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


METHODS
Male 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.


RESULTS
THC 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
Adolescent exposure of rats to THC and/or MDMA induced long-term, sex-dependent neurochemical and glial alterations, and revealed interactions between the two drugs.


BACKGROUND
This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6.
Department of Animal Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain; Instituto Cajal, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain.
Ana Belen
AB
Lopez-Rodriguez
Alvaro
A
Llorente-Berzal
Luis M
LM
Garcia-Segura
Maria-Paz
MP
Viveros
D000293:Adolescent; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D004660:Encephalitis / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012737:Sex Factors
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D002186:Cannabinoids; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D043884:Receptor, Cannabinoid, CB1; D012701:Serotonin; D013759:Dronabinol; D018817:N-Methyl-3,4-methylenedioxyamphetamine
CB1 receptor; MDMA; THC; adolescence; astrocytes; reactive microglia; serotonin transporter; sex differences