Ecstasy, Memory and Sex Differentiation

Journal of Physiology and Pharmacology Advances Ecstasy, Memory and Sex Differentiation Pezhman L, Sheikhzade F. and Hatami H. J Phys Pharm Adv 2013, 3(11): 266-271 Online version is available on: www.grjournals.com

ISSN: 2251-7693 ECSTASY, MEMORY AND SEX DIFFERENTIATION Ecstasy, Memory and Sex Differentiation 1 Pezhman L, 2 Sheikhzade F. and Hatami H. Original Article 1 Department of Physiology, Faculty of Medicine, Tabriz Medical University of Tabriz, Iran 2 Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Iran Abstract While Ecstasy (MDMA)use has been associated with a decline in various aspects of mnemonic function in animals and humans, little is known about ecstasy-induced gender differences on learning and memory. The objectives of the present study were to investigate the effect of ecstasy treatment on spatial memory in male and female rats. 28 male and female rats were randomly divided in to 4 male and female control and treatment groups. Treatment groups received ecstasy 10 mg/kg, ip, for 5 consecutive days. characteristic learning and spatial memory was assessed using Morris Water Maze for 5 consecutive days following the treatment period. No significant differences were seen in male Latency, Speed and Pathlengwas compare to females. soits logical to conclude that action of MDMA in CNS areas involved in spatial memory may be independent of sex hormone. Keywords: Ecstasy, spatial memory, sex differentiation, Morris Water Maze. Corresponding author: Department of Physiology, Faculty of Medicine, Tabriz Medical University, Tabriz, Iran. Received on: 28 Oct 2013 Revised on: 15 Nov 2013 Accepted on: 22 Nov 2013 Online Published on: 30 Nov 2013 266 J. Phys. Pharm. Adv., 2013, 3(11): 266-271

PEZHMAN ET AL Introduction MDMA or 3, 4- Methylenedioxymethamphetamine (C 11 H 15 N 2 O), is a hallucinogenic compound that known as ecstasy, an amphetamine derivative which is highly abused among young adults (Piechal A et al., 2011) because of its ability to produce strong feelings and hyperactivity (Cheze et al., 2007) first was developed in 1914 as an appetite suppressant. It is most used orally and rarely snorted (Henry J., 1992) Various side effects of ecstasy was reported but it most affects the nervous system and strongly activate CNS and causes brain cell damage (Parrott., 2002). Chemically, MDMA acts like catecholamines and produces sympathomimetic effects such as increase in heart rate, blood pressure, and transient anxiety behaviors (Davidson et al., 2001). It is believed that MDMA exerts its effects through the alteration of neurotransmitters (Parrott. 2002).Various central effects of amphetamine were reported including release and depletion of serotonin, dopamine and norepinephrine and alteration of mono amino oxidase activity in brain. Administration of Ecstasy increase 5-HT release in several brain regions and damages dopaminergic system. In addition, other neurotransmitters as glutamate, acetylcholine and NO are affected by methamphetamines (Richard et al., 2003) acute administration of methamphetamine produces prolonged increases in glutamate release, neurotransmitter involved in synaptic plasticity (Frank et al., 1993). Previous evidences appear that neurotransmitters can influence learning and memory (Wenk et al., 1987) and ecstasy affects memory, through interaction with neurotransmitter system (Laws et al., 2007). Evidence of hydroxyl radicals formation and activation of apoptosis pathways, indicated, Ecstasy causes permanent damage in brain cells (Mark et al., 2009). One of these regions is hippocampus which is involved in learning and spatial memory. Spatial memory is the part of memory responsible for recording information about one's environment and its spatial orientation (Olson et al., 1979).There are 267 J. Phys. Pharm. Adv., 2013, 3(11): 266-271 specific areas of the brain associated with spatial memory. Morris water maze (MWM) is an instrument that spatial learning and memory can be examined by, and especially it is sensitive to lesions of the hippocampus (Charles et al., 2006). According to the inconsistent evidences about effects of MDMA on memory in previous studies, further studies are needed in this regard. With the probability of ecstasy influence on memory, in this study we aimed to investigate the effects of (i.p) administration of MDMA on spatial learning and memory of male and female rats in MWM task. Materials and Methods Animal Groups In this study, 28 Wister rats weighting (250±5 g) were randomly divided into 4 groups including Male and Female Treatment groups (received ecstasy) and Male and Female Control groups. They were housed at a controlled temperature (22 ± 2 C) and under a 12-h light-dark cycle. Animals had free access to water and food. All experimental and animal care procedures were performedwith the approval of the Tabriz University InstitutionalAnimal Care and Use Committee. Ecstasy Treatment Ecstasy addiction was induced by intraperitoneal injection of MDMA (10 mg/kg) for 5 days. MDMA was dissolved in physiological saline and injected in a volume of 1ml/kg. Morris Water Maze The behavioral training and testing was conducted in a circular pool (diameter 136 cm, depth 60 cm) filled with water (25 cm height) at a temperature of 20 ± 1C. A circular platform (diameter 10 cm) was placed 2 cm below the water surface and centered in a quadrant. The position of the platform remained consistent for all animals across all training trials. The rats were trained in four groups with each group consisting 7 number of animals.during training, each animal was started from one of four equally spaced compass-point positions (north, south, east, or west) at the inside perimeter of the tank facing out toward the wall of the tank. Subjects were allowed to swim until they

