Methylphenidate Amplifies the Potency and Reinforcing Effects Of

Total Page:16

File Type:pdf, Size:1020Kb

Methylphenidate Amplifies the Potency and Reinforcing Effects Of ARTICLE Received 1 Aug 2013 | Accepted 7 Oct 2013 | Published 5 Nov 2013 DOI: 10.1038/ncomms3720 Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression Erin S. Calipari1, Mark J. Ferris1, Ali Salahpour2, Marc G. Caron3 & Sara R. Jones1 Methylphenidate (MPH) is commonly diverted for recreational use, but the neurobiological consequences of exposure to MPH at high, abused doses are not well defined. Here we show that MPH self-administration in rats increases dopamine transporter (DAT) levels and enhances the potency of MPH and amphetamine on dopamine responses and drug-seeking behaviours, without altering cocaine effects. Genetic overexpression of the DAT in mice mimics these effects, confirming that MPH self-administration-induced increases in DAT levels are sufficient to induce the changes. Further, this work outlines a basic mechanism by which increases in DAT levels, regardless of how they occur, are capable of increasing the rewarding and reinforcing effects of select psychostimulant drugs, and suggests that indivi- duals with elevated DAT levels, such as ADHD sufferers, may be more susceptible to the addictive effects of amphetamine-like drugs. 1 Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. 2 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada M5S1A8. 3 Department of Cell Biology, Medicine and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA. Correspondence and requests for materials should be addressed to S.R.J. (email: [email protected]). NATURE COMMUNICATIONS | 4:2720 | DOI: 10.1038/ncomms3720 | www.nature.com/naturecommunications 1 & 2013 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms3720 ecent epidemiological studies show that rates of illicit drug (n ¼ 11). This resulted in escalation of first-hour intake (one-way use have declined in recent years, whereas abuse of analysis of variance (ANOVA); F(4,10) ¼ 20.00, Po0.001) as well Rprescription drugs, including stimulant medications such as overall rate of intake (one-way ANOVA; F(4, 10) ¼ 7.956, as Ritalin, are on the rise1. Methylphenidate (MPH), the active Po0.001; Fig. 1a,b). On an FR1 schedule, it is impossible to compound in Ritalin, is prescribed for attention deficit and differentiate whether increased intake is due to tolerance or hyperactivity disorder (ADHD) and narcolepsy, and is commonly increased motivation to take drug; hence, we measured used off-label, with up to 17% of college students reporting abuse reinforcing efficacy using a progressive ratio (PR) paradigm19. of MPH for its cognitive enhancing or euphoric effects2. MPH is We found an increase in breakpoint for MPH (Student’s t-test; taken orally, intranasally or intravenously, and is one of the t12 ¼ 2.068, Po0.05; Fig. 1c) following MPH self-administration prescribed drugs most diverted onto the illicit market3,4. MPH (n ¼ 7 per group). abuse occurred at rates comparable to cocaine abuse in the 5 United States in 2008 . However, although there are numerous MPH increases MPH potency and MPH-induced dopamine studies outlining the neurochemical consequences of therapeutic overflow. The reinforcing and rewarding effects of many drugs of MPH use, there is a paucity of data outlining the neurobiological abuse are related to their ability to elevate dopamine in the adaptations that occur during MPH abuse. nucleus accumbens (NAc)20. Although the NAc shell is involved When taken via the same route of administration, the in the acute rewarding effects of drugs and acquisition of self- subjective effects of MPH are indistinguishable from cocaine or administration, the NAc core has a critical role in cue-reward amphetamine (AMPH), two commonly abused and highly 6,7 learning as well as continued responding for drugs after repeated addictive drugs . In addition, the behavioural effects of MPH administration