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Director's Report 2/01 Director's Report 2/01 Director's Report to the National Advisory Council on Drug Abuse February, 2001 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 Extramural Policy and 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] 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/DirRep201/DirectorRepIndex.html[11/17/16, 9:48:57 PM] Director's Report 2/01 - Basic Research Director's Report to the National Advisory Council on Drug Abuse February, 2001 Research Findings Basic Research Role for GDNF in Biochemical and Behavioral Adaptations to Drugs of Abuse Drs. David Russell and Eric Nestler and their research team at the Yale University examined a role for Glial-Derived Neurotrophic Factor (GDNF) in adaptations to drugs of abuse. Infusion of GDNF into the ventral tegmental area (VTA), a dopaminergic brain region important for addiction, blocks certain biochemical adaptations to chronic cocaine or morphine as well as the rewarding effects of cocaine. Conversely, responses to cocaine are enhanced in rats by intra-VTA infusion of an anti-GDNF antibody and in mice heterozygous for a null mutation in the GDNF gene. Chronic morphine or cocaine exposure decreases levels of phosphoRet, the protein kinase that mediates GDNF signaling in the VTA. Together, these results suggest a feedback loop, whereby drugs of abuse decrease signaling through endogenous GDNF pathways in the VTA, which then increases the behavioral sensitivity to subsequent drug exposure. Messer, C.J., Eisch, A.J., Carlezon, W.A. Jr., Whisler, K., Shen, L., Wold, D.H., Westphal, H., Collins, F., Russell, D.S., and Nestler, E.J. Role for GDNF in Biochemical and Behavioral Adaptations to Drugs of Abuse. Neuron, 26(1), pp. 247-257, 2000. Mechanisms Responsible for Methamphetamine-Induced Rapid Decrease in Dopamine Transporter Function Single and multiple high-dose administrations of methamphetamine (METH) decrease dopamine (DA) transporter function, as assessed in striatal synaptosomes (approximately 33% and 78% reductions, respectively). These effects occur within 60 minutes after in vivo treatment and persist even after METH is removed from the synaptosomal preparation. The large reduction in DAT function after multiple METH injections appears to have two separate components with distinct underlying mechanisms. Phase I occurs after either a single or multiple METH administrations and is not dependent on drug-induced changes in dopaminergic function or hyperthermia. It is hypothesized that phase I is due to a METH-induced internalization of DAT causing a temporary loss of transporter function. Phase II only occurs after multiple METH administrations and is dependent on activation of DA receptors, hyperthermia and free radical formation. Even though there is no loss of DAT protein, it is possible this phase II response of DAT to METH is somehow related to the neurotoxic potential of this drug, as similar factors are necessary for this drug to induce long-term deficits in monoamine systems after multiple METH treatments. The precise nature of these two phases of METH-induced reduction in DAT activity requires further study and may be important for understanding both the short- and long-term consequences of abusing this drug. Metzger, R.R., Haughey, H.M., Wilkins, D.G., Gibb, J.W., Hanson, G.R., and Fleckenstein, A.E. Methamphetamine-Induced Rapid Decrease in Dopamine Transporter Function: Role of Dopamine and Hyperthermia. J. Pharmacol. Exp. Ther., 295(3), pp. 1077- 1085, 2000. Pigment Measurement is Important for Hair Testing for Several Drugs of Abuse In rats with pigmented hair, cocaine, ecogonine methyl ester (EME) and norcocaine (NCOC) were detected in dose- related concentrations whereas in rats with non-pigmented hair none of these were detected. In rats with pigmented hair, cocaine was twice as likely as its metabolite benzoylecgonine (BE) to be detected. Melanin binds to basic drugs with a net positive charge. Cocaine concentrations in pigmented hair peaked after cocaine disappears from the blood. In rats with pigmented hair, maximal hair concentrations of cocaine were found three days after serum https://archives.drugabuse.gov/DirReports/DirRep201/DirectorReport1.html[11/17/16, 9:49:01 PM] Director's Report 2/01 - Basic Research concentrations became undetectable. In rats with non-pigmented hair, concentrations of cocaine were undetectable for two days. In rats, while amphetamine binds preferentially to pigmented