Captopril and losartan revert addictive-like behaviours in mice with chronic exposure to inhalants

Inhalants are gases or volatile liquids at room temperature that can be used for intoxication purposes. The main component of the most commonly consumed inhalants in Mexico is toluene. One of the main behavioral effects derived from chronic exposure to inhalants is addiction. Drug addiction has been associated with alterations in the release of dopamine at the mesolimbic dopaminergic system. In addition, there are reports in the literature that suggest that the renin angiotensin aldosterone system (RAAS) play a role in several drug´s consumption. In this regard, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor-type 1 antagonists (ARAs) have been shown to activate the counter-regulatory axis of RAAS (ECA2 / Ang 1-7 / RMas), facilitating its beneficial effects on the central nervous system. There are previous reports showing that ACEIs and ARAs are able to revert addictive-like behaviors induced by cocaine, amphetamines and alcohol; however the participation RAAS in the modulation of addiction induced by inhalants has not been studied. In the present work, the effect of one ACE inhibitor and one ARA on the expression of addictive behavior induced by chronic exposure to toluene was investigated. With this purpose adolescent Swiss-webster male mice were exposed to toluene (0 or 4000 ppm, during 4 weeks), and the induction of the addictive behavior was evaluated with the behavioral sensitization model. In the second phase of the work, the effect of captopril and losartan on the expression of behavioral sensitization was explored. This evaluation was conducted in independent groups of animals under the same experimental protocol during the induction phase, but at the end of the toluene exposure animals were treated with captopril (20 mg/kg at day, i.p., for 20 days) or losartan (10 mg/kg at day, i.p., for 20 days). At the end of the treatments, all animals were challenged with toluene at 4000 ppm, and the expression of locomotor activity was analyzed. The results showed toluene induce a behavioral sensitization, being statistically significant from the second to the fourth week of toluene-exposure. On the other hand, treatment with captopril or losartan statistically reduces the expression of behavioral sensitization in animals with a previous exposure to toluene. This work suggest that inhibitors of RAAS are compounds that worthwhile to continue been studying, as they could be considered in the rehabilitation strategies in the attention of users dependent to inhalants.