as in the current paradigm21,22. We found and other psychostimulants are similar. For example, MPH dopamine uptake in the NAc core to be supersensitive to MPH resembles both cocaine and AMPH in extended access self- inhibition following MPH self-administration (two-way ANOVA; administration experiments, which result in escalation of intake F ¼ 25.11, Po0.05; Fig. 1d,e; n ¼ 5 control, 6 MPH self- over sessions, a change thought to model the switch from abuse to (1, 9) 8–11 administration), which is consistent with our microdialysis addiction . Because of the similar subjective and behavioural data demonstrating increased MPH-induced dopamine overflow profile of MPH compared with highly addictive drugs, it is in the NAc (two-way ANOVA; F(1, 5) ¼ 20.80, Po0.001; critically important to ascertain the neurochemical consequences Supplementary Fig. S1A; n ¼ 4 control, 5 MPH self- of abuse of MPH. administration). The proposed mechanism for augmented MPH MPH, AMPH and cocaine exert their rewarding and reinfor- potency is increased DAT levels, which has been suggested to cing effects by inhibiting the dopamine transporter (DAT) and 23 12 modulate the potency of dopamine releasers . Indeed, after MPH elevating synaptic dopamine levels . In addition, changes in self-administration (n ¼ 31 per group), the maximal rate of potency at the DAT are predictive of changes in the rewarding dopamine uptake was increased (V ; Student’s t-test; effects of these compounds in place preference paradigms13.To max t60 ¼ 2.434, Po0.01; Fig. 1g,h) as was the peak amplitude of elucidate the consequences of MPH self-administration on the stimulated dopamine release (Fig. 1h; Student’s t-test; t ¼ 2.719, abuse/addiction potential of psychostimulants, we determined 24 Po0.01). We showed previously that the increase in Vmax after the changes in blocker and releaser potency at the DAT as well as MPH was due to increased total DAT levels24. concomitant changes in motivation and drug-seeking behaviours for AMPH, MPH and cocaine. MPH self-administration resulted in increased maximal rates MPH self-administration increases dopamine releaser potency. of dopamine uptake mediated by increased DAT levels. Previous To further understand the impact of MPH self-administration on work has shown that fluctuations in DAT levels can alter the psychostimulant potencies, we used voltammetry and micro- potency of psychostimulants14, although the specific drugs dialysis to examine the ability of a number of DAT blockers and affected and the direction of potency shifts remain equivocal. dopamine releasers to enhance dopamine signals in the NAc core. Here we proposed that MPH self-administration-induced We found that MPH self-administration had no effect on blocker elevations in DAT levels would result in enhanced potency and potency, but enhanced the potency of releasers. Thus, the ability reinforcing efficacy of releasers and MPH. To test this hypothesis, of the blockers cocaine (Fig. 2a,c; n ¼ 5 control, 6 MPH self- we used transgenic DAT overexpressing mice (DAT-tg), which administration) and nomifensine (Fig. 2b,d; n ¼ 5 per group) to have elevated levels of native, non-drug-altered DATs. Using inhibit dopamine uptake was unaffected by MPH self-adminis- these mice, we elucidated a basic mechanism whereby increased tration. In contrast, the potency of AMPH (two-way ANOVA; DAT levels drive enhanced potency and motivation to obtain F(1, 4) ¼ 76.81, Po0.001; Fig. 2e,g; n ¼ 5 per group) and MPH and releaser drugs such as AMPH while leaving the effects methamphetamine (two-way ANOVA; F(1, 10) ¼ 33.51, Po0.001; of blockers such as cocaine unchanged. The robust enhancement Fig. 2f,h; n ¼ 7 control, 5 MPH self-administration) was in the potency of releasers, but not blockers, following increases increased. in DAT levels in DAT-tg mice is particularly important as it The increase in drug potency for dopamine uptake inhibition suggests that individual variations in DAT levels in the human