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Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Amphetamines: Neurobiological Mechanisms, Pharmacology and Effects : Neurobiological Mechanisms, Pharmacology and

Copyright © 2012. Nova Science Publishers, Incorporated. All rights reserved. Amphetamines: Neurobiological Mechanisms, Pharmacology and Effects : Neurobiological Mechanisms, Pharmacology and

NEUROSCIENCE RESEARCH PROGRESS

AMPHETAMINES

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NEUROBIOLOGICAL MECHANISMS, PHARMACOLOGY AND EFFECTS

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AMPHETAMINES

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NEUROBIOLOGICAL MECHANISMS, PHARMACOLOGY AND EFFECTS

ANTOINE RINCÓN EDITOR

Nova Biomedical Books New York

Amphetamines: Neurobiological Mechanisms, Pharmacology and Effects : Neurobiological Mechanisms, Pharmacology and

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Library of Congress Cataloging-in-Publication Data Rincon, Antoine. Amphetamines : neurobiological mechanisms, pharmacology, and effects / editor, Antoine Rincsn. p. ; cm. Includes bibliographical references and index. Amphetamines. 2. Amphetamines-ISBN:  (eBook) Physiological effect. 3. Nervous system--Drug effects. I. Rincsn, Antoine. II. Title. [DNLM: 1. Amphetamines--pharmacology. 2. Amphetamine-Related Disorders. 3. Amphetamines-therapeutic use. QV 102] RM666.A493R56 2011 615.7'8--dc23 2011022161

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Amphetamines: Neurobiological Mechanisms, Pharmacology and Effects : Neurobiological Mechanisms, Pharmacology and

Contents

Preface Chapter I

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Chapter II

Chapter III

Chapter IV

vii Psychpharmacology and Neurotoxicology of Methamphetamine and 3,4-Methylenedioxymethamphetamine Laurel M. Pritchard and Emily Hensleigh Methamphetamine and 3,4-MethyleneDioxymethamphetamine: From Classical to New Molecular Mechanisms of Neurotoxicity J. Camarasa, S. Garcia-Rates, D. Pubill, and E. Escubedo Enhance or Reduce the Rewarding Effects: Interpretation of Drug Dependence by Amphetamine Sensitization Yia-Ping Liu, and Che-Se Tung Amphetamine Effects on Allergic Lung Inflammation Ana Paula Ligeiro de Oliveira, Adriana Lino-dos-Santos-Franco, Momtchilo Russo, Wothan Tavares-de-Lima, and João Palermo-Neto

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vi Chapter V

Chapter VI

Chapter VII

Contents Withdrawal from Amphetamine as an Animal Model of Schizophrenia D. Peleg-Raibstein and J. Feldon Regulating the Expression Patterns of Bizarre Behavior: A Therapeutic Option for AmphetamineType Drug-Induced Stereotypy? Junichi Kitanaka, , Nobue Kitanaka, Tomohiro Tatsuta, Yoshio Morita, Hiroshi Kinoshita, and Motohiko Takemura The Importance of Contextual Control over Amphetamine Dependence: Evidence from an Animal Model of Addiction M. L. Andersen, , R. Frussa-Filho and S. Tufik

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Index

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Preface Amphetamines are a family of substituted phenethylamine compounds that achieve their neurochemical and behavioral effects by liberating vesicular biogenic amine stores. Classified as psychostimulants, these drugs are commonly misused and abused. This book presents current research in the study of the neurobiological mechanisms, and pharmacology effects of amphetamines. Topics discussed include the neurotoxicity of methamphetamine; amphetamine effects on cardiac, endocrine and gastrointestinal systems; amphetamine dependence sensitization and tolerance hypotheses and amphetamine effects on allergic lung inflammation, amphetamine withdrawal and schizophrenia. Chapter 1- The amphetamines are a family of substituted phenethylamine compounds that achieve their neurochemical and behavioral effects by liberating vesicular biogenic amine stores. Classified as psychostimulants/entactogens, these drugs are commonly misused and abused. Long-term use of substituted amphetamines, in particular methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), causes loss of monoaminergic nerve terminals and associated behavioral and cognitive deficits. The rising prevalence of methamphetamine and MDMA abuse has prompted a new wave of research on their mechanisms of reinforcement, dependence and neurotoxicity. This chapter reviews the molecular mechanisms of action, behavioral effects, and mechanisms of neurotoxicity of methamphetamine and MDMA, with a focus on the results of preclinical research. Chapter 2- Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) have become popular as recreational drugs of abuse over the last decades. There is a substantial amount of evidence

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supporting a requirement for dopamine and serotonin in METH and MDMAinduced neurotoxicity as well as the role of hyperthermia in the neurotoxic damage induced by these two amphetamine derivatives. A large number of studies indicate that METH and MDMA have a different neurochemical profile of neurotoxicity depending on animal species. In rats MDMA causes a long-term dysfunction of the serotonergic system, whereas in mice this dysfunction is linked also to the dopaminergic system. Similarly, METH affects the dopaminergic neurotransmission in both rats and mice. Chapter 3- The augmentation of responses induced by repeated administration of psychostimulants has been studied for many years. This effect is termed as sensitization and is generally recognized a as a result of long-term adaptation of neural systems, which is thought to underlie several aspects of drug addiction. Amphetamine sensitization has been studied extensively for its clinical manifestations with liability to dependence and its preclinical applicability serving to explore the dopamine rewarding mechanism underlying the drug addiction. However, evidences revealed that both the sensitization and the desensitization (i.e., tolerance) of amphetamine effects are crucially involved in the process of addiction. Therefore, the enhancement or reduction of the rewarding effect appears equally important in the establishment of the drug addiction. Based on the current neurobiological theories of addiction, the present article reviews the related amphetamine works to date to provide a plausible interpretation of amphetamine dependence by giving consideration to both the sensitization and tolerance hypotheses. Chapter 4- Amphetamine (AMPH) is a highly abused drug that presents potent stimulating effects on the central nervous system (CNS) and has been shown to induce behavioral, biochemical and immunological effects. Drugs that modify CNS activity such as AMPH can modulate the burden and course of several diseases, such as carcinoma, arthritis, obesity, rheumatism and asthma. Asthma is characterized by pulmonary cellular infiltration, vascular exudation and airway hyperresponsiveness. In this context, it is a goal in their lab to better understand the relationships between acute and chronic exposure do AMPH and immune mechanisms in experimental asthma. Thus, their results showed that single (12 hours before challenge) or repeated (21 days before challenge) AMPH treatments induced opposite actions on BAL cellularity of allergic rats: single treatment decreased whereas repeated treatment increased the total number of cells as well as macrophages, neutrophils and eosinophils. Moreover, AMPH effects on lung inflammatory response and cellularity allergic rats relied at least partially on corticosterone serum levels. The authors have also showed that reserpine treatment precluded

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Preface

ix

the effects of single AMPH treatment on cellular migration to the lung of OVA-sensitized and challenged rats, presumably via VMAT2-driven interactions. On the other hand, the authors also observed that repeated AMPH treatment exacerbated the lung inflammatory response of allergic rats, an effect not detected 72 and 120 h after abrupt withdrawal from similar repeated AMPH treatment. The authors findings also suggest that single AMPH treatment down-regulates other parameters of lung inflammation, such as vascular permeability and tracheal responsiveness. According to their data it seems feasible to suggest that AMPH produces a dual effect: acute treatment reduces and repeated treatment exacerbates allergic lung inflammation, most probably through corticosterone and/or cathecolamines dependent mechanisms. Chapter 5- This reviewIn this chapter, I discuss current attempts presents an attempt to develop an animal model of some aspects of schizophrenia directly derived from the ‗endogenous dopamine sensitization‘ hypothesis of this disorder. The establishment of the model consists of examination of behavioral, neurochemical and neuroanatomical consequences of various repeated amphetamine administration schedules. These schedules are known to produce behavioral sensitization as is argued to be the case in nonmedicated first episode schizophrenics in which their impact is studied during withdrawal from drug administration in the absence of a drug challenge. Evidence demonstrates that during withdrawal deficits in latent inhibition (LI) and pre-pulse inhibition (PPI), two translational phenomena disrupted in schizophrenia, can be reinstated following treatment with both typical and atypical antipsychotic drugs. In addition, the model demonstrates that indeed the treated animals exhibit augmented locomotor activity in response to a challenge injection of amphetamine. Furthermore, withdrawal from amphetamine leads to cognitive deficits in attentional set shifting, working memory, and visual-spatial attention similarly to what is observed in schizophrenic patients. In conclusion, it is suggested that amphetamine withdrawal constitutes a highly valuable animal model of schizophrenia with face, construct, and predictive validity. Chapter 6- Amphetamine-type drug-induced positive symptoms, such as abnormal experiences (delusions and hallucinations) and bizarre behavior (hyperreactivity to both real and non-existent stimuli, locomotor hyperactivity, and stereotypy), are thought to lead to temporary or persistent psychosis, antisocial behavior, and criminal assaults. Therefore, the treatment of positive symptoms with medication is an important issue for individuals and society, but no effective treatment for amphetamine abuse has been established. In this

