Sex-Dependent Psychoneuroendocrine Effects of THC and MDMA in an Animal Model of Adolescent Drug Consumption

Abstract

Ecstasy is a drug that is usually consumed by young people at the weekends and frequently, in combination with cannabis. In the present study we have investigated the long-term effects of administering increasing doses of delta-9-tetrahydrocannabinol [THC; 2.5, 5, 10 mg/kg; i.p.] from postnatal day (pnd) 28 to 45, alone and/or in conjunction with 3,4-methylenedioxymethamphetamine [MDMA; two daily doses of 10 mg/kg every 5 days; s.c.] from pnd 30 to 45, in both male and female Wistar rats. When tested one day after the end of the pharmacological treatment (pnd 46), MDMA administration induced a reduction in directed exploration in the holeboard test and an increase in open-arm exploration in an elevated plus maze. In the long-term, cognitive functions in the novel object test were seen to be disrupted by THC administration to female but not male rats. In the prepulse inhibition test, MDMA-treated animals showed a decrease in prepulse inhibition at the most intense prepulse studied (80 dB), whereas in combination with THC it induced a similar decrease at 75 dB. THC decreased hippocampal Arc expression in both sexes, while in the frontal cortex this reduction was only evident in females. MDMA induced a reduction in ERK1/2 immunoreactivity in the frontal cortex of male but not female animals, and THC decreased prepro-orexin mRNA levels in the hypothalamus of males, although this effect was prevented when the animals also received MDMA. The results presented indicate that adolescent exposure to THC and/or MDMA induces long-term, sex-dependent psychophysiological alterations and they reveal functional interactions between the two drugs.

Acute and long-term effects of Δ9-tetrahydrocannabinol on object recognition and anxiety-like activity are age- and strain-dependent in mice

“…Thus, it is possible that mice never exposed to shipping stress may display different behavioral responses to THC than that seen in the current study. The use of only male mice in the current study is also a major drawback, as females may show sex-specific differences in these tasks as well as susceptibility to THC treatment in adulthood and across development (Rodriguez de Fonsesca et al, 1993; Podhorna & Brown, 2002; Moore et al, 2007; Llorent-Berzal et al, 2013; Balsevich et al, 2014). Future studies should include female mice and may consider pair housing animals to reduce the harm of long-term isolated housing.…”

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

“…Many studies demonstrate that cannabis produces severe behavioural and neurophysiological impairments and that these deficits are more evident when this substance is taken during critical developmental periods like adolescence (Viveros et al ., ). In fact, previous reports have shown that chronic adolescent administration of CB 1 receptor agonists induces alterations of the emotional behaviour, the cognitive function as well as psychotic‐like symptomatology in adult rats (Biscaia et al ., ; Schneider and Koch, 2003; 2007; O'Shea et al ., 2004; 2006; Llorente‐Berzal et al ., 2011; 2013a; Mateos et al ., ; Zamberletti et al ., ). The administration of CB 1 receptor agonists during adolescence also induces long‐term neurochemical changes in the brain (Rubino et al ., ; Llorente‐Berzal et al ., 2013a) and sex‐dependent changes in expression and functionality of hippocampal CB 1 receptors (Mateos et al ., ; López‐Gallardo et al ., ).…”

“…Other indicators of MDMA‐related insults are markers of neurotoxicity, such as cell death rate (Schmued, ), glial fibrilar acidic protein (GFAP) levels (Johnson et al ., ; Frau et al ., ) and neuroinflammation via activation of microglial cells (Monks et al ., ; Connor et al ., ). Although it is known that MDMA consumption during adolescence induces several long‐lasting behavioural impairments on mood and cognitive function (Piper, ; Llorente‐Berzal et al ., 2013a), there is scarce information about long‐lasting neurotoxicity induced by adolescent MDMA exposure.…”

“…In a recent study, we have reported long‐term endocrine, behavioural and molecular effects of an adolescent treatment with THC and/or MDMA by using a protocol that mimics the pattern of drug consumption in young humans (Llorente‐Berzal et al ., 2013a). In brief, we used an MDMA administration schedule based on Meyer et al .…”

“…In particular, we focused on glial (astrocytes and microglia) cells and on the serotonin transporter (SERT) and CB 1 receptors. In view of the numerous sexual dimorphisms found in our previous study (Llorente‐Berzal et al ., 2013a), we also analysed here males and females. The present results demonstrate that chronic treatment with THC and/or MDMA during adolescence induced sex‐dependent long‐term effects on astrocyte and reactive microglia markers, as well as on CB 1 receptor expression and serotoninergic neurotoxicity.…”