by releasers following MPH self-administration was accompanied population (for example, ADHD15, post-traumatic stress by increases in drug-induced dopamine overflow as measured disorder16, early-life stress17, repeated stressors18) may predict using in vivo microdialysis. AMPH (two-way ANOVA; susceptibility to abuse of compounds such as MPH, AMPH and F(1, 5) ¼ 11.51, Po0.0001; n ¼ 5 control, 6 MPH self-administra- methamphetamine. tion; Supplementary Fig. S1B), but not cocaine (n ¼ 6 per group; Supplementary Fig. S1C), resulted in increased drug-induced dopamine overflow in the NAc. This confirms that shifts in the Results ability of releasers to inhibit dopamine uptake correspond to MPH self-administration increases MPH reinforcement.To shifts in the ability of releaser to augment extracellular dopamine determine the neurochemical consequences of MPH adminis- levels. tration, we allowed rats 6-h access to the most reinforcing dose of MPH (0.56 mg kg À 1 per infusion11) on a fixed ratio one (FR1) MPH increases releaser reinforcement and drug-seeking. Given schedule, with a maximum of 40 injections for 5 consecutive days the enhanced potency of dopamine releasers, it is possible that 2 NATURE COMMUNICATIONS | 4:2720 | DOI: 10.1038/ncomms3720 | www.nature.com/naturecommunications & 2013 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms3720 ARTICLE a 1 h 1 2 3 Session 4 5 bc 300 CTRL * 12 MPH SA * 250 11 * * 200 10 9 150 Final ratio 8 100 MPH injections per h 7 50 0 0 12345 Session de 10 µM MPH 40 * height CTRL 30 M) MPH SA µ Normalized peak 30 s 20 –0.4 +11.0 * Current (nA) +1.2 +2.0 (app. Km, (app. 10 –0.4 –7.0 –0.4 +21.0 uptake Inhibition of DA 0 vs Ag/AgCl +1.2 +3.0 V –0.4 –14.0 –6.5 –6.0 –5.5 –5.0 –4.5 Log [MPH] (M) 15 s fgh CTRL 4 * 1.5 MPH SA * height 3 M) µ ) 1.0 Normalized peak –1 –0.4 +19.0 M s CTRL Current (nA) µ 2 +1.2 ( –0.4 max 0.5 +2.0 V –0.4 MPH SA 1 per pulse ( [DA] vs Ag/AgCl +1.2 V –0.4 –9.0 0 0.0 15 s CTRL MPH SA CTRL MPH SA Figure 1 | MPH self-administration increases dopamine uptake and MPH potency.
Recommended publications
  • Methylphenidate Hydrochloride
    Application for Inclusion to the 22nd Expert Committee on the Selection and Use of Essential Medicines: METHYLPHENIDATE HYDROCHLORIDE December 7, 2018 Submitted by: Patricia Moscibrodzki, M.P.H., and Craig L. Katz, M.D. The Icahn School of Medicine at Mount Sinai Graduate Program in Public Health New York NY, United States Contact: [email protected] TABLE OF CONTENTS Page 3 Summary Statement Page 4 Focal Point Person in WHO Page 5 Name of Organizations Consulted Page 6 International Nonproprietary Name Page 7 Formulations Proposed for Inclusion Page 8 International Availability Page 10 Listing Requested Page 11 Public Health Relevance Page 13 Treatment Details Page 19 Comparative Effectiveness Page 29 Comparative Safety Page 41 Comparative Cost and Cost-Effectiveness Page 45 Regulatory Status Page 48 Pharmacoepial Standards Page 49 Text for the WHO Model Formulary Page 52 References Page 61 Appendix – Letters of Support 2 1. Summary Statement of the Proposal for Inclusion of Methylphenidate Methylphenidate (MPH), a central nervous system (CNS) stimulant, of the phenethylamine class, is proposed for inclusion in the WHO Model List of Essential Medications (EML) & the Model List of Essential Medications for Children (EMLc) for treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) under ICD-11, 6C9Z mental, behavioral or neurodevelopmental disorder, disruptive behavior or dissocial disorders. To date, the list of essential medications does not include stimulants, which play a critical role in the treatment of psychotic disorders. Methylphenidate is proposed for inclusion on the complimentary list for both children and adults. This application provides a systematic review of the use, efficacy, safety, availability, and cost-effectiveness of methylphenidate compared with other stimulant (first-line) and non-stimulant (second-line) medications.