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chapter, the authors will review some of the evidence for a specific neuronal contribution to the alteration of the overall frequency and expression pattern of amphetamine-induced stereotypies in rodents and consider which agents are effective at treating amphetamine-type drug-induced positive symptoms in humans. Chapter 7- Among the various substances of abuse, methamphetamine has become one of the most notorious because of its potency and highly addictive properties. Adverse effects on a wide range of behavioral processes have been correlated to amphetamine: motor activity, attention, learning, aggression, sexual behavior, sleep, classical conditioning and operant behavior. In particular, sensitization to locomotor activity of rodents became clearly predominant over other behavioral parameters in neuropsychopharmacology studies. This predominance occurred because the neuronal plasticity underlying locomotor activity sensitization has been suggested to model the neurophysiological adaptations that contribute to compulsive drug craving. In addiction, while environment can be critical for both craving and drug-seeking behavior in humans, under some circumstances behavioral sensitization can come under complete contextual control. This chapter firstly presents the pharmacological properties of methamphetamine emphasizing its addictive properties. Subsequently, new research focusing the role of environmental context in abuse of amphetamines is reviewed considering the locomotor sensitization rodent model of addiction as the experimental paradigm.

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In: Amphetamines … Editor: Antoine Rincón

ISBN: 978-1-61470-305-1 ©2012 Nova Science Publishers, Inc.

Chapter I

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Psychpharmacology and Neurotoxicology of Methamphetamine and 3,4-Methylenedioxymethamphetamine Laurel M. Pritchard and Emily Hensleigh Department of Psychology, University of Nevada Las Vegas, Nevada, U. S.

Abstract The amphetamines are a family of substituted phenethylamine compounds that achieve their neurochemical and behavioral effects by liberating vesicular biogenic amine stores. Classified as psychostimulants/entactogens, these drugs are commonly misused and abused. Long-term use of substituted amphetamines, in particular 

Author Note: Correspondence concerning this chapter should be addressed to Laurel Pritchard, Department of Psychology, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-5030. Contact: [email protected].

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Laurel M. Pritchard and Emily Hensleigh methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), causes loss of monoaminergic nerve terminals and associated behavioral and cognitive deficits. The rising prevalence of methamphetamine and MDMA abuse has prompted a new wave of research on their mechanisms of reinforcement, dependence and neurotoxicity. This chapter reviews the molecular mechanisms of action, behavioral effects, and mechanisms of neurotoxicity of methamphetamine and MDMA, with a focus on the results of preclinical research.

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Introduction The substituted amphetamines are a family of compounds whose common chemical structure includes a phenethylamine core, with a methyl group in the α- position. Substitutions at the amine or phenyl groups result in a wide variety of psychoactive compounds, including methamphetamine, methylenedioxyamphetamine (MDA), 3,4 methylenedioxymethamphetamine (MDMA or ‗ecstasy‘), dimethoxymethamphetamine (DMA), and trimethoxyphenethylamine (mescaline). The position and type of substitution influences the neurochemical actions and behavioral effects of amphetamines. For example, potent stimulant effects appear to depend on the presence of a methyl group at the α- position, whereas sertotonin-releasing effects are associated with a substitutions at position 4 of the phenyl group (Freeman and Alder, 2002). For most substituted amphetamines, the more biologically active isomer is the dextrorotary (d-) enantiomer (Steele et al., 1987). For the purposes of this chapter, we will focus on the two most commonly abused substituted amphetamines: methamphetamine and MDMA. Methamphetamine (METH) was first synthesized from ephedrine in the late nineteenth century and later developed as a nasal decongestant and bronchiodilator (Anglin et al., 2000). It‘s acute stimulant and euphorigenic effects, coupled with enhanced blood-brain barrier penetration afforded by the addition of a methyl group, contribute to METH‘s high abuse liability. However, unlike MDMA, METH does have recognized medical uses, particularly in the treatment of attention deficit hyperactivity disorder. As such, it is classified by the U.S. Drug Enforcement Administration as a Schedule II drug (Department of Justice [DOJ], n.d.). With the rise of clandestine labs that synthesize METH from readily-available chemicals and over-the-counter pseudoephedrine, reported use of METH and treatment admissions for METH abuse and dependence rose sharply in the throughout the 1990‘s and early 2000‘s (Substance Abuse and Mental Health Services

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Administration [SAMHSA], 2006a; SAMHSA, 2006b). Relative to other psychostimulants, the chronic health effects of METH, which include cognitive and psychomotor impairment, psychosis, depression, severe dental problems, anorexia and increased risk for HIV and other sexually-transmitted infections, are regarded as especially pernicious. MDMA, or ―ecstasy‖ was first synthesized in the early twentieth century, but the first reports of its psychoactive effects did not emerge until the late 1970‘s (Shulgin and Nichols, 1978). In the 1980‘s, it gained some popularity as an adjunctive for psychotherapy, due to its reported ability to elevate selfesteem, elicit feelings of intimacy, and enhance communication, so-called entactogenic effects (Grinspoon and Bakalar, 1986). In 1985, MDMA was classified by the U.S. Drug Enforcement Administration as a Schedule I Controlled Substance (DOJ, n.d.), indicating that it had high abuse potential and no legitimate, safe medical use. While use of illicit drugs in general has steadily declined over the past few decades, MDMA use among adolescents and young adults increased dramatically during the 1990‘s and early 2000‘s (National Institute on Drug Abuse, 2010). Given the potentially serious acute and long-term health effects of MDMA, its popularity among young people has made it a focus of considerable public health concern.

1. Molecular Mechanisms of Action Like most amphetamines, the primary sites of action for methamphetamine and MDMA are monoamine transporters. These drugs enter monoamine nerve terminals via plasmalemmal transporters, or possibly by diffusion in the case of MDMA (Camarero, Sanchez, O‘Shea, Green, and Colado, 2002), liberate vesicular stores via interaction with the vesicular monoamine transporter 2 (VMAT2) (Partilla et al., 2006; Rudnick and Wall, 1992), and reverse the direction of transport such that cytoplasmic monoamines are released into the extracellular space (Seiden et al., 1993; Sulzer et al., 2005). MDMA inhibits all the monoamine transporters with similar potency, with the following rank order: serotonin transporter (SERT) > norepinephrine transporter (NET) > dopamine transporter (DAT). In contrast, methamphetamine has its most potent effects on NET activity, followed closely by DAT, and much lower potency at the SERT (Han and Gu, 2006). Based on voltammetry experiments in mouse striatal slices, METH also

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appears to inhibit 5-HT uptake with a potency similar to the selectiveserotonin reuptake inhibitor, fluoxetine (John and Jones, 2007). Though MDMA also interacts with a number of neurotransmitter receptors, only a few exhibit binding affinities in the range of MDMA brain concentrations achieved in vivo after systemic administration. These include the 5-HT2, α2- adrenergic, M1 muscarinic, H1 histamine, and sigma (σ) receptors (Battaglia et al, 1988). Methamphetamine has been shown to interact with σ and α7 nicotinic (nAChR) receptors (Brammer, Gilmore, and Matsumoto, 2006; Garcia-Ratés, Camarasa, Escubedo, and Pubill, 2007). In addition to direct effects on transporters and receptors, methamphetamine and MDMA also influence the activity of enzymes involved in monoamine synthesis and inactivation (Egashira, Yamamoto, and Yamanaka, 1987; Stone et al., 1986). The neurochemical consequences of these mechanisms of action will be discussed in more detail in the next section.

