Behavioral and neurochemical effects of repeated MDMA administration during late adolescence in the rat

Abstract

Adolescents and young adults disproportionately abuse 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’); however, since most MDMA research has concentrated on adults, the effects of MDMA on the developing brain remain obscure. Therefore, we evaluated place conditioning to MDMA (or saline) during late adolescence and assessed anxiety-like behavior and monoamine levels during abstinence. Rats were conditioned to associate 5 or 10 mg/kg MDMA or saline with contextual cues over 4 twice-daily sessions. Five days after conditioning, anxiety-like behavior was examined with the open field test and brain tissue was collected to assess serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal raphe, amygdala, and hippocampus by high-pressure liquid chromatography (HPLC). In a separate group of rats, anxiety-like and avoidant behaviors were measured using the light–dark box test under similar experimental conditions. MDMA conditioning caused a place aversion at 10, but not at 5, mg/kg, as well as increased anxiety-like behavior in the open field and avoidant behavior in light–dark box test at the same dose. Additionally, 10 mg/kg MDMA decreased 5-HT in the dorsal raphe, increased 5-HT and 5-HIAA in the amygdala, and did not alter levels in the hippocampus. Overall, we show that repeated high (10 mg/kg), but not low (5 mg/kg), dose MDMA during late adolescence in rats increases anxiety-like and avoidant behaviors, accompanied by region-specific alterations in 5-HT levels during abstinence. These results suggest that MDMA causes a region-specific dysregulation of the serotonin system during adolescence that may contribute to maladaptive behavior.

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…With regard to the longstanding controversy on the role of 5-HT in the regulation of behavior in animal models of anxiety, Green and McGregor have suggested that MDMA-induced 5-HT depletion might produce either anxiolytic effects in rats with a high basal level of anxiety, or anxiogenic effects in rats with a low basal level of anxiety (Green and McGregor, 2002;Winstanley et al, 2004). However, a recent study by Cox and coworkers has refuted this speculation, by showing an anxiety-like behavior following repeated administration of MDMA and/or abstinence from MDMA (Cox et al, 2014).…”

A study of the neurotoxic effects of tramadol and cannabis in adolescent male albino rats

“…The resulting supernatant was collected and diluted 1:4 in fluorescence dilution solution (0.01M HCl, 0.5mM EDTA, and 1mg/ml ascorbic acid). 39 HPLC columns are packed with very fine particles (stationary phase). The separation was done on Hypersil C18 (5 µm, 100 x 4.6 mm) columns, Surveyor, ThermoScientific Company, USA, with mobile phase as described later and the flow rate was 1.5 ml/min 25 o C.…”

“…Concentrations of serotonin were quantified by interpolating peak areas relative to those generated by a range of standards that were run in parallel to unknowns and calculated as µg of 5-HT to mg of wet tissue weight. 39 …”

The neurotoxicity of amphetamines during the adolescent period

“…A recent study examined the effects of repeated administration of MDMA (5 or 10 mg/kg, i.p., once daily for four days) to rats during late adolescence (PND 38–41) on place conditioning, anxiety behaviour, and monoamine levels (Cox et al, 2014). The treatment with 5 mg/kg of MDMA had no effect on any of the studied parameters.…”