    [Show full text]
  • Free PDF Download
    European Review for Medical and Pharmacological Sciences 2019; 23: 3-15 Use of cognitive enhancers: methylphenidate and analogs J. CARLIER1, R. GIORGETTI2, M.R. VARÌ3, F. PIRANI2, G. RICCI4, F.P. BUSARDÒ2 1Unit of Forensic Toxicology, Sapienza University of Rome, Rome, Italy 2Section of Legal Medicine, Universita Politecnica delle Marche, Ancona, Italy 3National Centre on Addiction and Doping, Istituto Superiore di Sanità, Rome, Italy 4School of Law, University of Camerino, Camerino, Italy Abstract. – OBJECTIVE: In the last decades, phenidate analogs should be undertaken to re- several cognitive-enhancing drugs have been duce the uprising threat, and education efforts sold onto the drug market. Methylphenidate and should be made among high-risk populations. analogs represent a sub-class of these new psy- choactive substances (NPS). We aimed to re- Key Words: view the use and misuse of methylphenidate and Cognitive enhancers, Methylphenidate, Ritalin, Eth- analogs, and the risk associated. Moreover, we ylphenidate, Methylphenidate analogs, New psycho- exhaustively reviewed the scientific data on the active substances. most recent methylphenidate analogs (methyl- phenidate and ethylphenidate excluded). MATERIALS AND METHODS: Literature Introduction search was performed on methylphenidate and analogs, using specialized search engines ac- cessing scientific databases. Additional reports Consumption of various pharmaceutical drugs were retrieved from international agencies, in- by healthy individuals in an attempt to improve stitutional websites, and drug user forums. cognitive faculties is on the rise, whether for aca- RESULTS: Methylphenidate/Ritalin has been demic or recreational purposes1. These substances used for decades to treat attention deficit disor- are stimulants that preferentially target the cate- ders and narcolepsy. More recently, it has been used as a cognitive enhancer and a recreation- cholamines of the prefrontal cortex of the brain to al drug.
    [Show full text]
  • FSI-D-16-00226R1 Title
    Elsevier Editorial System(tm) for Forensic Science International Manuscript Draft Manuscript Number: FSI-D-16-00226R1 Title: An overview of Emerging and New Psychoactive Substances in the United Kingdom Article Type: Review Article Keywords: New Psychoactive Substances Psychostimulants Lefetamine Hallucinogens LSD Derivatives Benzodiazepines Corresponding Author: Prof. Simon Gibbons, Corresponding Author's Institution: UCL School of Pharmacy First Author: Simon Gibbons Order of Authors: Simon Gibbons; Shruti Beharry Abstract: The purpose of this review is to identify emerging or new psychoactive substances (NPS) by undertaking an online survey of the UK NPS market and to gather any data from online drug fora and published literature. Drugs from four main classes of NPS were identified: psychostimulants, dissociative anaesthetics, hallucinogens (phenylalkylamine-based and lysergamide-based materials) and finally benzodiazepines. For inclusion in the review the 'user reviews' on drugs fora were selected based on whether or not the particular NPS of interest was used alone or in combination. NPS that were use alone were considered. Each of the classes contained drugs that are modelled on existing illegal materials and are now covered by the UK New Psychoactive Substances Bill in 2016. Suggested Reviewers: Title Page (with authors and addresses) An overview of Emerging and New Psychoactive Substances in the United Kingdom Shruti Beharry and Simon Gibbons1 Research Department of Pharmaceutical and Biological Chemistry UCL School of Pharmacy
    [Show full text]
  • Comparison of the Inhibitory and Excitatory Effects of ADHD Medications Methylphenidate and Atomoxetine on Motor Cortex
    Neuropsychopharmacology (2006) 31, 442–449 & 2006 Nature Publishing Group All rights reserved 0893-133X/06 $30.00 www.neuropsychopharmacology.org Comparison of the Inhibitory and Excitatory Effects of ADHD Medications Methylphenidate and Atomoxetine on Motor Cortex ,1 2 3 1 1 4 Donald L Gilbert* , Keith R Ridel , Floyd R Sallee , Jie Zhang , Tara D Lipps and Eric M Wassermann 1 2 Division of Neurology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA; University of Cincinnati 3 4 School of Medicine, Cincinnati, OH, USA; Division of Psychiatry, University of Cincinnati, Cincinnati, OH, USA; Brain Stimulation Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures.