2. Acute Effects

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2.1. Acute Neurochemical Effects Acute administration of MDMA and METH influences, to varying degrees, the dynamics of monoamine neurotransmission. In general, these effects are characterized by rapid, massive release of monoamines, resulting in short-term increases in extracellular concentrations, long-term depletion of intracellular stores, and compensatory regulation of synthetic and degradation pathways. The acute effects on each of the monoamines will be considered separately, and long-term monoamine depletion will be discussed in the section on neurotoxicity (3.2). In vivo microdialysis studies have demonstrated increases in extracellular serotonin (5-HT) concentrations after acute administration of MDMA (Gough, Ali, Slikker, and Holson, 1991; Gudelsky and Nash, 1996; Nixdorf, Burrows, Gudelsky, and Yamamoto, 2001; Sabol and Seiden, 1998; Shankaran and Gudelsky, 1998; Yamamoto, Nash, and Gudelsky,1995). Elevated extracellular 5-HT has been observed in brain regions rich in serotonergic terminals, such as the striatum, prefrontal cortex and hippocampus (Gough et al., 1991; Gudelsky and Nash, 1996; O‘Shea et al., 2005) after systemic MDMA treatment. METH also produces increases in extracellular 5-HT in the ventral hippocampus (Kuczenski, Segal, Cho, and Malega, 1995; Rocher and

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Gardier, 2001). METH elevates extracellular 5-HT in the rat nucleus accumbens and increases 5-HT release from whole brain synaptosomes in a dose-dependent manner (Zolowska et al., 2009). METH and MDMA also induce 5-HT release from cell bodies in the midbrain raphe nuclei, as evidenced by ex vivo slice experiments (Higuchi et al., 2008). A comparison of METH and MDMA revealed that MDMA is approximately three times as potent as METH in an assay of [3H]5-HT release from synaptosomes (Berger , Gu, and Azmitia, 1992). 5-HT release induced by both compounds can be reduced by pre-treatment with selective serotonin reuptake inhibitors (Berger et al., 1992; Gudelsky and Nash, 1996; Mechan et al., 2002) or reserpine (Sobol and Seiden, 1998), indicating that both the plasmalemmal and vesicular transporters are involved in the 5-HT-releasing effect. MDMA-induced DA release has been observed in vivo in the striatum (Colado et al., 1999; Yamamoto and Spanos, 1988) and nucleus accumbens (Yamamoto and Spanos, 1988), as well as in ex vivo slice preparations of the striatum (Riegert et al., 2008) and olfactory bulb (Vizi et al., 2004). Rapid MDMA-induced DA release is associated with reduced levels of DA metabolites, DOPAC and HVA, in brain tissue and dialysates hours after drug administration, indicating decreased DA turnover (Gough et al., 1991). The mechanisms responsible for MDMA-induced DA release, however, remain uncertain. MDMA-evoked striatal DA release is attenuated by pretreatment with fluoxetine (Fitzgerald and Reid, 1990; Koch and Galloway, 1997) and cocaine (Fitzgerald and Reid, 1990). However, the selective DA transporter blocker GBR 12909 enhances MDMA-induced DA release in the mouse striatum (Camarero et al., 2002), indicating that release may not be DA transporter-mediated. An alternative mechanism is provided by the observation that MDMA-induced DA release is enhanced by the 5-HT2 receptor agonist, DOI (Gudelsky et al., 1994), which suggests that DA release may be a downstream effect of MDMA-induced 5-HT release. Similarly, acute METH injection evokes DA release in the nucleus accumbens (Desai, Paronis, Martin, Desai, and Bergman, 2010, Zhang, Loonam, Noailles, and Angulo, 2001), striatum, substantia nigra and ventral tegmentum (Dobbs and Mark, 2008; Zhang et al., 2001). Local infusion of the 5-HT2A/2C antagonist ritanserin attenuates METH-induced DA release in the substantia nigra and striatum (Yamamoto et al., 1995), suggesting that METHevoked DA release may depend on 5-HT release and consequent stimulation of 5-HT2 receptors. Recent evidence suggests that released DA may be a key mediator of METH-induced toxicity in serotonergic neurons (see below for further discussion of neurotoxicity). Interestingly, lobeline and its

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defunctionalized analogues inhibit METH-induced DA release (Nickell et al., 2010; Wilhelm, Johnson, Eshelman, and Janowsky, 2008), METH neurotoxicity (Eyerman and Yamamoto, 2005) and METH self-administration (Harrod, Dwoskin, Crooks, Klebaur, and Bardo, 2001), likely by preventing interaction with the vesicular monoamine transporter (VMAT2) (Nickell et al., 2010). For this reason, lobeline-like compounds have been suggested as a potential therapy for METH abuse and dependence. Though NE release has been observed after acute MDMA exposure in brain slice (Fitzgerald and Reid, 1990; Milnar, Mascalchi, Morini, Giachi, and Corradetti, 2008) and synaptosomal preparations (Rothman et al., 2001), there is limited evidence that MDMA induces NE release in vivo. Some indirect evidence for in vivo NE release exists, as systemic, intracortical or intra-VTA administration of the α1 receptor antagonist prazosin attenuates the locomotor response to MDMA in rats (Selken and Nichols, 2007). Interestingly, MDMA may have a higher affinity for the human NET than for SERT or DAT (Verrico, Miller and Madras, 2007; Rothman et al., 2001), which contrasts with the rank order of affinities in the rat, and suggests that inhibition of NE reuptake and/or NE release may play a more important role in the effects of MDMA in humans than in other species. Methamphetamine stimulates NE release in a number of in vitro systems, including rat synaptosomes (Rothman et al., 2001), cells transfected with human NET cDNA (Wall, Gu and Rudnick, 1995) and prefrontal cortical slices from rat brain (Ohmori, Koyami and Yamashita, 1991). In vivo, increased extracellular NE concentrations have been observed in the rat hippocampus (Kuczenski et al., 1995) and hypothalamic paraventricular nucleus (Yoshihara, Honma, Mitome, and Honma, 1996) after acute METH. Adrenergic neurons appear to be relatively spared from the neurotoxic effects of METH, and recent evidence suggests METH-stimulated NE release may actually protect against its neurotoxic effects on DA-ergic neurons. Weinshenker and colleagues (2008) found that inhibition of NE synthesis in the mouse brain enhanced METH-induced DA release, DA depletion and loss of dopaminergic markers.

2.2. Acute Physiological and Autonomic Effects Acute METH administration elicits autonomic responses typical of sympathomimetics, including piloerection, salivation, and increased blood pressure, heart and respiration rates (Mendelson et al., 2006; Schindler, Zhen,

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Tella, and Goldberg, 1992). Many studies of the sympathetic efficacy of methamphetamine have been carried out using norepinephrine-mediated twitch responses in the isolated rat vas deferens (Glezer and Finberg, 2003; Urabe et al., 1987). METH-induced increases in blood pressure and heart rate are completely blocked by α1 and ß adrenergic receptor antagonists, respectively (Schindler et al., 1992), consistent with the role of norepinephrine in autonomic regulation of cardiovascular function. In rodent studies designed to mimic a binge pattern of administration, the METH-induced increase in mean arterial pressure sensitized over successive binges, and significant myocardial pathology was observed (Varner, Ogden, Delcarpio, and MelegSmith, 2002). These findings suggest that the cardiovascular risks posed by METH may be exacerbated by the typical pattern of use observed in humans. Interestingly, either acute or subchronic pretreatment with the monoamineoxidase B inhibitor, selegeline, decreases the cardiovascular effects of METH in squirrel monkeys (Schindler, Gillman, Graczyk, Wang, and Gee, 2003). The acute autonomic effects of MDMA are similar to those of METH, with some important differences. For example, the effects of MDMA on heart rate are biphasic, with moderate doses (above 1.0 mg/kg) decreasing heart rate in rats (Jaehne, Salem, and Irvine, 2005). MDMA also triggers cutaneous vasoconstriction (Blessing and Seaman, 2003), which contributes to its hyperthermic effects (discussed below) by limiting heat dissipation. When administered in a pattern similar to the ―weekend‖ pattern favored by recreational users over six weeks, rats developed tolerance to MDMA-induced increases in heart rate, but not hyperthermia (Jaehne, Salem, and Irvine, 2008), suggesting that even experienced users remain at risk for complications of recreational MDMA use. Perhaps the most potentially dangerous property of substituted amphetamines is their ability to induce hyperthermia. Under normothermic conditions (ambient temperature 20-22°C), both METH and MDMA typically induce hyperthermia in experimental animals, though there are a few reports of acute hypothermia (Malberg and Seiden, 1998; Marston, Reid, Lawrence, Olverman, and Butcher, 1999). Effects of MDMA on body temperature are largely dependent on ambient temperature. At ambient temperatures above 20°C, acute MDMA administration generally produces an increase in body temperature of 1-2°C (Dafters, 1994; Dafters and Lynch, 1998). At ambient temperatures of 10-17°C, the response is typically hypothermic (Broening, Bowyer, and Slikker, 1995; Dafters, 1994; Dafters and Lynch, 1998; Malberg and Seiden, 1998), and animals housed in cool environments after MDMA administration exhibit attenuated hyperthermic responses (Dafters, 1994). The

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mechanisms responsible for amphetamine-induced hyperthermia are not entirely clear. Because selective serotonergic agents can induce hyperthermia (Nimmo, Kennedy, Tullett, Blyth, and Dougall, 1993; Shioda, and Kato, 2010), it was long believed that hyperthermic effects of MDMA were 5-HTmediated (Schmidt, Ritter, Sonsalla, Hanson, and Gibb, 1990). However, more recent evidence suggests that both METH and MDMA-induced hyperthermia involves dopaminergic (Mechan et al., 2002; Numachi et al., 2007) and noradrenergic (Makisumi et al., 1998; Pachmerhiwala, Bhide, Straiko, and Gudelsky, 2010) mechanisms. The neurotoxic effects of substituted amphetamines are more robust in the context of hyperthermia (see section 3.2). Given the exquisite sensitivity of the hyperthermic response to ambient temperature, controlling environmental conditions may represent an important strategy by which to limit neurotoxic damage in MDMA users.

