two interacting receptors, A2AR, which is a therapeutic target for neuroprotection, and CB1R, which is the most abundant G protein-coupled receptor (GPCR) in the brain.
Highlights
CB1 R and A2A R, the two receptors colocalized at the plasma membrane level and methamphetamine pretreatment did not induce any significant change in colocalization (Figure 1F)
To further explain the mechanism by which methamphetamine may block CB1 R action, we focused on the σ1 receptor (σ1 R), which is a transmembrane receptor that does not belong to the G protein-coupled receptor (GPCR) family
It is a target of cocaine and its functionality in rodents is altered upon methamphetamine treatment [22,26,33]
Summary
Methamphetamine is one of the most consumed drugs of abuse in developed countries. It causes significant health and socio-economic problems that impact on sufferers, families, and the civil Society as a whole. Cocaine and methamphetamine share their ability to increase the brain levels of one of the main neurotransmitters, dopamine. The two drugs share some of the mechanisms that lead to addiction, but they display differential trends. Five dopamine receptors have been identified so far: D1 , D2 , D3 , D4 and D5. They belong to the superfamily of G protein-coupled receptor (GPCRs) and, in mammals, they
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