    [Show full text]
  • Methylphenidate-Induced Dendritic Spine Formation and ⌬Fosb Expression in Nucleus Accumbens
    Methylphenidate-induced dendritic spine formation and ⌬FosB expression in nucleus accumbens Yong Kima, Merilee A. Teylana, Matthew Barona, Adam Sandsa, Angus C. Nairna,b, and Paul Greengarda,1 aLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10065; and bDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT 06508. Contributed by Paul Greengard, December 23, 2008 (sent for review December 3, 2008) Methylphenidate is the psychostimulant medication most com- dopamine and glutamate is within the dendritic spines of MSN, and monly prescribed to treat attention deficit hyperactivity disorder notably chronic exposure to psychostimulants has been found to (ADHD). Recent trends in the high usage of methylphenidate for increase the number of dendritic branch points and spines of MSN both therapeutic and nontherapeutic purposes prompted us to in NAcc (17, 18). investigate the long-term effects of exposure to the drug on GABAergic MSN, which represent 90–95% of all neurons in neuronal adaptation. We compared the effects of chronic methyl- striatum, are comprised of 2 intermingled subpopulations. One phenidate or cocaine (15 mg/kg, 14 days for both) exposure in mice subpopulation of MSN express high levels of dopamine D1 recep- on dendritic spine morphology and ⌬FosB expression in medium- tors (together with substance P and dynorphin) (MSN-D1), and the sized spiny neurons (MSN) from ventral and dorsal striatum. other MSN express high levels of dopamine D2 receptors (together Chronic methylphenidate increased the density of dendritic spines with enkephalin) (MSN-D2) (19–22). Through the use of selective in MSN-D1 (MSN-expressing dopamine D1 receptors) from the core agonists and antagonists, both D1 and D2 receptors have been and shell of nucleus accumbens (NAcc) as well as MSN-D2 (MSN- shown to be required for psychostimulant-dependent behavioral expressing dopamine D2 receptors) from the shell of NAcc.
    [Show full text]
  • Synthetic Cathinones ("Bath Salts")
    Synthetic Cathinones ("Bath Salts") What are synthetic cathinones? Synthetic cathinones, more commonly known as "bath salts," are synthetic (human- made) drugs chemically related to cathinone, a stimulant found in the khat plant. Khat is a shrub grown in East Africa and southern Arabia, and people sometimes chew its leaves for their mild stimulant effects. Synthetic variants of cathinone can be much stronger than the natural product and, in some cases, very dangerous (Baumann, 2014). In Name Only Synthetic cathinone products Synthetic cathinones are marketed as cheap marketed as "bath salts" should substitutes for other stimulants such as not be confused with products methamphetamine and cocaine, and products such as Epsom salts that people sold as Molly (MDMA) often contain synthetic use during bathing. These cathinones instead (s ee "Synthetic Cathinones bathing products have no mind- and Molly" on page 3). altering ingredients. Synthetic cathinones usually take the form of a white or brown crystal-like powder and are sold in small plastic or foil packages labeled "not for human consumption." Also sometimes labeled as "plant food," "jewelry cleaner," or "phone screen cleaner," people can buy them online and in drug paraphernalia stores under a variety of brand names, which include: Flakka Bloom Cloud Nine Lunar Wave Vanilla Sky White Lightning Scarface Image courtesy of www.dea.gov/pr/multimedia- library/image-gallery/bath-salts/bath-salts04.jpg Synthetic Cathinones • January 2016 • Page 1 How do people use synthetic cathinones? People typically swallow, snort, smoke, or inject synthetic cathinones. How do synthetic cathinones affect the brain? Much is still unknown about how synthetic cathinones affect the human brain.