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2.3. Behavioral Effects Like other psychostimulants, METH and MDMA acutely increase locomotor activity. The locomotor stimulant effects of these drugs have traditionally been attributed to their indirect dopamine agonist properties. However, more recent evidence suggests that 5-HT-releasing effects are also involved (Bankson and Cunningham, 2002; Fletcher, Korth, Robinson, and Baker, 2002; Steed, Jones and McCreary, 2011). In line with its higher relative potency for DA release, METH induces significant stereotypy at a dose that produces only locomotor activation for MDMA (Clemens, Cornish, Hunt, and McGregor, 2007). Though METH is typically regarded as a more potent psychostimulant than d-amphetamine, direct comparisons of the unconditioned locomotor effects of these two drugs do not bear this out (Shoblock, Sullivan, Maisonneve, and Glick, 2003). Instead, locomotor activation in response to METH is only greater than that for the same dose of d-amphetamine in the presence of a conditioned stimulus (Hall, Stanis, Marquez Avila, and Gulley, 2008). METH and MDMA also exhibit reinforcing properties, though the relative reinforcing strengths of the two compounds differ. Perhaps the simplest measure of the reinforcing effects of drugs of abuse is conditioned place preference. Both METH and MDMA support dose-dependent conditioned place preference (Bilsky, Hui, Hubbell, and Reid, 1990; Cunningham and Noble, 1992; Marona-Lewicka, Rhee, Sprague, and Nichols, 1996). MDMAinduced place conditioning may depend on the social environment or on stress,

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as Meyer and colleagues (2002) have reported it occurs only in individuallyhoused rats. Interestingly, both drugs, at relatively low doses, can induce conditioned aversions (Cunningham and Noble, 1992; Lin, Atrens, Christie, Jackson, and McGregor, 1993; Parker, 1995). It is unclear whether such aversive reactions are due to conditioned associations with the subjective effects of the drugs themselves or with acute withdrawal. Both compounds have also been studied extensively in self-administration paradigms with rodents and non-human primates. Methamphetamine is readily self-administered intravenously, and animals given prolonged, daily access escalate their intake over repeated training sessions (Kitamura, Wee, Specio, Koob, and Pulvirenti, 2006; Woolverton, Cervo and Johanson, 1984). In rats, responding for METH is inhibited by SCH23390, but not by eticlopride (Brennan, Carati, Lea, Fitzmaurice, and Schenk, 2009), suggesting that maintenance of METH self-administration depends primarily on D1, rather than D2 dopamine receptors. D3 dopamine receptor antagonists and partial agonists decrease breakpoint for METH in a progressive ratio schedule of reinforcement (Orio, Wee, Newman, Pulvirenti, and Koob, 2010) and prevent priming-induced reinstatement of METH seeking behavior (Higley et al., 2011). In contrast, a D1, but not a D2 receptor antagonist attenuated METHinduced reinstatement of drug seeking (Carati and Schenck, 2011). Taken together, these findings suggest that both D1 and D3, but not D2 receptors, play an important role in the reinforcing and incentive motivational properties of METH. As is the case for other psychostimulants, glutamate also plays an important role in METH reinforcement, as mGluR5 receptor antagonists inhibit METH self-administration and reinstatement of METH seeking (Gass, Osborne, Watson, Brown, and Olive, 2009; Osborne and Olive, 2008). Reinstatement of METH seeking is suppressed by nicotinic agonists (Hiranita, Nwata, Sakimujra, Anggadiredja, and Yamamoto, 2006) in nicotine-naïve rats, but is elicited by nicotine in previously nicotine exposed rats (Neugebauer, Harrod, and Bardo, 2010). These observations may explain the high rates of tobacco use among abstinent and current methamphetamine users and have important implications for monitoring and management of tobacco use in treatment of METH dependence. MDMA, on the other hand, does not support robust self-administration, and often requires pre-training with cocaine (Banks, Sprague, Czoty, and Nader, 2008; Schenck, 2009). The mechanisms responsible for MDMA reinforcement are uncertain. SERT knockout mice do not self-administer MDMA, but also show delayed acquisition of operant responding for food (Trigo et al., 2007). 5-HT2A receptor knockout mice exhibit attenuated

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MDMA self-administration, and a 5-HT2A receptor antagonist prevents cueinduced reinstatement of MDMA-seeking (Orejarena, Lanfumey, Maldonado, and Robledo, 2010). Taken together, these results suggest that the reinforcing effects of MDMA are at least partly serotonin-mediated. However, dopamine may also play an important role in MDMA reinforcement. For example, the magnitude of priming-induced reinstatement of MDMA seeking is correlated with the magnitude of acute MDMA-induced striatal DA release (ColussiMas, Wise, Howard, and Schenk, 2010). Reinstatement of drug seeking by a priming injection of MDMA can be attenuated by D1 and D2 dopamine receptor antagonists, whereas cue-induced reinstatement is attenuated by SSRIs (Schenk, Gittings, and Colussi-Mas, 2011). These studies suggest dissociable roles for DA and 5-HT in the incentive motivational properties of MDMA and drug-associated cue learning, respectively. Polydrug use and environmental conditions can strongly influence the reinforcing properties of substituted amphetamines. For example, it has been reported that the reinforcing (Jones et al., 2010) and euphoric (HernandezLopez et al., 2002) effects of MDMA can be enhanced by co-administration with alcohol, possibly via a shift from primarily serotonin-releasing effects to primarily dopamine-releasing effects. Reinforcing effects of both METH and MDMA are also intensified when self-administered at high ambient temperatures (Banks et al., 2008; Cornish et al., 2003; Cornish et al., 2008). At least for METH, this enhancing effect of high temperatures appears to be independent of changes in pharmacokinetics (Cornish et al., 2008). Furthermore, high ambient temperatures can exacerbate the neurotoxic effects of amphetamines (Malberg and Seiden, 1998; Miller and O‘Callaghan, 2003; O‘Shea et al., 2006). Recreational users frequently self-administer METH and MDMA along with alcohol in ―rave‖ settings, where they engage in high levels of physical activity at elevated ambient temperatures. The evidence outlined above suggests that these environmental conditions may drive increased drug use and further compound users‘ risk for long-term health and cognitive effects (see sections 3.2-3.3). Anecdotal reports suggest that MDMA induces feelings of emotional closeness and openness to others, so called entactogenic or empathogenic effects. Such effects are frequently cited as the primary reason for recreational use and were the rationale for the adjunctive use of MDMA in psychotherapy (Grinspoon and Bakalar, 1986). A recent placebo controlled, double-blind study of the effects of MDMA and METH on socioemotional processing revealed that MDMA uniquely increased self-reports of ―loving‖ and ―friendly‖ feelings, but also decreased accuracy for recognition of fearful

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facial expressions (Bedi, Hyman, and de Wit, 2010). These findings suggest that MDMA promotes social approach behaviors. The entactogenic effects of MDMA, coupled with its enhancement of self-esteem, may contribute to increased incidence of risky sexual practices among MDMA users (Sterk, Klein, and Elifson, 2008). However, sensation seeking and risk-taking have been proposed as predisposing traits for psychostimulant abuse (Laviola, Adriani, Terranova, and Gerra, 1999). Clearly, further research is needed to clarify the relationship between risk-taking and MDMA‘s effects on socioemotional processing and sexual behavior.

3. Effects of Chronic Exposure in Animals

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3.1. Changes in Transporters, Receptors, and Enzymes with Chronic Exposure Long-term exposure to METH or MDMA influences expression and function of their transporter targets, as well as receptors and synthetic enzymes for monoamines. Subchronic (10 days) METH exposure increases DAT, but not NET expression in the nucleus accumbens (Broom and Yamamoto, 2005). Interestingly, reduced DAT and tyrosine hydroxylase expression induced by short-term METH self-administration may not persist over long periods of withdrawal in rats (Stefanski, Lee, Yassar, Cadet, and Goldberg, 2002). Extended access to self-administered METH, which produces escalating drugtaking in rats, reduces DAT and tyrosine hydroxylase protein expression in the prefrontal cortex and striatum (Krasnova et al., 2010; Schwendt et al., 2009), but does not alter NET (Schwendt et al., 2009) or SERT expression (Krasnova et al., 2010). A longer period of voluntary METH intake (one month) results in decreased NE reuptake in the cerebellar cortex that persists for at least two weeks after the last day of METH exposure (Wang, Chou, Jeng, Morales, and Wang, 2000). It is not clear how this downregulation of NET function is related to neurotoxicity, but it could represent a mechanism by which neuroprotective effects of NE (see section 2.1) are maximized to prevent damage to DA-ergic neurons by chronic METH exposure. Binge administration of MDMA, usually characterized by several moderate-to-high doses in a single day, decreases SERT binding in the rat cortex and hippocampus (Piper, Ali, Daniels, and Meyer, 2010; Thompson et

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al., 2004). Binge-induced decreases in SERT binding can be prevented by intermittent pre-treatment with MDMA (Piper et al., 2010; Piper, Vu, Safain, Olvier, and Meyer, 2006), suggesting that the pattern of early drug use may be an important determinant of long-term neurotoxic effects. Rats given a singleday binge regimen or allowed to self-administer MDMA for 15 days exhibit reduced SERT binding in the frontal cortex, hippocampus, striatum and brainstem (Schenk et al., 2009). In contrast, mice do not exhibit changes in hippocampal or cortical SERT binding after sub-chronic MDMA self- or passive administration (Orejarena et al., 2009). Surprisingly, changes in monoamine transporter expression have typically not been observed in the brains of non-human primates after long-term self-administration of MDMA (Banks et al., 2008; Fantegrossi et al., 2004).

