Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system X_c⁻ activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

Background. Several studies have shown that the ethanol-derived metabolite salsolinol can activate the mesolimbic system, suggesting that salsolinol is the active molecule mediating the rewarding effects of ethanol. In vitro and in vivo studies suggest that salsolinol exerts its action on neuron excitability through a mechanism involving opioid neurotransmission. However, there is not direct pharmacologic evidence showing that salsolinol activates opioid receptors. Methods. The ability of racemic (R/S)-salsolinol, and its stereoisomers (R)-salsolinol and (S)-salsolinol, to activate the µ-opioid receptor was tested in cell-based (light-emitting) receptor assays. To further characterizing the interaction of salsolinol stereoisomers with the µ-opioid receptor, a molecular docking study was performed using the crystal structure of the µ-opioid receptor. Results. This study shows that salsolinol activates the µ-opioid receptor by the classical G protein-adenylate cyclase pathway with an EC50 of 2 x 10-5 M. The agonist action of salsolinol was fully blocked by the µ-opioid antagonist naltrexone. The EC50 for the purified stereoisomers (R)-salsolinol and (S)-salsolinol were 6 x 10-4 M and 9 x 10-6 M respectively. It was found that the action of racemic salsolinol on the µ-opioid receptor did not promote the recruitment of β-arrestin. Molecular docking studies showed that the interaction of (R)- and (S)-salsolinol with the µ-opioid receptor is similar to that predicted for the agonist morphine. Conclusions. It is shown that (R)-salsolinol and (S)-salsolinol are agonists of the µ-opioid receptor. (S)-salsolinol is a more potent agonist than the (R)-salsolinol stereoisomer. In silico analysis predicts a morphine-like interaction between (R)- and (S)-salsolinol with the µ-opioid receptor. These results suggest that an opioid action of salsolinol or its enantiomers is involved in the rewarding effects of ethanol.