    [Show full text]
  • Illicit Methylphenidate Use in an Undergraduate Student Sample: Prevalence and Risk Factors
    Illicit Methylphenidate Use in an Undergraduate Student Sample: Prevalence and Risk Factors Christian J. Teter, Pharm.D., Sean Esteban McCabe, Ph.D., Carol J. Boyd, Ph.D., and Sally K. Guthrie, Pharm.D. Study Objectives. To assess the prevalence of illicit methylphenidate use among undergraduate college students at a large university, and to identify alcohol and other drug use behaviors, as well as the negative consequences and risk factors, associated with illicit methylphenidate use. Design. Internet survey. Setting. Large public university. Subjects. Thirty-five hundred randomly selected undergraduate students. Measurements and Main Results. Of the 2250 students who completed the survey, 3% reported past-year illicit methylphenidate use. Illicit methylphenidate users were significantly more likely to use alcohol and drugs and report adverse alcohol- and drug-related consequences than prescription stimulant users or students who did not use stimulants. Undergraduate men and women were equally likely to report past-year illicit methylphenidate use. Weekly party behavior was significantly associated with past-year illicit methylphenidate use. Conclusion. Illicit use of prescription-only stimulants on college campuses is a potentially serious public health issue. More work is needed to promote understanding and awareness of this problem among clinicians and researchers. (Pharmacotherapy 2003;23(5):609–617) The misuse of alcohol and illicit drugs among Recent years have brought increasing evidence traditional-age undergraduate students
    [Show full text]
  • The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines
    The ICD-10 Classification of Mental and Behavioural Disorders: Clinical descriptions and diagnostic guidelines World Health Organization F10 - F19 Mental and behavioural disorders due to psychoactive substance use Overview of this block F10. – Mental and behavioural disorders due to use of alcohol F11. – Mental and behavioural disorders due to use of opioids F12. – Mental and behavioural disorders due to use of cannabinoids F13. – Mental and behavioural disorders due to use of sedative hypnotics F14. – Mental and behavioural disorders due to use of cocaine F15. – Mental and behavioural disorders due to use of other stimulants, including caffeine F16. – Mental and behavioural disorders due to use of hallucinogens F17. – Mental and behavioural disorders due to use of tobacco F18. – Mental and behavioural disorders due to use of volatile solvents F19. – Mental and behavioural disorders due to multiple drug use and use of other psychoactive substances Four- and five-character codes may be used to specify the clinical conditions, as follows: F1x.0 Acute intoxication .00 Uncomplicated .01 With trauma or other bodily injury .02 With other medical complications .03 With delirium .04 With perceptual distortions .05 With coma .06 With convulsions .07 Pathological intoxication F1x.1 Harmful use F1x.2 Dependence syndrome .20 Currently abstinent .21 Currently abstinent, but in a protected environment .22 Currently on a clinically supervised maintenance or replacement regime [controlled dependence] .23 Currently abstinent, but receiving treatment with
    [Show full text]
  • Do You Know... Cocaine
    Do You Know... Street names: blow, C, coke, crack, flake, freebase, rock, snow Cocaine What is cocaine? Cocaine is a stimulant drug. Stimulants make people feel more alert and energetic. Cocaine can also make people feel euphoric, or “high.” Pure cocaine was first isolated from the leaves of the coca bush in 1860. Researchers soon discovered that cocaine numbs whatever tissues it touches, leading to its use as a local anesthetic. Today, we mostly use synthetic anesthetics, rather than cocaine. In the 1880s, psychiatrist Sigmund Freud wrote scientific papers that praised cocaine as a treatment for many ailments, including depression and alcohol and opioid addiction. After this, cocaine became widely and legally available in patent medicines and soft drinks. As cocaine use increased, people began to discover its dangers. In 1911, Canada passed laws restricting the importation, manufacture, sale and possession of cocaine. The use of 1/4 © 2003, 2010 CAMH | www.camh.ca cocaine declined until the 1970s, when it became known How does cocaine make you feel? for its high cost, and for the rich and glamorous people How cocaine makes you feel depends on: who used it. Cheaper “crack” cocaine became available · how much you use in the 1980s. · how often and how long you use it · how you use it (by injection, orally, etc.) Where does cocaine come from? · your mood, expectation and environment Cocaine is extracted from the leaves of the Erythroxylum · your age (coca) bush, which grows on the slopes of the Andes · whether you have certain medical or psychiatric Mountains in South America.