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3.2. Neurotoxicity Prolonged administration of substituted amphetamines can lead to permanent alterations in neurotransmitter systems and extensive neuronal insults in humans and animal models. Human studies indicate decreased markers of DA terminals in chronic METH abusers (Volkow, Chang, Wang, Fowler, Francheschi et al., 2001; Volkow, Chang, Wang, Fowler, LeonidoYee, et al., 2001). Similarly, animal studies indicate decreased levels of tyrosine hydroxylase, DA transporters, and DA levels in the striatum after prolonged administration or high doses of METH (Wagner, 1980; Cadet, Jayanthi, and Deng, 2003). Furthermore, prolonged administration of MDMA results in decreased levels of 5-HT transporters and 5-HT content in the rat hippocampus (White, 1996). Early studies in animal models indicate several mechanisms behind the neurotoxic insults of amphetamines. The following section outlines mechanisms of neurotoxicity induced by substituted amphetamines in animal models. As mentioned above, prolonged administration or acute administration of high doses of METH or MDMA results in neurotoxic insults including: DA and 5-HT depletions, decreased markers of DA and 5-HT systems, and degeneration of DA and 5-HT terminals. Marked DA and 5-HT depletions occur in several species. Rhesus monkeys subjected to an escalating dosing pattern of METH showed decreased DA levels six months after drug cessation (Seiden, Fischman, and Schuster, 1976). Rodent studies indicate depleted levels of DA in the striatum for up to eight weeks after high doses of METH (Wagner, Seiden, and Schuster, 1979; Wagner et al., 1980). Additionally,

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neurotoxic doses of METH lead to decreased 5-HT levels and 5-HT metabolites in the striatum (Ricaurte, Schuster, and Seiden 1980). Comparable effects occur after similar dosing patterns of MDMA. Multiple doses of MDMA result in decreased 5-HT levels and metabolites in the cortex, hypothalamus, hippocampus, and striatum (Battaglia, et al., 1987). Although MDMA causes the immediate release of DA, long term decline in DA levels is not apparent. Dopamine release, however, likely potentiates the long-term 5HT-depleting effects of MDMA (Stone, Johnson, Hanson, Gibb 1989; Schmidt, Ritter, Sonsalla, Hanson, Gibb, 1995). Neurotoxic doses of METH and MDMA also lead to reduced markers of DA and 5-HT neurons. Neurotoxic dosing patterns of METH result in decreased tyrosine hydroxylase protein and mRNA in the striatum. High doses of METH also lead to decreased DAT protein levels, tryptophan hydroxylase activity, and DA metabolite levels in the striatum (Hotchkiss and Gibb, 1980; Itzhak and Ali, 1996; Wagner et. al, 1980). Additionally, METH leads to deficits in markers of 5-HT systems, including decreased concentrations of 5HT and its metabolite, 5-HIAA, in the rat striatum (Bakhit, Morgan, Peat, andGibb, 1981). MDMA administration has similar effects in 5-HT systems, including decreased tyrosine hydroxylase activity in the rat cortex and striatum, and decreased SERT protein levels in rodents and primates (Scheffel et al., 1998; Ricaurte, Martello, Katz, and Martello, 1992a; Ricaurte and McCann, 1992b). Neurotoxic regimens of MDMA also lead to decreased 5HIAA in CSF of primates and decreased levels of this 5-HT metabolite in the cortex, striatum, and hippocampus of rodents and primates (Battaglia, et al., 1987; Ricaurte et al., 1988; DeSouza, Kelly, Harkin, and Leonard, 1997). Finally, markers of neurotoxic damage also include degeneration of DA and 5-HT terminals. High doses of METH lead to swelling and degeneration of DA nerve terminals in the striatum (Lorez, 1981; Ricaurte, Guillery, Seiden, Schuster, and Moore, 1982). Repeated administration of MDMA to primates also leads to 5-HT nerve terminal damage and swelling of 5-HT terminals (Ricaurte et al., 1988). The aforementioned findings suggest first, neurotoxic doses of METH lead to deficits in striatal DA and 5-HT systems which persistent for several weeks in rodents and for years in primates (Ricaurte, Martello, Katz, and Martello, 1992). Second, neurotoxic doses of MDMA lead to deficits in 5-HT systems also which persistent for weeks in rodents and several years in primates (Battaglia et al., 1987; Scheffel et al., 1998). Lastly, neurotoxic deficits caused by METH affect DA and 5-HT systems whereas MDMA appears to result in greater deficits in 5-HT systems and relatively minor deficits in DA systems. The relatively 5-HT-specific neurotoxic effects

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of MDMA likely result from differences in the relative potencies of METH and MDMA for acute DA and 5-HT release, as previously discussed in section 1.1; however, more research on the explanations for the differing neurotoxic effects of these drugs is warranted. Neurotoxicity occurs after high doses or prolonged administration of substituted amphetamines and several events contribute to the aforementioned neurotoxic damages. Factors contributing to neurotoxic damage of substituted amphetamines include: hyperthermia, increased intracellular and extracellular DA concentrations, glutamate induced excitotoxicity, oxidative stress, inflammatory responses, and activation of cell death pathways (Reviewed in Cadet, Krasnova, Jayanthi, and Lyles, 2007; Yamamoto, Moszcynska, and Gludelsky, 2010). The following elaborates on these mechanisms of METH and MDMA toxicity. Administration of METH or MDMA results in elevated brain and body temperatures. This hyperthermic response promotes and exacerbates neurotoxic events in DA and 5-HT systems. Evidence suggests warm environmental conditions increase neurotoxic damage and cool environmental conditions protect against DA and 5-HT depletions observed after high doses of METH (Bowyer et al., 1994). Likewise, high temperatures potentiate neurotoxic damage, and cool conditions protect against 5-HT depletions after high doses of MDMA (Dafters, 1994). However, several pharmacological manipulations can enhance or diminish neurotoxic effects independent of hyperthermia (Callahan, Cord, Yuan, McCann, and Ricaurte, 2001; Itzhak, Martin, and Ali, 2000). These findings suggest hyperthermia potentiates several, but not all, mechanisms of neurotoxicity including increasing enzymatic processes of reactive oxygen species formation and glutamate induced excitotoxicity. Discussions of these mechanisms appear in subsequent paragraphs. METH and MDMA induce oxidative stress, or the formation of free radicals in biological systems. Free radical production occurs after increased intracellular and extracellular DA release caused by METH and MDMA (Cadet and Brannock, 1998). Blocking formation of hydroxyl radicals after METH administration ameliorates the damaging effects on DA terminals (Kondo, Ito, and Sugita, 1994). Additionally, blocking hydroxyl radical formation after administration of MDMA ameliorates the damaging effects on 5-HT terminals (Colado and Green, 1995). Formation of free radicals by METH or MDMA can be counteracted by administration of antioxidants and free radical scavengers, leading to decreased damage to DA and 5-HT terminals (Wagner et al., 1985; Gudelsky, 1996). Excess DA release,

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occurring after administration of METH or MDMA, leads to the formation of free radicals (Cadet and Brannock, 1998). DA-dependent free radical production likely contributes to the damages observed at DA and 5-HT terminals (Cadet, Ali, and Epstein, 1994; Shankaran, Yamamoto, Gudelsky, 1999). Other factors also contribute to the production of free radicals and the deleterious effects of oxidative stress. Aside from DA, excess extracellular 5HT also likely contributes to free radical formation (Colado, O‘Shea, Esteban, Granados, Green, 1999). Enzymatic degredation of METH and MDMA by MAO might alternatively add to free radical formation (Olanow, 1992; LaVoie and Hastings, 1999). Lastly, several immediate effects of METH and MDMA potentiate oxidative damage. First, both METH and MDMA reduce antioxidants at monoaminergic terminals, suggesting a diminished ability to remove free radicals (Chen et al., 2007). Second, elevated body temperatures caused by METH and MDMA may supplement free radical formation, thus potentiating terminal damage (Kil et al., 1996; O‘Shea, Easton, Fry, Green, and Marsden, 2002). Third, hyperthermia and free radicals can further potentiate breakdown of the blood brain barrier (Sharma, Sjoquist, and Ali, 2007). Along with increased monoamine release, METH and MDMA also release glutamate in the striatum, eventually leading to excitotoxicity (Nash et al., 1988). Battaglia et al. (2002) demonstrated that blocking METH-induced glutamate release decreases neurotoxic loss of DA terminals. Likewise, blocking NMDA glutamate receptors attenuates MDMA induced 5-HT depletion (Colado, Granados, O‘Shea, Esteban, and Green, 1998). Glutamate release additionally leads to the production of nitric oxide (NO). Excess NO availability may also mediate neurotoxic damage via increased formation of hydroxyl radicals (Beckman et al., 1990). Inhibiting formation of NO, by blocking nitric oxide synthase, decreases damages observed in DA and 5-HT terminals after MDMA or METH administration (Taraska and Finnegan, 1997). Finally, these glutamate-dependent events occur without increased temperatures, suggesting hyperthermia and excess release of glutamate mediate their neurotoxic effects at monoaminergic terminals via independent mechanisms. Further evidence suggests excess glutamate may potentiate other neurotoxic mediators, such as inflammatory responses. METH-induced glutamate release activates inflammatory responses in the brain, as evidenced by activation of microglia and cytokine release. Microglial activation co-occurs in areas of METH induced terminal damage, including striatum, prefrontal cortex, and somatosensory cortex (Kuczenski, Everall, Crews, Adame, Grant, and Mashliah, 2007; LaVoie, Card, Hastings, 2004).

