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Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
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F Recent Advances in Addiction Research

MOLECULAR BIOLOGY, BIOCHEMISTRY, BRAIN IMAGING, AND ANATOMY

General Issues
  • Cloning and molecular studies on subtypes of key neurotransmitter and neuropeptide receptors, transporters, and enzymes involved in drug action.

  • Dopamine systems: identification, cloning, and characterization of five distinct dopamine receptor subtypes; chromosomal mapping of human and mouse dopamine receptor genes; elucidation of mechanisms controlling dopamine receptor expression and signaling; cloning and characterization of the gene and complementary deoxyribonucleic acid sequence (cDNA) for the dopamine transporter; chromosomal mapping of human dopamine transporter; and increased understanding of molecular anatomy and regulatory mechanisms of dopaminergic systems in common reward mechanisms.

  • Gene knockouts: evaluation of specific receptors, transporters, or enzymes in drug action by selective deletion from genome Transgenic animals: evaluation of specific receptors or enzymes in drug action by selective insertion into novel cells or animals and use of gene-selective switches to turn on and off transgene function.

  • Signal transduction processes: role of G-proteins, nitric oxide, cyclic adenosine monophosphate (cAMP), phosphorylation, and other processes in drug action, tolerance, and dependence.

Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
×

 

  • Mechanisms of receptor sensitization and desensitization have been identified and are currently being related to mechanisms of addictive syndromes.

  • Use of positron-emission tomography and single photon emission computed tomography imaging to evaluate drug action on dynamics of energy utilization and neurotransmitter function in living animals and humans.

Nicotine
  • Characterization of the nicotinic-cholinergic receptor within the central nervous system.

  • Demonstration that nicotine reward may be mediated by dopamine release.

Opioids
  • Endogenous opioid receptors cloned and characterized (mu, kappa delta).

  • Mu, kappa, delta receptor locations mapped in the brain.

  • Regulation studies of opioid genes and processing of opioid peptides in normal and drug-treated states.

  • Receptor cloning increases the likelihood of developing more selective agonist and antagonist drugs for each receptor subtype.

  • Characterization of processes by which opioid receptor activation regulates neuronal function, secondary messenger systems, ion channel function, and gene expression.

Stimulants
  • Specific interaction sites for cocaine and amphetamine identified on dopamine transporter.

  • Genetically altered mice for dopamine receptors and transporter have produced exciting new models for role of dopamine in cocaine and amphetamine action and brain reward systems in general.

  • Excitatory amino acids implicated in dopamine-mediated effects of cocaine; potential therapeutic implications.

Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
×
Alcohol
  • Identification of ?-isoform of GABAA receptor, which has high-affinity binding site for alcohol (i.e., alcohol receptor?).

  • Physiologically relevant doses of alcohol (10–50 mM) shown to: enhance Cl- flux mediated by the GABAA-benzodiazepine receptor complex; inhibit Ca++ flux mediated by the NMDA-glutamate receptor system; and enhance Na+ and K+ flux mediated by the 5-HT3 receptor.

  • Acute alcohol effects on NMDA-glutamate receptor and downstream actions of increased intracellular Ca++ on nitric oxide production implicated in acute tolerance development.

  • Chronic alcohol down-regulation of GABAA-benzodiazepine receptor complex and up-regulation of NMDA-glutamate receptor complex implicated in chronic tolerance development.

  • Low-to-moderate doses of alcohol increase the release of endogenous opioid peptides that may contribute to its effect on brain reward systems.

  • Alcohol's effect on firing of dopamine neurons in the ventral tegmental area (VTA) and increases in extracellular dopamine in the nucleus accumbens (NAc) may also contribute to the positive reinforcing effects of alcohol.

  • Serotonin, glutamate, opioid, and GABAergic neurons may modulate alcohol's reinforcing effects or mediate negative reinforcement from alcohol withdrawal.

ANIMAL MODELS, EXPERIMENTAL THERAPEUTICS, AND GENETICS

General Issues
  • Expanded research into the neurobiological basis and behavioral mechanisms for ''craving" and reinitiation of drug use.

  • Use of animal self-administration models, place-preference testing, drug discrimination, and other behavioral models in conjunction with:

    • in vitro and in vivo neurochemistry (microdialysis, neurotransmitter-selective electrodes, autoradiography),

    • brain imaging,

    • new strains of drug-responsive and nonresponsive animals,

    • quantitative trait loci (QTL) gene mapping, and

    • molecular biology (transgenic, gene knockout, antisense DNA).

Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
×
  • Mechanisms of somatic dependence established (locus coeruleus and other brainstem nuclei); predicted use of clonidine or other alpha-adrenergic drugs for treatment of somatic withdrawal.

Nicotine
  • Development of a model wherein animals self-administer nicotine to blood levels approximating those of human cigarette smokers.

  • Models for examination of "inhaled" nicotine.

Opioids
  • Discovery of mechanisms by which opioids activate brain reward pathways (via VTA and NAc).

  • Modulation of brain reward pathways by kappa agonists and antagonists; potential role of kappa agonists in blocking opioid reinforcement.

  • Prevention and/or reversal of opioid tolerance and dependence by NMDA antagonists, CCK antagonists, delta receptor agonists, and nitric oxide synthase inhibitors.

  • Substantial progress on molecular adaptations produced by acute or chronic opioids in the brain.

Stimulants
  • Development of robust animal models of cocaine and amphetamine self-administration.

  • Experimental evaluation of selective dopamine-subtype-selective agonists, antagonists, partial agonists, and other therapies as treatments for cocaine dependence.

  • Demonstration that the neurochemical consequences of cocaine self-administration are different from involuntary injection of cocaine, suggesting different transmitter pathways involved in anticipation of reward versus behavioral response.

Alcohol
  • Development of several genetically stable strains of high- or low-alcohol-preferring rats from common outbred animal stock.

Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
×

 

  • Experimental evaluation of opioid antagonists, serotonin reuptake inhibitors, 5-HT3 antagonists, and dopamine D2 receptor antagonists as treatments for alcohol dependence.

  • QTL gene mapping of chromosomes associated with alcohol preference, sensitivity, tolerance, and withdrawal.

  • Identification of genetic variants of principal enzymes of alcohol metabolism that influence alcohol drinking and dependence.

Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
×

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Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
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Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
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Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
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Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
×
Page 196
Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
×
Page 197
Suggested Citation:"Appendix F." Institute of Medicine. 1997. Dispelling the Myths About Addiction: Strategies to Increase Understanding and Strengthen Research. Washington, DC: The National Academies Press. doi: 10.17226/5802.
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Every year about half a million men, women, and children in the United States die from the effects of using nicotine, alcohol, and illegal drugs: one of every four American deaths. Yet research to solve this terrible problem is often perceived as less important than other types of biomedical investigation.

Focusing on four major classes of drugs with the greatest social and economic impact--nicotine, alcohol, opioids, and stimulants--Dispelling the Myths About Addiction examines what is known about addiction and what is needed to develop a talented cadre of investigators and to educate the public about addiction research. The committee explores these areas:

  • Economic costs of addiction.
  • What has been learned about addiction from research into basic neurobiology and the brain, psychosocial and behavioral factors, and epidemiology.
  • Education and training of researchers and the research infrastructure.
  • Public perceptions and their impact on public policy in this field.

This volume outlines the challenges and opportunities in addiction research today and makes recommendations to educators, treatment professionals, public and private institutions, and others for how to build support for addiction research and treatment.

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