    [Show full text]
  • Differentially Affect Monoamine Transporters and Abuse Liability
    Neuropsychopharmacology (2017) 42, 1950–1961 © 2017 American College of Neuropsychopharmacology. All rights reserved 0893-133X/17 www.neuropsychopharmacology.org N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability Ernesto Solis Jr1, John S Partilla2, Farhana Sakloth3, Iwona Ruchala4, Kathryn L Schwienteck5, 4 4 3 5 *,2 Louis J De Felice , Jose M Eltit , Richard A Glennon , S Stevens Negus and Michael H Baumann 1In Vivo Electrophysiology Unit, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA; 2Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, 3 National Institutes of Health, Baltimore, MD, USA; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA; 4 5 Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of – abuse that interacts with transporters, but limited structure activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability.
    [Show full text]
  • Monoamine Reuptake Inhibitors in Parkinson's Disease
    Hindawi Publishing Corporation Parkinson’s Disease Volume 2015, Article ID 609428, 71 pages http://dx.doi.org/10.1155/2015/609428 Review Article Monoamine Reuptake Inhibitors in Parkinson’s Disease Philippe Huot,1,2,3 Susan H. Fox,1,2 and Jonathan M. Brotchie1 1 Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8 2Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, University of Toronto, 399BathurstStreet,Toronto,ON,CanadaM5T2S8 3Department of Pharmacology and Division of Neurology, Faculty of Medicine, UniversitedeMontr´ eal´ and Centre Hospitalier de l’UniversitedeMontr´ eal,´ Montreal,´ QC, Canada Correspondence should be addressed to Jonathan M. Brotchie; [email protected] Received 19 September 2014; Accepted 26 December 2014 Academic Editor: Maral M. Mouradian Copyright © 2015 Philippe Huot et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The motor manifestations of Parkinson’s disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters.
    [Show full text]
  • Narcolepsy: Current Treatment Options and Future Approaches
    REVIEW Narcolepsy: current treatment options and future approaches Michel Billiard Abstract: The management of narcolepsy is presently at a turning point. Three main avenues Department of Neurology, Gui de are considered in this review: 1) Two tendencies characterize the conventional treatment of Chauliac Hospital, Montpellier, France narcolepsy. Modafi nil has replaced methylphenidate and amphetamine as the fi rst-line treat- ment of excessive daytime sleepiness (EDS) and sleep attacks, based on randomized, double blind, placebo-controlled clinical trials of modafi nil, but on no direct comparison of modafi nil versus traditional stimulants. For cataplexy, sleep paralysis, and hypnagogic hallucinations, new antidepressants tend to replace tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) in spite of a lack of randomized, double blind, placebo-controlled clinical trials of these compounds; 2) The conventional treatment of narcolepsy is now challenged by sodium oxybate, the sodium salt of gammahydroxybutyrate, based on a series of randomized, double-blind, placebo-controlled clinical trials and a long-term open label study. This treatment has a fairly good effi cacy and is active on all symptoms of narcolepsy. Careful titration up to an adequate level is essential both to obtain positive results and avoid adverse effects; 3) A series of new treatments are currently being tested, either in animal models or in humans, They include novel stimulant and anticataplectic drugs, endocrine therapy, and, more attractively,
    [Show full text]