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Increased METH terminal damage occurs in a dose dependent manner, which also correlates with levels of activated microglia (Thomas et al., 2004).

Figure 1. Summary of Pathways Involved in METH and MDMA Neurotoxicity. While long-term or high-dose administration of either METH or MDMA can induce neurotoxic effects, the affected neural populations and cellular pathways involved may differ. METH neurotoxicity affects both dopaminergic and serotonergic neurons, whereas MDMA neurotoxicity is limited to serotonergic systems. Glutamate excitotoxicity and inflammatory responses appear to play important roles in METH‘s neurotoxic effects, but these mechanisms have, thus far, not been demonstrated for MDMA. The extent to which MDMA neurotoxicity is mediated by activation of apoptotic pathways is also not clear.

As mentioned above, blocking glutamate NMDA receptors decreases METH terminal damage (Battaglia, 2002). NMDA receptor blockade also reduces microglia activation after METH toxicity (Thomas and Kuhn, 2005).

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Oddly, microglia activation does not exhibit similar effects after MDMA administration. Few studies reported microglia activation after MDMA insult (Orio et al., 2004). This suggests microglial activation may not play as big a role in MDMA toxicity compared to that of METH; however, more research is needed. Finally, METH, and to a lesser extent, MDMA, activates several apoptotic pathways. High doses of METH activate pro-apoptotic pathways in the mouse cortex and concurrently inhibit anti-apoptotic pathways (Jayanthi, Deng, Bordelon, McCoy, and Cadet, 2001). Neurotoxic doses of METH release cytochrome c from the mitochondria, resulting in activation of the caspase 9 and 3 cell death pathways (Cadet, Jayanthi, and Deng, 2005). High doses of METH also activate cell death pathways resulting from endoplasmic reticulum stress (Jayanthi, Deng, Noailles, Ladenheim, Cadet, 2004). Few studies report activation of apoptotic pathways by MDMA. Tamburini et al. (2006) reported MDMA caused caspase 3 activation in limbic regions, but no such activation was observed in the striatum. Future studies need to characterize the differences between MDMA and METH activation of apoptotic pathways. This section reviewed deficits in DA and 5-HT systems caused by METH or MDMA administration as well as outlined several contributing factors to these deficits (summarized in figure 1). Markers of METH or MDMA neurotoxicity include: DA and 5-HT depletions, decreased markers of DA and 5-HT systems, and degeneration of DA and 5-HT terminals. Processes causing and contributing to these effects include: hyperthermia, increased intracellular and extracellular DA, glutamate induced excitotoxicity, oxidative stress, microglia activation, and apoptotic pathway activation (Reviewed in Cadet et al., 2007; Yamamoto et al., 2010). Future research needs to examine these mechanisms in relation to the location, neuronal phenotype, and severity of neurotoxic damage. Furthermore, thorough characterization of the interactive nature of these contributing events will be critical to understanding, preventing and treating MDMA- and METH-induced neurotoxicity. Psychosis refers to a state characterized by hallucinations and paranoia which may persist for several hours or an indefinite period of time. Chronic METH use can produce psychotic symptoms that are often difficult to distinguish from those of schizophrenia. Similar to schizophrenia, reported symptoms of METH psychosis, either short or long term, include disorganized speech, delusions, as well as auditory, tactile, and visual hallucinations (Chen et al., 2003).

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4. Behavioral Effects of Chronic Use in Humans

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4.1. Psychosis MDMA may also induce delusions and hallucinations both short and long term (Brown and Osterloth, 1987; Davison and Parrott, 1997). To date, few studies exist on MDMA psychosis (reviewed in Soar, Turner, Parrot, 2001). Therefore, the majority of this section focuses on METH-induced psychosis. The research literature on METH and MDMA psychosis are inconsistent. The dosage and pattern of administration of METH and MDMA which result in psychosis vary considerably between studies. Furthermore, large variability exists among symptom onset and duration of psychosis (Bell, 1973; Mcguire and Fahy, 1991). Psychotic symptoms may occur several minutes to several hours after METH administration, or may not occur at all. After onset, symptoms can dissipate without evolving into long-term psychosis; however, in other cases symptoms may last over six months after cessation of METH use (Ujike and Sato, 2004). Similar results occur after MDMA administration. Reports of delusions and hallucinations persisting several weeks after MDMA abstinence occurred in some users (Brown and Osterloh, 1987). However, reports of psychosis after MDMA use remain variable and often occur in poly drug users (Schifano et al., 1998). Reasons for these discrepancies between the psychotomimetic effects of METH and MDMA remain largely unknown but may be related to their relative potencies for DA and 5-HT release. It remains unclear what determines the duration of METH psychosis, especially considering that psychosis does not correspond with the extent of METH abuse. Counterintuitively, increased use of METH corresponds to decreased psychotic symptoms but increased impairments in cognitive functioning (Nordahl, Salo, and Leamon, 2003 for review; Zweben et al., 2004). Reasons for this negative correlation between psychotic symptoms and prolonged use of METH deserve further study; however several identified factors may contribute to the development of psychotic symptoms. Sekine et al. (2003) reported psychotic symptoms negatively correlate with DAT levels in the striatum and prefrontal cortex. DAT levels in striatal and cortical regions additionally correspond with cognitive deficits, discussed in the next section. This suggests neurotoxic effects likely underlie cognitive deficits associated with METH but may not underlie psychotic symptoms.

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Further evidence suggests long term psychosis or recurrent psychotic symptoms may result from stress or genetic factors. During METH cessation several environmental factors may trigger psychotic symptoms (Ujike and Sato, 2004). Sensitivity to environmental stressors and METH psychosis may result from alterations in NE and DA systems. Yui et al. (2000) examined NE and DA plasma metabolite levels in relation to stress-induced METH psychotic flashbacks. Results indicated that mild psychosocial stressors precipitated psychotic flashbacks, and plasma concentrations of NE and DA metabolites were increased during flashbacks. The authors hypothesized that hypersensitivity of noradrenergic systems to stress may predispose some METH users to psychotic flashbacks. Development of recurrent or prolonged METH psychosis may be related to genetic factors and variations in neurotransmitter systems. Several genes variations, mainly related to DA systems and oxidative stress, show a significant relationship with development of METH psychosis (reviewed in Bousman et al., 2009 and Barr et al., 2006). However, most gene association studies of METH psychosis have been conducted in relatively small, ethnically homogeneous samples. Therefore, it remains to be seen whether specific risk alleles exist in the general population. Finally, family history may predict likelihood of developing METH psychosis. METH abusers with a family history of schizophrenia reportedly exhibit psychotic symptoms months after abstinence from METH. Conversely, individuals without a family history of schizophrenia exhibit quicker recovery from psychotic episodes after abstinence from METH (Chen et al., 2005). Reports of familial psychosis in MDMA users exhibiting psychotic symptoms range between 24-50%. Such statistics must be interpreted with caution, however, as these reports consist mainly of case studies (Mcguire et al., 1994; Soar, Turner, Parrot, 2001). Several issues need addressing in future research on drug-induced psychosis. First, research must characterize MDMA psychosis while controlling for polydrug use. Second, although better characterized than MDMA, METH psychosis still needs further characterization, including factors precipitating its onset, time course, and underlying neurological alterations associated with its development. Finally, larger studies with ethnically diverse samples will help to clarify genetic risk for METH psychosis. These issues must be addressed before a complete understanding of drug-induced psychosis can be achieved.