hair, its non-basic analog, N- acetylamphetamine, is taken up equally in both pigmented and non-pigmented hair. In mice, while the cation 45CA2 associated with melanocytes and melanosomes of forming pigmented hair within 5 minutes of dosing, the anion 38Cl- did not associate in the hair of either pigmented or non-pigmented hair. Hubbard, D.L., Wilkins, D.G., and Rollins, D.E. The Incorporation of Cocaine and Metabolites into Hair: Effects of Dose and Hair Pigmentation. Drug Metab. Dispos., 28, pp. 1464-1469, 2000. Heroin Modulation of Immune Status Heroin use is associated with an increased incidence of several types of infections, including HIV, yet few studies have assessed whether heroin produces pharmacological alterations of immune status that might contribute to the increased rate of infections among heroin users. Two recent studies by Dr. Donald Lysle and his colleagues have evaluated the immunomodulatory effects of a single heroin injection in the rat. The first study investigated whether a single heroin administration produces dose-dependent alterations in immune status. The results show that heroin produces a dose-dependent, naltrexone-reversible suppression in stimulated proliferation of T-cells, B-cells, production of interferon-g, and cytotoxicity of natural killer (NK) cells in the spleen. Thus, heroin affects both functional and phenotypic measures of immune status. Fecho, K., Nelson, C.J., and Lysle, D.T. Phenotypic and Functional Assessments of Immune Status in the Rat Spleen Following Acute Heroin Treatment. Immunopharmacology, 46, pp. 193-207, 2000. A second study examined the rate of splenocyte death by necrosis or apoptosis. The results showed that a single injection of heroin decreased the total number of leukocytes in the spleen in a dose-dependent, naltrexone-reversible manner. Moreover, the heroin-induced decrease in splenic leukocytes was not associated with an increase in circulating leukocytes. Fecho, K., and Lysle, D.T. Heroin-Induced Alterations in Leukocyte Numbers and Apoptosis in the Rat Spleen. Cellular Immunology, 202, pp. 113-123, 2000. Endomorphin-1, Antinociception and Immune Modulation Central opioid receptors have been known for some time to be involved in immunomodulation. However, only recently has an endogenous agonist possessing high selectivity and affinity for the mu opioid receptor, endomorphin- 1, been identified. Little is known about the immunomodulatory and antinociceptive effects of endomorphin-1. Dr. Donald Lysle and his colleagues found in rats that endomorphin-1 produced naltrexone-reversible antinociception in both the hotplate assay and in the warm water tail withdrawal assay. However, there were no immunomodulatory effects up to 120 minutes after injection. These observations suggest that it may be possible to develop therapeutic strategies for separating antinociception and immunomodulatory properties through the m-opioid receptor. Carrigan, K.A., Nelson, C.J. and Lysle, D.T. Endomorphin-1 Induces Antinociception without Immunomodulatory Effects in the Rat. Psychopharmacology, 151, pp. 299-305, 2000. Methamphetamine Neurotoxicity Has Behavioral Consequences in Rats Dr. John F. Marshall's group has been studying the degeneration of neurons in the somatosensory cortex after repeated methamphetamine. Given the general lack of studies of cognitive functioning after neurotoxic regimens of methamphetamine, they studied a spatial (hippocampus-dependent) and a cued (caudate nucleus-dependent) water maze task one week after a neurotoxic regimen of methamphetamine. Rats treated with methamphetamine had impaired acquisition of the cued, but not the spatial, task. By contrast, the methamphetamine group had impaired retention (tested 24 hr after acquisition) of the spatial task. The swimming speed was not affected in any tests, indicating that these effects were not due to impaired motor function. Autoradiography demonstrated that dopamine transporter was markedly reduced in the striatum, and serotonin transporter was reduced in the hippocampus. Thus, methamphetamine neurotoxicity has different consequences on hippocampus- and caudate-dependent memory tasks in rats. Schršder, N., and Marshall, J. Differential Effects of Methamphetamine-Induced Neurotoxicity on Hippocampus-Dependent and Caudate Nucleus-Dependent Memory Processes. Society for Neuroscience Abstracts, 26, Abstract 484.14, p. 1311, 2000. More Evidence for Glutamate's Role in Addiction Sensitization
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