Sex‐dependent long‐term effects of adolescent exposure to THC and/or MDMA on neuroinflammation and serotoninergic and cannabinoid systems in rats

Abstract

BACKGROUND AND PURPOSEMany young people consume ecstasy as a recreational drug and often in combination with cannabis. In this study, we aimed to mimic human consumption patterns and investigated, in male and female animals, the long-term effects of Δ 9 -tetrahydrocannabinol (THC) and 3,4-methylenedioxymethamphetamine (MDMA) on diverse neuroinflammation and neurotoxic markers. EXPERIMENTAL APPROACHMale and female Wistar rats were chronically treated with increasing doses of THC and/or MDMA during adolescence. The effects of THC and/or MDMA on glial reactivity and on serotoninergic and cannabinoid systems were assessed by immunohistochemistry in the hippocampus and parietal cortex. KEY RESULTSTHC increased the area staining for glial fibrilar acidic protein in both sexes. In males, both drugs, either separately or in combination, increased the proportion of reactive microglia cells [ionized calcium binding adaptor molecule 1 (Iba-1)]. In contrast, in females, each drug, administered alone, decreased of this proportion, whereas the combination of both drugs resulted in a 'normalization' to control values. In males, MDMA reduced the number of SERT positive fibres, THC induced the opposite effect and the group receiving both drugs did not significantly differ from the controls. In females, MDMA reduced the number of SERT positive fibres and the combination of both drugs counteracted this effect. THC also reduced immunostaining for CB1 receptors in females and this effect was aggravated by the combination with MDMA. CONCLUSIONS AND IMPLICATIONSAdolescent exposure of rats to THC and/or MDMA induced long-term, sex-dependent neurochemical and glial alterations, and revealed interactions between the two drugs. LINKED ARTICLES IntroductionPolydrug use among young people is a very frequent phenomenon and has increased in the last few years. In particular, cannabis is the most widely taken, illegal, co-drug in 3,4-methylenedioxymethamphetamine (MDMA) users, especially among younger adults (Parrott et al., 2007;Schulz, 2011). Thus, 98% of the ecstasy users had also taken cannabis in a sample of East Coast college students (Wish et al., 2006). Motivation for polydrug use might be influenced by psychophysiological aspects, for example, the transient relief exerted by one of the drugs of some undesired effects caused by the other substance. Specifically, acute cannabis consumption has been described by MDMA (ecstasy) abusers as a symptomatic relief against the feeling of anhedonia and depression, which follows ecstasy's high (see Schulz, 2011;Parrott et al., 2007). Cannabis is the most commonly used illicit drug among young people in Europe (EMCDDA, 2012). It is obtained from extracts of the hemp Cannabis sativa and its main psychotropic substance is Δ 9 -tetrahydrocannabinol (THC) (Bossong and Niesink, 2010; Klein et al., 2011). THC binds to cannabinoid CB1 receptors (receptor nomenclature follows Alexander et al., 2013) that are highly expressed in the brain and are involved in multiple functions, including neural developmen...

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