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4.2. Cognitive Deficits Long term use of METH and MDMA results in several cognitive deficits, some of which have been linked to specific neurochemical abnormalities in drug users. These deficits mainly relate to monoamine abnormalities reported in blood plasma and in PET studies. These variations also typically occur in frontal cortical and striatal brain circuits. Cognitive deficits associated with these changes occur in tasks involving attention, executive function, speed of processing, and working memory in METH abusers and chiefly memory deficits in MDMA abusers (Scott et al., 2007; Green et al., 2003). The following section reviews long term cognitive deficits associated with METH and MDMA use. METH abuse results in deficits in attentional control and executive function, as well as working memory impairments. Clinical observations of individuals recovering from METH abuse indicate increased distractibility and difficulty maintaining attention (Salo, Nordahl, and Possin, 2002). Attentional deficits also occur in current and long-term METH users in laboratory tests of attention and executive function, including the Stroop task and Trail Making Tests (Simon et al., 2000; Kalechstein, Newton, and Green, 2003). METH abusers also exhibit deficits in tests of verbal working memory, which correlate with decreased markers of DA systems (Volkow et al., 2001b; Chang et al., 2002). These deficits in cognitive tasks correspond to marked changes in neurotransmitter systems in chronic METH abusers. Executive functions, attentional control, and working memory rely on activity in frontal cortical regions. Decreased DAT levels occur in the dorsolateral prefrontal cortex and orbital frontal cortex of chronic METH abusers. These deficits further correlate with decreased performance on working memory tasks (Volkow et al., 2001a; Volkow et al., 2001b). Other alterations in DA systems, including decreased D2 receptor density in the prefrontal cortex and decreased VMAT2 in the striatum, correspond with decreased glucose metabolism in the orbital frontal cortex and cognitive deficits in METH abusers (Volkow et al., 2001c; Johanson, 2006). Cortical DAT levels and, to a lesser extent, cognitive functions, may recover after prolonged abstinence (at least 12 months) from METH (Volkow et al., 2001d; Johanson et al., 2006). It remains unclear whether reductions in DA-ergic markers in METH abusers reflect temporary down-regulation of these proteins or loss of DA-ergic terminals. Taken together, these findings suggest alterations in brain DA systems correspond

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with cognitive deficits observed in long-term METH users, and these deficits may recover after abstinence. Deficits in 5-HT systems also occur in METH abusers, but have not been associated with specific cognitive deficits. Lower SERT levels occur throughout the brain of long term METH abusers (Sekine et al., 2001). Alterations in SERT and 5-HT content may relate to aggressive behavior and development of psychosis, rather than cognitive effects (Sekine et al., 2001; Iyo, Sekine, and Mori, 2004). However, 5-HT alterations and effects on cognition need further characterization in relation to METH abuse. Cognitive deficits in association with neurological changes in MDMA users appear less clear. Impaired memory performance corresponded with higher 5-HT2A receptor binding in MDMA users, suggesting impaired 5-HT function in MDMA users may relate to cognitive impairments (Reneman et al., 2001). Deficits in working memory of MDMA users positively correlated with 5-HT metabolites in CSF (Bolla et al., 1998). Deficits in cognitive functioning correlated with reported MDMA use, but reduced levels of 5-HIAA were not related to reductions in cognitive functioning (McCann et al., 1999; Bhattachary and Powell, 2001). MDMA users also exhibit global decreases in SERT density, which correlate with degree of MDMA use (McCann et al., 2005). Unlike METH however, MDMA abstinence was not associated with recovery in neurotransmitter content. While these studies provide strong evidence that long-term alterations in 5-HT signaling may be involved in MDMA-related cognitive impairments, the results must be interpreted cautiously. It is difficult to determine whether the neurochemical changes or cognitive deficits are specific to MDMA, as nearly all MDMA users also use marijuana and other illicit drugs. Several issues need consideration when determining the extent of long term neurological alterations and METH or MDMA use. First, cognitive deficits in relation to polydrug use need further investigation, especially with regard to MDMA. Second, this area of research would benefit from classification of the cognitive effects and closer examination of the relationships between duration and frequency of drug use and severity of cognitive impairment. Finally, genetic and environmental factors that may contribute to METH- and MDMA-induced cognitive impairment should be identified.

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Conclusion The substituted amphetamines METH and MDMA are widely abused and have an array of behavioral and physiological effects consistent with their classifications as psychostimulants, hallucinogens, entactogens and sympathomimetics. Both compounds potently release monoamines from brain and peripheral nerve terminals via their interactions with plasmalemmal and vesicular monoamine transporters. MDMA is believed to preferentially release 5-HT, while METH has more pronounced effects on DA and NE release, which may account for differences in the acute behavioral effects, reinforcing efficacy and long-term neurochemical effects of these two drugs. While the acute physiological and locomotor-activating effects of METH and MDMA are similar, METH lacks the effects on socioemotional processing that are characteristic of MDMA and presumably 5-HT-mediated. On the other hand, METH may be a more potent reinforcer, as evidenced by much higher rates of self-administration in animals. Recent research on the cellular mechanisms responsible for the reinforcing effects of these drugs shows promise for development of compounds to effectively treat psychostimulant abuse and dependence. Chronic or high-dose exposure to METH and MDMA produces neurotoxic effects characterized by depletion of brain DA and 5-HT, loss of markers of monoaminergic neurons, and degeneration of DA and 5-HT nerve terminals, though the neurotoxic effects of MDMA appear to be specific to serotonergic neurons. In humans, similar neurochemical alterations have been associated with persistent cognitive deficits and psychotic symptoms. The physiological, cellular, and molecular mechanisms underlying the neurotoxic effects of METH and MDMA remain under intense investigation, but likely include hyperthermia, glutamate excitotoxicity, oxidative stress and activation of inflammatory responses, culminating in activation of cell death pathways. Future research on these mechanisms of neurotoxicity should clarify the interactions between multiple cellular pathways leading to neuronal damage and identify cellular targets for therapies designed to prevent or reverse the long-term neurotoxic effects of these drugs.

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recurrences in methamphetamine psychosis. Addiction Biology 5, 343– 350. Zhang, Y., Loonam, T. M., Noailles, P. A., and Angulo, J. A. (2001). Comparison of cocaine- and methamphetamine-evoked dopamine and glutamate overflow in somatodendritic and terminal field regions of the rat brain during acute, chronic and early withdrawal conditions. Annals of the New York Academy of Sciences, 937, 93-120. Zolkowska, D., Jain, R., Rothman, R. B., Partilla, J. S., Roth, B. L., Setola, V., Prisinzano, T. E., et al. (2009). Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil. Journal of Pharmacology and Experimental Therapeutics, 329(2), 738-746. Zweben, J. E., Cohen, J. B., Christian, D., Galloway, G. P., Salinardi, M., Parent D. et al. (2004). Psychiatric symptoms in methamphetamine users. American Journal of Addictions 13, 181–190.

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Chapter II

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Methamphetamine and 3,4-MethyleneDioxymethamphetamine: From Classical to New Molecular Mechanisms of Neurotoxicity J. Camarasa, S. Garcia-Rates, D. Pubill, and E. Escubedo Department of Pharmacology and Therapeutic Chemistry (Section Pharmacology) and Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain

Abstract Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) have become popular as recreational drugs of abuse over the last decades. There is a substantial amount of 

Corresponding author: J. Camarasa. Department of Pharmacology and Therapeutic Chemistry (Section Pharmacology), School of Pharmacy. University of Barcelona. 08028 Barcelona. Spain. Tel: +34- 934024530/31. Fax: +34-934035982. E-mail: [email protected].

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J. Camarasa, S. Garcia-Rates, D. Pubill, et al. evidence supporting a requirement for dopamine and serotonin in METH and MDMA-induced neurotoxicity as well as the role of hyperthermia in the neurotoxic damage induced by these two amphetamine derivatives. A large number of studies indicate that METH and MDMA have a different neurochemical profile of neurotoxicity depending on animal species. In rats MDMA causes a long-term dysfunction of the serotonergic system, whereas in mice this dysfunction is linked also to the dopaminergic system. Similarly, METH affects the dopaminergic neurotransmission in both rats and mice. During the last years, our research has been focused in the study of the neurotoxic effects of MDMA and METH on the central nervous system and their pharmacological prevention. We have used a synaptosomal preparation from striatum of mice or rats as a reliable in vitro model to study reactive oxygen species (ROS) production by these amphetamine derivatives, which is well correlated with their dopaminergic injury in in vivo models. Using this preparation we have demonstrated that blockade of alpha7 acetylcholine nicotinic receptor subtype with methyllycaconitine and memantine, a clinical useful drug preventing Alzheimer‘s disease progression, antagonized ROS production induced by METH and MDMA. In studies at molecular level, we have demonstrated that both, MDMA and METH, displace competitively the binding of selective radioligands for homomeric alpha7 and heteromeric alpha4beta2 acetylcholine nicotinic receptor subtypes, indicating that these compounds directly interact with them. In all the cases MDMA displayed higher affinity than METH and it was higher for heteromeric than for homomeric subtype. Preincubation of differentiated PC12 cultured cells with MDMA or METH induced an up-regulation of acetylcholine nicotinic receptors in a concentration- and time-dependent manner, as many nicotinic receptor ligands do, supporting their functional interaction with these receptors. We have demonstrated that this up-regulation also occurs in vivo after determined MDMA dosing schedules. Moreover, we provide evidence that heteromeric nicotinic receptors play an important role in the behavioral (locomotor activity) sensitization and potential addictive properties of MDMA in mice. In conclusion, the interaction of METH and MDMA with nicotinic receptor subtypes expands the pharmacological targets of amphetamines and can account for some of their effects.