ECSTASY, MEMORY AND SEX DIFFERENTIATION located the hidden platform. The animals were left on the platform for 15 s after the end of each trial, then removed from the pool, and entered the next trial. Training consisted of four trial blocks per day for 5 consecutive days following the treatment period After the end of 4th trial, animals removed from the pool, towel dried and returned to their cage. Swimming time in seconds to the platform (latency), swimming distance (path length) in centimeters prior to reaching the platform and animal swimming speed were recorded by a camera and Maze Router software. Statistical Analysis Results are expressed in mean ± SEM and data were analyzed by using ONE WAY ANOVA. Result Although an overall decrease in latency was seen from block one to five, both treatment and control groups demonstrated no significant difference in latency. There was no significant difference in latency between male and female groups also, (Fig 1). Fig. 1: MWM average latency (s) to escape platform. 268 J. Phys. Pharm. Adv., 2013, 3(11): 266-271

PEZHMAN ET AL Fig. 2: MWM average speed (cm/s) swam to escape platform. Fig. 3: MWM average distance (cm) swam to escape platform. The mean value of swimming speed in control and treatment groups of both male and female rats was not significantly different, (Fig 2). In accordance with swimming distance data, no significant differences in path length were seen between male and female animals in both control and treatment groups, (Fig 3). Discussion The results of the present study suggest that, ecstasy use did not affect spatial memory in male and female rats. The literature of MDMA effects on spatial memory in animals and human is complex and contradictory. Some evidences suggests a positive correlation between ecstasy and spatial ability(soetens et al., 1993., Martinez et al.,1980)in contrast, several reports indicate that treatment with ecstasy has impaired spatial learning and retention of spatial information in animals(feredric et 269 J. Phys. Pharm. Adv., 2013, 3(11): 266-271

ECSTASY, MEMORY AND SEX DIFFERENTIATION al.,1997.,rodgers., 2000)and humans(vorhees et al.,2004.,kuypers et al., 2007). Evidence from animal and human studies suggests that long-term of amphetamines exposure cause neuronal damage. Multiple neurotransmitters, free radicals, apoptotic proteins and inflammatory cytokines all contribute to the development of neurotoxicity of MDMA, result in cell damage (Gouzoulis-Mayfrank et al., 2009). Ecstasy affectsboth behavioral and cognitive processes in many ways by affecting monoaminergic system.ecstasy use shown to damage both dopaminergic and 5-HT systems.the dopaminergic system exhibits modulatory effects on many cognitive functions, including memory and attention (Nordahlet al., 2003). Serotonin syndrome is reported after adult chronic MDMA administration (Parrott A., 2002). Ecstasy-induced damage to DA systems may contribute to some of the cognitive deficits observed in methamphetamine-dependent subjects. DR Axonsare vulnerable to the neurotoxic amphetamine derivatives (Laura et al., 1991). Reduced serotonin levels in human and animals have been linked to impaired memory performance. Impaired long-term memory but not short memory performance was reported in ecstasy users (Gouzoulis-Mayfranka et al., 2000). MDMA administration to adult animals causes reductions in brain serotonin (5-HT) and its metabolite, 5 hydroxyindoleaceticacid (5-HIAA). long-term reductions in 5-HT have functional consequences (Colado et al., 1997).Our data suggest that MDMA exposure to rat brain may have produced alterations in serotonin and dopamine neurochemistry. In addition, compensatory mechanisms such as increase in neurotrophins (BDNF, NT-3 and NT-4) might be the brains ameliorative response to minimize MDMA effects (James et al., 2003). Evidences suggest neurotrophins play a role in theregulation of synaptic plasticity and response to various types of neuronal injury (Hatami et al., 2010). Correlation between increased levels of BDNF and changes in monoamine levels was proved (James et al., 2003) In our study, MDMA administration may not produce theexpected depletion of monoamines or the brain exhibits ameliorative response to the pharmacologic insult.also modifications resulted from peripheral injections of ecstasy, in previous experiments, suggest the susceptibility of LTP in promotion of synaptic plasticity against damaging effects of ecstasy.(morales et al., 2005). Some investigators observed no association between ecstasy and spatial memory (Kupers et al., 2007) the result of our experiments are consistent with studies performed bygouzoulis-myfrank et al., (2000) and Morgan et al., (1998). Previous experimental findings revealed potent effects of Sex steroids on mood, mental and memory in the animals and human. Evidences suggested, effects of sex steroids in female rats may be mediated, in part, by the action of estrogen on the 5-hydroxytryptamine2A receptor (5-HT2AR) and serotonin transporter (SERT) in brain. Sex steroids manipulation on central 5-HT2AR and SERT in rats revealed that, testosterone and estrogen increase the content of 5-HT2AR mrna and SERT mrna in the dorsal raphe nucleus (DR) and the density of 5-HT2AR and SERT binding sites in higher centers of the brain. The action of testosterone depends upon its conversion to estrogen by aromatase. Regionselective sensitivity of DR serotonin neurons to sex steroids may explain the possible role of interactions between sex hormones and serotonin mechanisms involve in learning and memory (Fink et al., 1999). In our investigation it seems that ecstasy did not affect spatial memory, differently in male and female rats so its logical to conclude that action of MDMA in CNS areas involved in spatial memory may be independent of sex hormones. Future investigations into higher doses of ecstasyexposures and consequences of elevated trophic activityaresuggested in future studies. Conclusion Taking into consideration the result of this study and previously available data, it is suggested that action of MDMA on spatial memory can be independent of sex hormonses. 270 J. Phys. Pharm. Adv., 2013, 3(11): 266-271

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