(±)-3,4-Methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: A comparison of single vs once per week treatment for 5 weeks

Division of Neurology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, United States
Neuropharmacology (Impact Factor: 5.11). 12/2008; 55(7):1121-1130. DOI: 10.1016/j.neuropharm.2008.07.006


3,4-Methlylenedioxymethamphetamine (MDMA) administration (4 × 15 mg/kg) on a single day has been shown to cause path integration deficits in rats. While most animal experiments focus on single binge-type models of MDMA use, many MDMA users take the drug on a recurring basis. The purpose of this study was to compare the effects of repeated single-day treatments with MDMA (4 × 15 mg/kg) once weekly for 5 weeks to animals that only received MDMA on week 5 and saline on weeks 1–4. In animals treated with MDMA for 5 weeks, there was an increase in time spent in the open area of the elevated zero maze suggesting a decrease in anxiety or increase in impulsivity compared to the animals given MDMA for 1 week and saline treated controls. Regardless of dosing regimen, MDMA treatment produced path integration deficits as evidenced by an increase in latency to find the goal in the Cincinnati water maze. Animals treated with MDMA also showed a transient hypoactivity that was not present when the animals were re-tested at the end of cognitive testing. In addition, both MDMA-treated groups showed comparable hyperactive responses to a later methamphetamine challenge. No differences were observed in spatial learning in the Morris water maze during acquisition or reversal but MDMA-related deficits were seen on reduced platform-size trials. Taken together, the data show that a single-day regimen of MDMA induces deficits similar to that of multiple weekly treatments.

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    • "Camarasa, Marimon, Rodrigo, Escubedo, & Pubill, 2008) tasks, while others have found impairments in reference memory task acquisition (e.g. Skelton et al., 2008), retention (e.g. Able, Gudelsky, Vorhees, & Williams, 2006), or both (Cunningham, Raudensky, Tonkiss, & Yamamoto, 2009). "
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    ABSTRACT: The effects of acute and sub-chronic MDMA were assessed using a procedure designed to test rodent working memory capacity: the odor span task (OST). Rats were trained to select an odor that they had not previously encountered within the current session, and the number of odors to remember was incremented up to 24 during the course of each session. In order to separate drug effects on the OST from more general performance impairment, a simple olfactory discrimination was also assessed in each session. In Experiment 1, acute doses of MDMA were administered prior to select sessions. MDMA impaired memory span in a dose-dependent fashion, but impairment was seen only at doses (1.8 and 3.0 mg/kg) that also increased response omissions on both the simple discrimination and the OST. In Experiment 2, a sub-chronic regimen of MDMA (10.0 mg/kg, twice daily over four days) was administered after OST training. There was no evidence of reduced memory span following sub-chronic MDMA, but a temporary increase in omission errors on the OST was observed. In addition, rats exposed to sub-chronic MDMA showed delayed learning when the simple discrimination was reversed. Overall, the disruptive effects of both acute and sub-chronic MDMA appeared to be due to non-mnemonic processes, rather than effects on specific memory functions.
    Neurobiology of Learning and Memory 10/2014; 114. DOI:10.1016/j.nlm.2014.06.012 · 3.65 Impact Factor
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    • "Rather, adult animals have deficits in the CWM only when tested with distal cues present but not when distal cues are removed [66] [67]. While procedural differences may account for the differences in effects between adult and neonatal administration of MDMA, the most important difference appears to be the period of development when animals are treated. "
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    ABSTRACT: The abuse of methylenedioxymethamphetamine (MDMA) during pregnancy is of concern. MDMA treatment of rats during a period of brain growth analogous to late human gestation leads to neurochemical and behavioral changes. MDMA from postnatal day (P)11-20 in rats produces reductions in serotonin and deficits in spatial and route-based navigation. In this experiment we examined the impact of MDMA from P11-20 (20 mg/kg twice daily, 8 h apart) on neuronal architecture. Golgi impregnated sections showed significant changes. In the nucleus accumbens, the dendrites were shorter with fewer spines, whereas in the dentate gyrus the dendritic length was decreased but with more spines, and for the entorhinal cortex, reductions in basilar and apical dendritic lengths in MDMA animals compared with saline animals were seen. The data show that neuronal cytoarchitectural changes are long-lasting following developmental MDMA exposure and are in regions consistent with the learning and memory deficits observed in such animals.
    Toxicology Reports 09/2014; 1. DOI:10.1016/j.toxrep.2014.08.018
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    • "In addition, the parietal cortex sends projections to the entorhinal cortex, which has an important function in egocentric learning (Parron and Save, 2004). We have previously reported egocentric deficits in the Cincinnati water maze after treatment with MDMA (Able et al., 2006; Skelton et al., 2008). However, these deficits are seen at longer intervals after MDMA treatment and cannot be directly attributed to the BDNF expression changes seen here. "
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    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.
    The Journal of Comparative Neurology 08/2012; 520(11):2459-74. DOI:10.1002/cne.23048 · 3.23 Impact Factor
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