title: Cocaine, metamfetamine, and MDMA abuse: the role and clinical importance of neuroadaptation.
abstract: BACKGROUND
  This article reviews the role and clinical importance of specific neuroadaptations that may occur following use of cocaine, metamfetamine, and 3,4,methylenedioxymetamfetamine (MDMA).
  
  
  METHODS
  A literature search was performed using OVID MEDLINE and PubMed for all years to the present date, which identified 250 papers of which 154 were considered relevant. MECHANISMS OF ACTION OF COCAINE AND METAMFETAMINE: Cocaine and metamfetamine increase central nervous system synaptic dopamine primarily by increasing the release of dopamine into the synapse and binding to the dopamine reuptake transporter, which prevents the reuptake of dopamine from the synapse back into the nerve cell. Synaptic dopamine then stimulates post synaptic receptors. The continued release of dopamine and prevention of reuptake results in a supraphysiological concentration of dopamine, which causes euphoria or a "high." The greater the concentration of dopamine, the greater the high. Continued supraphysiological concentrations of dopamine and postsynaptic receptor stimulation may cause physiological and anatomical changes (neuroadaptations) in the central nervous system (CNS) synapse that attempt to maintain homeostasis. An example of a dopaminergic neuroadaptation is the decrease in number of post synaptic D2 receptors that occurs when synaptic dopamine concentrations remain supraphysiological. This neuroadaptation attempts to maintain homeostasis, that is, the decreased number of D2 receptors provides fewer receptors to be constantly stimulated by increased synaptic dopamine. Although metamfetamine also increases synaptic dopamine similarly to cocaine, metamfetamine also increases cytoplasmic dopamine, which causes CNS oxidative stress and neurotoxicity. The clinical impact of the oxidative stress is unknown. MECHANISMS OF ACTION OF MDMA: MDMA increases concentrations of synaptic serotonin by increasing the release of serotonin and binding to the serotonin reuptake transporter, preventing the reuptake of serotonin from the synapse back into the nerve cell. An example of a serotonergic neuroadaptation is a decrease in the number of serotonin presynaptic autoreceptors (one of the regulators of synaptic serotonin concentration) to maintain homeostasis. MDMA also causes a decrease in serotonergic biochemical markers and neuronal axotomy in rats and nonhuman primates. Abstinence may allow reinnervation, but the axonal regrowth pattern is abnormal. Whether axotomy and reinnervation also occur in humans is unknown. Pharmacogenomics may play a role in the varied response of the individual to MDMA.
  
  
  CONCLUSIONS
  Neuroadaptations may be transient or permanent. The duration of drug use or drug concentration needed to cause neuroadaptations is unknown, but some neuroadaptations begin shortly after initiation of drug use and are dependent on variables such as genetics and age at the initiation of use. Understanding the concept of neuroadaptation and some specific neuroadaptations that occur will allow clinicians to better understand the interindividual variability in response to drugs of abuse.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 373232, USA. donna.seger@vanderbilt.edu
authors.forename: Donna
authors.initials: D
authors.lastname: Seger
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D003042:Cocaine / Q000633:toxicity*; D004298:Dopamine / Q000502:physiology; D006801:Humans; D008694:Methamphetamine / Q000633:toxicity*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D018384:Oxidative Stress; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000502:physiology; D012701:Serotonin / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D019966:Substance-Related Disorders / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects; D050493:Vesicular Monoamine Transport Proteins / Q000502:physiology
chemical_list: D000697:Central Nervous System Stimulants; D017448:Receptors, Dopamine D2; C493452:SLC18A2 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin; D008694:Methamphetamine; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine