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Director's Report 2/00 Director's Report 2/00 National Institute on Drug Abuse Director's Report to the National Advisory Council on Drug Abuse February, 2000 Index Research Findings Basic Research Behavioral Research Treatment Research and Development Research on AIDS and Other Medical Consequences of Drug Abuse Epidemiology, Etiology and Prevention Research Services Research Intramural Research Program Activities Review Activities Congressional Affairs International Activities Meetings and Conferences Media and Education Activities Planned Meetings Publications Staff Highlights Grantee Honors [Office of Director] [First Report Section] https://archives.drugabuse.gov/DirReports/DirRep200/DirectorRepIndex.html[11/17/16, 9:37:32 PM] Director's Report 2/00 Archive Home | Accessibility | Privacy | FOIA (NIH) | Current NIDA Home Page The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , a component of the U.S. Department of Health and Human Services. Questions? _ See our Contact Information. https://archives.drugabuse.gov/DirReports/DirRep200/DirectorRepIndex.html[11/17/16, 9:37:32 PM] Director's Report 2/00 - Basic Research National Institute on Drug Abuse Director's Report to the National Advisory Council on Drug Abuse February, 2000 Research Findings Basic Research A Brain Protein Is Involved in Switching On Cocaine Addiction Chronic exposure to cocaine causes the delta-FosB transcription factor to be expressed persistently in the nucleus accumbens. Thus, researchers hypothesized that delta-FosB may mediate some of the long-lived increases in sensitivity to the stimulant and rewarding effects of cocaine. Dr. Eric Nestler of Yale University and his colleagues tested whether delta-FosB expression actually increased the responsiveness to cocaine by generating genetically altered mice that produced large quantities of delta-FosB in the nucleus accumbens. The animals exhibited increased responsiveness to the rewarding and locomotor-activating effects of cocaine. The researchers then showed that delta- FosB increases the expression of a glutamate receptor, GluR2, in the nucleus accumbens. Indeed, overexpression of GluR2 expression in the nucleus accumbens was sufficient to account for the enhanced sensitivity to cocaine's rewarding effects seen in the mice with augmented levels of delta-FosB. The authors concluded that delta-FosB, by altering gene expression, enhances sensitivity to cocaine and may thereby contribute to cocaine addiction. This research offers insight into the nature of the switch from use to addiction, by demonstrating that sustained expression of delta-FosB is involved in the increased sensitivity to cocaine that may be related to addiction. Kelz, M.B., Chen, J., Carlezon, W.A. Jr., Whisler, K., Gilden, L., Beckmann, A.M., Steffen, C., Zhang, Y.J., Marotti, L., Self, D.W., Tkatch, T., Baranauskas, G., Surmeier, D.J., Neve, R.L., Duman, R.S., Picciotto, M.R., Nestler, E.J. Expression of the Transcription Factor Delta FosB in the Brain Controls Sensitivity to Cocaine. Nature, 401(6750), pp. 272-276, 1999. Methamphetamine May Kill Cortical Neurons via Excessive Sensory Stimulation Dr. John F. Marshall found that a group of pyramidal neurons located in the somatosensory cortex of the rat are killed by moderate, repeated doses of methamphetamine, in addition to the well-known injury to dopamine- and serotonin- containing terminals elsewhere in the brain. He hypothesizes that the cortical neurons die from a combination of hyperthermia and intense, prolonged excitation resulting from the rats' repetitive head and whisker movements during exposure to methamphetamine. His first experiments determined that the cortical neurons that die following a neurotoxic regimen of methamphetamine are located within the histochemically identified whisker "barrels" of the rat. The methamphetamine treatment induced Fluoro-Jade (fluorescent dye that specifically marks dying cells) positive cortical neurons only in cytochrome oxidase-stained "barrels" (discrete units containing about 2500 neurons arranged in a cylindrical array; each barrel contains the sensory representation of an individual whisker) of the somatosensory cortex. He reasons that some of the affected neurons are corticostriatal glutamatergic neurons, which, as they begin to degenerate, release excessive glutamate in the striatum, which contributes to damaging dopamine terminals in that structure. His most recent experiments demonstrated that removal of one set (left or right) of whiskers leads to reduced numbers of degenerating cortical neurons within the contralateral somatosensory cortex (consistent with the crossed projections of the whiskers). This provides evidence that the degeneration of somatosensory cortex neurons after methamphetamine depends at least in part on the stimuli arising from body movement. O'Dell, S.J. and Marshall, J.F. Effects of Vibrissae Removal on Methamphetamine-Induced Damage to Neurons in Rat Somatosensory Cortex. Society for Neuroscience, 25, Abstract 836.17, 1999. https://archives.drugabuse.gov/DirReports/DirRep200/DirectorReport1.html[11/17/16, 9:37:37 PM] Director's Report 2/00 - Basic Research Differential Effects of Neuropeptide Y and the Mu-Agonist DAMGO on 'Palatability' vs. 