(±)3,4‐methylenedioxymethamphetamine (“ecstasy”) treatment modulates expression of neurotrophins and their receptors in multiple regions of adult rat brain

Abstract

(±)3,4-Methylenedioxymethamphetamine (MDMA), a widely used drug of abuse, rapidly reduces serotonin levels in the brain when ingested or administered in sufficient quantities, resulting in deficits in complex route-based learning, spatial learning, and reference memory. Neurotrophins are important for survival and preservation of neurons in the adult brain, including serotonergic neurons. In this study, we examined the effects of MDMA on the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their respective high-affinity receptors, tropomyosin receptor kinase (trk)B and trkC, in multiple regions of the rat brain. A serotonergic-depleting dose of MDMA (10 mg/kg × 4 at 2-hour intervals on a single day) was administered to adult Sprague-Dawley rats, and brains were examined 1, 7, or 24 hours after the last dose. Messenger RNA levels of BDNF, NT-3, trkB, and trkC were analyzed by using in situ hybridization with cRNA probes. The prefrontal cortex was particularly vulnerable to MDMA-induced alterations in that BDNF, NT-3, trkB, and trkC mRNAs were all upregulated at multiple time points. MDMA-treated animals had increased BDNF expression in the frontal, parietal, piriform, and entorhinal cortices, increased NT-3 expression in the anterior cingulate cortex, and elevated trkC in the entorhinal cortex. In the nigrostriatal system, BDNF expression was upregulated in the substantia nigra pars compacta, and trkB was elevated in the striatum in MDMA-treated animals. Both neurotrophins and trkB were differentially regulated in several regions of the hippocampal formation. These findings suggest a possible role for neurotrophin signaling in the learning and memory deficits seen following MDMA treatment.

Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring

“…Semi-adjacent sections were processed for the in situ hybridization localization of GAD 67 mRNA using a 35 S-labeled cDNA probe, as previously described (Seroogy and Herman, 1997; Hemmerle et al, 2012, 2015; Makinson et al, 2015). Briefly, slides were pretreated, dehydrated and delipidated prior to hybridization.…”

“…Analysis of the film autoradiograms was performed by taking densitometry measurements utilizing Scion Image software (NIH) as described previously (Numan et al, 2005; Hemmerle et al, 2012, 2015). At least six sections per area per animal were measured from the following regions: prefrontal cortex (PFC, including prelimbic, infralimbic and anterior cingulate cortex subdivisions), frontal, parietal and piriform cortices, striatum, hippocampus, and thalamus.…”

Chronic social subordination stress modulates glutamic acid decarboxylase (GAD) 67 mRNA expression in central stress circuits

“…Slides were stored at −20°C until processing for the detection of BDNF and GAD67 mRNAs by using in situ hybridization, as detailed previously (Seroogy and Herman, 1997, Hemmerle et al, 2012). Briefly, the sections were fixed in a 4% paraformaldehyde/0.1 M phosphate-buffered saline (PBS) solution for 10 min, rinsed twice in 0.1 M PBS, once in 0.1 M PBS with 0.2% glycine for 5 min and then twice in 0.1 M PBS for 5 min each.…”

Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

“…123 The administration of 4 doses over a period of 6 h to rats led to robust increases in BDNF transcript levels in several cortical regions both 1 h and 7 h following dosing. 124 The largest effects were seen in the prefrontal cortex with increases in TrkB expression observed in that region 24 h after dosing. 124 Here, MDMA produced weaker effects on NT3 and TrkC gene expression.…”

“…124 The largest effects were seen in the prefrontal cortex with increases in TrkB expression observed in that region 24 h after dosing. 124 Here, MDMA produced weaker effects on NT3 and TrkC gene expression. 124 Chronic treatment with MDMA in mice 125 and subchronic administration of large doses (20 mg/kg) in rats 126 led to increases in BDNF transcription and translation in the hippocampus.…”