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.



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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.

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  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.

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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).

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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.

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  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.

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