'Energy' A variety of studies suggest that Neuropeptide Y (NPY) is an important regulator of energy metabolism. In contrast, the opioid peptides appear to influence the rewarding aspects of feeding. In this study, Dr. Levine and his research team stimulated feeding by injecting NPY or the mu-opioid agonist DAMGO into the paraventricular nucleus of rats. Following injection, rats were given free access to laboratory chow and a ten percent sucrose solution. Animals injected with saline derived ten percent of their kilocalories from the chow and 90 percent from the sucrose solution. Those rats injected with NPY derived 48 percent of their energy from chow and 52 percent from the sucrose solution. The DAMGO-injected rats derived only 15 percent of their kilocalories from chow and the remainder from the sucrose solution. Thus, while NPY and DAMGO both stimulated energy intake compared to saline controls, the effect on intake of a palatable dilute energy solution versus a bland laboratory chow was different. The results of this study reinforce the notion that NPY has a major effect on energy needs, whereas opioids influence the rewarding characteristics of foods. Giraudo, S.Q., Grace, M.K., Billington, C.J., Levine, A.S. Differential Effects of Neuropeptide Y and the Mu- Agonist DAMGO on 'Palatability' vs. 'Energy'. Brain Research, 834(1-2), pp. 160-163, 1999. Tolerance to Morphine-Induced Antinociception is Decreased by Chronic Sucrose or Polycose Intake Chronic intake of palatable fluids alters morphine-induced antinociception. Two experiments were conducted to evaluate how long-term access to palatable fluids alters the development of tolerance to morphine-induced antinociception. In the first experiment, adult male Long-Evans rats were given one of the following to drink for a three weeks period: either a 0.15 percent saccharin solution, a 32 percent sucrose solution, a 32 percent Polycose solution, or chow and water alone (control). Half of the animals in each dietary condition were pre-exposed to 7.5 mg/kg morphine while the other half received saline. After injection, all rats were given a tail flick (TF) test. To determine whether tolerance developed, a cumulative dose paradigm was employed 1 week after the initial morphine injection, and this was repeated at weekly intervals for 3 weeks. Antinociception was significantly lower in rats pre- exposed to morphine. Although all rats displayed decreased antinociception relative to the first morphine injection, rats that drank saccharin showed greater reductions in morphine-induced antinociception relative to rats that drank sucrose or Polycose. A second experiment was conducted to determine whether the initial pairing of the TF with morphine pre-exposure produced differences in the development of opioid tolerance. All conditions and procedures were identical to those used in the first experiment except that the initial morphine and saline injections were not followed by TF. As in the first experiment, rats that drank saccharin showed less antinociception than rats that drank sucrose or Polycose. The present results suggest that long-term intake of palatable nutritive solutions curbs tolerance to morphine-induced antinociception, whereas long-term intake of a nonnutritive, sweet saccharin solution does not. D'Anci, K.E. Tolerance to Morphine-Induced Antinociception is Decreased by Chronic Sucrose or Polycose Intake. Pharmacology. Biochem. Behav., 63(1), pp. 1-11, 1999. Cannabinoid Receptor Selectivity The cannabimimetic ligand WIN 55212-2 is an aminoalkylindole that has been variously reported to have a 10-20 fold higher affinity for the peripheral CB2 receptor than for the CNS CB1 receptor. A recent report by NIDA grantees Reggio and Song has provided new insight into the molecular basis for the differences in selectivity. It had previously been shown that lysine 192 in the third transmembrane helix of the CB1 receptor was necessary to maintain binding of the "classical" cannabinoid structure HU-210 and that of the endogenous ligand anandamide. However, mutating the lysine to alanine did not change the binding of WIN 55212-2. Further, the carbonyl oxygen in the latter is not necessary for binding, and the morpholino ring can be replaced by an alkyl group without loss of binding. The researchers
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