Innovations In Clinical Neuroscience

JAN-FEB 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 4 , N U M B E R 1 – 2 , J A N U A R Y – F E B R U A R Y 2 0 1 7 ] Innovations in CLINICAL NEUROSCIENCE 41 further research examining the behavior m odifying and neuroprotective potential of the IF regminen for the treatment of drug addiction in humans. INTRODUCTION M DMA, or 3,4-methylenedioxy- methamphetamine, is a chemical compound that is commonly used as a psychoactive recreational drug of abuse. Its reported effects are enhanced energy, endurance, sociability, psychodelic hallucinations, and sexual arousal. 1,2 "Ecstasy" (also known as "XTC," "E," or "X") and "molly" are popular "street" names for MDMA, though it's important to note that some formulations of ecstacy/molly may be contaminated with other amphetamines or may not actually contain 3,4-methylenedioxymeth- amphetamine at all. 2,3 MDMA is usually consumed orally in 80 to 250mg tablet form (rarely capsules). Often 2 to 3 tablets are taken together. 4 MDMA is listed as a Schedule 1 drug by the United States Drug Enforcement Agency, meaning that currently there are no accepted medical uses for MDMA in the United States, there is a lack of accepted safety for use under medical supervision, and there is a high potential for abuse. 5 However, MDMA is currently being studied for its potential use in the treatment of certain psychiatric disorders, particularly posttraumatic stress disorder. 6 MDMA facilitates serotonin (5-HT) neurotransmission and, to a lesser extent, the release of dopamine (DA) and noradrenaline (NE) from their respective axon terminals. MDMA acts by indirectly increasing serotonin at the synaptic cleft by binding to, and thus inhibiting, the 5- HT transporter involved in its reuptake. 2,4 In humans, even when taken in moderate doses for recreational purposes, MDMA may produce undesirable effects including anxiety, depression, impulsiveness, aggression, and deficits of memory and awareness. These effects are thought to be due to the known neurotoxic properties of MDMA, especially on the serotonin (5- HT) system in the forebrain. 2,7 The target areas of MDMA in the brain include the cerebral cortex and the hippocampus, both important for learning and memory functions. 4 MDMA neurotoxicity and its various behavioral effects have been investigated in several studies using different mice strains, including C57BL/6J, BALBC, Swiss Webster and NIH/Swiss mice. 8 –11 Animal studies from different species have shown that MDMA induces anxiogenic effects. 12 These effects are evaluated by various tests, including functional observational battery, models of anxiety, locomotor activity, and the elevated plus maze test. 3 The animals typically show decreased open-arm entries and increased enclosed entries that are indicators of anxiogenic effects. 12 Acute MDMA effects also include a dose-dependent hyperlocomotor response. 4 At the cellular level, MDMA can lead to toxic effects on neurons associated with various neurotransmitter systems, including nigrostriatal and mesolimbic dopaminergic pathways. 11,13–15 In mice, neurons of the CA1 area of hippocampus are more vulnerable than those in the adjacent regions and cortex. 16 Oxidative stress plays a major role in MDMA- induced neurotoxicity, and in various experimental studies mice have shown that MDMA increases free radicals and oxidative stress. 9,17,18 These findings indicate a higher susceptibility of the hippocampus to oxidative stress and are a primary target of MDMA in mice. 8,19–21 Additionally, MDMA has a suppressive effect on neurogenesis in the hippocampus in mice. 22 Calorie restriction (CR) is defined as the reduction in caloric intake without malnutrition. Intermittent feeding (IF) is a form of CR where meals are not limited in calories but decreased in frequency, such as alternate days of feeding. IF has been shown to increase the lifespan in humans, mice and other animal species and may ward off many neurodegenerative disorders. 2 3,24,25,26,49 It has been shown that IF is more effective than limited daily feeding in protecting the hippocampal neurons against excitotoxic injury in mammals, including humans and mice. 2 7–29 IF protects neurons against various toxic insults through various cellular, molecular, and genetic mechanisms and increases the ability of the brain to restore its function after injury. 3 0–32 In animal models of aging and neurotoxic studies, CR protected hippocampal, striatal, and cortical neurons and ameliorated functional decline. 33 Short-term CR has been reported to increase neurogenesis in the dentate gyrus of young mice and rats as well as increase the thickness of the CA1 pyramidal cell layer in the hippocampus of mice. 33,34 Mechanisms of neuroprotection of IF diet on the CA1 area of the hippocampus in mice include reduction in oxidative stress and increased hippocampal neurogenesis. 33–40 Dietary restriction (DR) also increased thickness of the CA1 pyramidal cell layer and induced expression of heat-shock protein 70 and glucose-regulated protein 78 in dopaminergic neurons, suggesting the involvement of these cytoprotective proteins in its neuroprotective actions. 33,41 Additionally, CR has also been reported to modify pharmacological effects and induction of mood-elevating and analgesic effects in humans, demonstrated antidepressant and FIGURE 1. The experimental design of study

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