Introduction Amphetamine derivatives, such as methamphetamine (METH, speed, ice) and 3,4-methylene-dioxymethamphetamine (MDMA, ecstasy) are widely

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abused drugs, mainly by young people in recreational settings and has become a major public health problem worldwide. Use of these psicostimulants has significant medical consequences, including psychosis, dependence, overdose, and death. The hyperthermia occurring in recreational users of MDMA can be fatal [1]. Beside their stimulatory effects, these drugs, at high doses, have been shown to be neurotoxic in animal models in which deleterious effects in dopamine (DA) and serotonin (5-HT) nerve terminals have been reported [2, 3]. Specifically, METH administration has been shown to produce long-term decreases in numerous measures of both dopaminergic and serotonergic function such as enzyme activity (tyrosine and/or tryptophan hydroxylase), monoamine content, and monoamine transporters [4-6], while the MDMAinduced depletions have typically been more specific to serotonergic terminal markers [7]. In addition, METH toxicity to DA and 5-HT terminals has been shown to persist for up to 4 years after drug administration in non-human primates [8]. Signs derived from neurotoxicity have been described in humans who are heavy users of such drugs and reduced levels of striatal dopamine transporter were found in human abstinent METH users, 3 years or more after the last use of drug [9-12]. However, more longitudinal and prospective studies are clearly needed in order to obtain a better understanding of the possible long-term sequelae of ecstasy use in humans [13]. The high coincidence of substituted amphetamine abuse by humans with HIV and/or chronic stress exposure suggests a potential enhanced vulnerability of these individuals to the neurotoxic actions of the amphetamines [14]. Abstinence may allow reinnervation, but the axonal re-growth pattern is abnormal. Whether axotomy and reinnervation also occur in humans is unknown [15]. The patterns of neurotoxicity of MDMA in mice and rats differ in that mice typically exhibit neurotoxicity to both DA- and 5-HT-containing neurons, whereas rats commonly display selective neurotoxicity to 5-HT-containing neurons [16, 17]. Two main theories account for MDMA-induced neurotoxicity. Firstly, this neurotoxicity may at least partially be a consequence of its metabolism [18]. This hypothesis is based on the fact that a direct intracerebral injection of MDMA failed to reproduce the neurotoxicity profile that appears after its peripheral administration [19]. It has been proposed that some quinone thioether adducts that result from the peripheral metabolism of MDMA might be the ultimate mediators of its neurotoxicity [20]. However, the specific neurotoxic profile of the different metabolites is controversial [21, 22] and

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remains to be well characterized. Recently we have investigated and compared the in vitro effects of MDMA and its metabolite alpha-methyl-dopamine (MeDA) on dopamine and serotonin transporter functionality, to provide evidence for the role of this metabolite in the neurotoxicity of MDMA in rodents. MeDA competes with 5-HT for its uptake to the serotonergic terminal but has no persistent effects on the functionalism of the serotonin transporter in contrast to the effect of MDMA. MeDA inhibits the uptake of DA into the serotonergic terminal and also MAOB activity, which could result in a reduction of the neurotoxicity induced by MDMA at the serotonergic neurons [23]. The other theory involves reactive oxygen species production, although the two theories cannot be considered mutually exclusive. Oxidative stress appears to be one of the main factors involved in the serotonergic and dopaminergic terminal injury induced by MDMA [24, 25]. This hypothesis was proposed as early as 1989 by Gibb‘s research group after they found that the inactivation of tryptophan hydroxylase induced by MDMA was reversed by sulfhydryl reducing compounds [26, 27]. In addition to reactive oxygen species, reactive nitrogen species appear to play an important role in mediating METH and MDMA-induced neurotoxicity. METH-induced toxicity in the mouse striatum can be attenuated by nitric oxide synthase (NOS) inhibition [28]. Similarly, Colado et al. [29] and ourselves [30] reported that specific neuronal NOS (nNOS) inhibitors provided significant neuroprotection against MDMA-induced neurotoxicity. Although oxidative stress has been proposed as a key neurotoxic mechanism induced by these drugs [31, 32], several aspects surrounding the concrete pathways involved in METH- and MDMA-induced reactive oxygen species (ROS) generation remain unresolved. Our research group has reported not only that METH and MDMA induce ROS production inside rat and mouse striatal synaptosomes, but also that endogenous DA is needed for this reaction to occur [33, 34]. We also determined that MLA, an antagonist of alpha7 nicotinic acetylcholine receptors (alpha7 nAChR), prevented in vitro ROS generation and attenuated in vivo neurotoxicity, thus implicating alpha7 nAChR in the toxicity of amphetamine derivatives [30]. Alpha7 nAChR are homomeric ligand-gated ion channels whose activation induces calcium influx. Calcium entry could favor the activation of Ca2+-dependent enzymes such as protein kinase C (PKC) and nNOS, which have similarly been implicated in the neurotoxicity of amphetamines [35, 36]. In light of these findings, we believed it necessary to assess whether METH and MDMA have a direct interaction with α7 nAChR.

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Certain previous reports suggested that amphetamines interact with different types of nicotinic receptors. Liu et al. [37] reported that Damphetamine acts as an agonist on nicotinic receptors (probably alpha7) in bovine chromaffin cells, inducing catecholamine release. In addition, Skau and Gerald had described that D-amphetamine inhibits alpha-bungarotoxin binding at the neuromuscular junction in mice [38], while Klingler et al. [39] recently identified nAChR as one of the physiological targets of MDMA in the neuromuscular junction. Our previous findings [30, 33, 34] relate such an interaction to neurotoxicity. Moreover, as it has been extensively reported that chronic treatment with nicotine and nicotinic ligands induces an up-regulation of nicotinic receptors in CNS [40, 41]. The effect of amphetamines on nicotinic receptor populations warrants further study. We demonstrated, using radioligand binding assays, the interaction of METH and MDMA with homomeric alpha7 nAChR and heteromeric subtypes of nicotinic receptors, such as alpha4beta2. We previously demonstrated in vitro that Ca2+ chelation with EGTA prevented the production of reactive oxygen species (ROS) to a similar extent as nAChR blockade [25, 33, 34]. This indicates that calcium influx, probably through alpha7 nAChR, is a key step in this process. Consequently, one of the objectives of our work was to investigate the effect of MDMA on Ca2+ levels in cultured PC12 cells and the involvement of different nAChR subtypes and other cell pathways related to Ca2+ mobilization. In addition, we investigated the effects of pretreatment with METH and MDMA on nAChR densities. PC12 cultured cells have been utilized by other scientists to study the neurotoxicity of amphetamines [42-44]. In addition, this cell line expresses nAChRs, including the alpha7 subtype [45-47], and also provides an in vitro model for the up-regulation of nAChR, which occurs following chronic exposure to nicotine [48, 49]. Moreover, the pathways involved in cytosolic Ca2+ increase induced by different selective nicotinic agonists have been characterized in this cell line [50]. For this reason, we chose this model and the isolated synaptosomes as the most appropriate for our purposes. We undertook some studies with the goal to develop an alternative in vitro model that might be useful for studying the molecular mechanisms of METHinduced dopaminergic neurotoxicity. With this purpose we used the fast and simple method for isolating synaptosomes described by Myhre and Fonnum [51]. Using this model the formation of intrasynaptosomal ROS was measured using the conversion of the non fluorescent 2‘,7‘–dichlorfluorescein – diacetate (DCFH-DA) to the highly fluorescent compound 2‘,7‘dichlorfluorescein (DCF).

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Involvement of DA, PKC and Neuronal NOS in METH- and MDMA-Induced ROS Production

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METH increases DCF fluorescence when added to our preparation, which indicates that it induces ROS production [33]. When we used synaptosomes from DA-depleted rats (pre-treated with reserpine or reserpine plus alphamethyl-p-tyrosine) the METH-induced ROS production was inhibited so we corroborate DA as the main source of ROS detected (Fig 1). Besides, METH, by altering the intracellular pH gradient, prevents vesicular monoamine transporter (VMAT) function and promotes DA release from vesicles to cytosol [52] where it can be oxidized. By this way, in vitro incubation of synaptosomes with substances that block VMAT (reserpine) prevents METH oxidative effect.

Figure 1. Effect of catecholamine depletion on METH-induced ROS in rat striatal synaptosomes. Rats were pretreated with saline (normal), reserpine (RES), or with reserpine plus alpha-methyl-p-tyrosine (RES + AMPT). Synaptosomes were obtained, and incubated alone (CTRL) or with 2 mM METH. *P