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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse
February, 1998

Research Findings

Intramural Research

Cellular Neurobiology Branch

Research in Neurodegenerative Processes

Ongoing work in the laboratory of DIR Director, Dr. Barry J. Hoffer has focused on neurodegenerative processes. Dr. Hoffer and colleagues have found that several trophic factors in the TGF-superfamily reduce the size of cerebral infarcts induced by middle cerebral artery occlusion. Interestingly, intracerebral grafts of fetal kidney, which contain large amounts of such factors, also reduce infarct size.

Investigators in this laboratory have also been collaborating with scientists in the intramural program of NICHD to study GDNF null mutated mice. GDNF is a trophic factor for midbrain dopamine neurons. Mice in which the GDNF gene is knocked out show little or no changes in midbrain DA neurons at birth. Postnatal changes cannot be studied in situ since the mice die 24-48 hours after birth. However, by using transplantation protocols, we can show profound decreases in DA neuron number and size in postnatal ventral mesencephalon in these null mutated animals.

Neuroscience Research Branch
Molecular Neuropsychiatry Section

Differential Regulation of Dopamine Transporter Following Chronic Self-administration of Bupropion and Nomifensine

Inhibition of dopamine (DA) transporter function is thought to be the principal mechanisms underlying cocaine's addictive effects. In contrast to cocaine, several other inhibitors of DA transporter function are not considered to possess abuse liability. These data provide evidence for heterogeneity among DA reuptake inhibitors, with some of these drugs being able to up-regulate DA transporters after their self-administration, whereas others lack this neuroadaptive response. Tella S., Ladenheim B. and Cadet J.L. JPET, 281, pp. 508-513, 1997.

Neurophysiological Signs in Cocaine Dependence: Increased EEG Beta During Withdrawal

The percent of EEG beta in frontal and central areas of the cocaine-dependent individuals was correlated with the frequency of cocaine use during the last 30 days. High levels of EEG beta may be a neurophysiological withdrawal sign in cocaine-dependent men. Herning R.I., Guo X., Better W.E., Weinhold L.L., Lange W.R., Cadet J.L., and Gorelick, D.A. Biol Psychiatry, 41, pp. 1087-1094, 1997.

p53-Knockout Mice are Protected against the Long-term Effects of Methamphetamine on Dopaminergic Terminals and Cell Bodies

These results provide concordant evidence for a role of the tumor suppressor, p53, in the long-term deleterious effects of a drug acting on brain dopamine systems. Hirata, H. and Cadet, J.L. J. Neurochem., 69, pp. 780-790, 1997.

Methamphetamine-Induced Serotonin Neurotoxicity is Attenuated in p53 Knockout Mice

These results suggest that the tumor suppressor, p53, plays an important role in METH-induced serotonergic neurotoxicity in mouse brain. These data provide further evidence for a role of p53 in the neurotoxic effects of METH. Hirata, H., and Cadet, J.L. Brain Research, 768, pp. 345-348, 1997.

Kainate-induced Hippocampal DNA Damage is Attenuated in Superoxide Dismutase Transgenic Mice

Peripheral administration of kainic acid (KA) can cause cell death in the hippocampus of rodents. This is thought to involve oxidative stress. These results provide further support for the involvement of oxygen-based radicals in the toxic effects of KA. Hirata H., and Cadet J.L. Molecular Brain Research, 48, pp. 145-148, 1997.

Differential Toxic Effects of Methamphetamine (METH) and Methylenedioxymeth- amphetamine (mdrla) Knockout Mice

These observations document, for the first time, a role for these proteins in the entry of METH and MDMA into the brain via the blood-brain barrier, with P-glycoprotein possibly facilitating the entry of MDMA but interfering wit that of METH into the brain. Mann, H., Ladenheim, B., Hirata, H., Moran, H.T., and Cadet, J.L. Brain Research, 769, pp. 340-346, 1997.

Overexpression of Superoxide Dismutase and Catalase in Immortalized Neural Cells: Toxic Effects of Hydrogen Peroxide

These results indicate that h3O2 can lead to the activation of endonuclease enzyme that breaks DNA into oligosomes. These which overexpress catalase or SOD will help to determine the specific role of h3O2 or O2- in the deleterious effects of a number of toxins. Mann, H., McCoy, M.T., Subramaniam, J., Van Remmen, H., and Cadet, J.L. Brain Research, 770, pp. 163-168, 1997.

Delta Opioid Peptide DADLE Protects Myocardium Against Ischemic Insult

A brief exposure of isolated rabbit hearts to opioid peptide DADLE (2 mM for 15 min) before a global ischemic insult dramatically improved the functional recovery of myocardium. The protection provided by DADLE was far superior to the standard cardioplegic procedure (80% versus 30% functional recovery respectively). DADLE might be a useful agent in reducing myocardial damage and facilitating cardiac transplantation. Bolling, S.F., Su, T-P, Childs, K.F., Ning, X.H., Horton, N., Kilgore, K., and Oeltgen, P.R. The Use of Hibernation Induction Triggers for Cardiac Transplant Preservation. Transplantation, 63, pp. 326-329, 1997.

Bear Winter Plasma Protects Myocardium Against Ischemic Insult

Plasma obtained from winter hibernating bear was shown to protect isolated rabbit hearts against global ischemia. However, unlike the effect seen with an opioid peptide DADLE, the plasma had to be administered in vivo to the rabbit before the heart was excised. Bolling, S.F., Tramontini, N.L., Kilgore, K., Su, T-P, Oeltgen, P.R., and Harlow, H.H. The Use of "Natural" Hibernation Induction Triggers for Myocardial Protection. Ann. Thoracic Surg., 64, pp. 623-627, 1997.

An Opioid/Sigma Receptor?

In an attempt to purify non-opioid sigma receptors, we have instead purified a protein which resembles the opioid/sigma receptors originally proposed by Martin and coworkers. It binds benzomorphans, naloxone, morphine, and haloperidol with high affinities. The protein showed three bands in SDS/PAGE. Tsao, L-I and Su, T-P. A Naloxone-Sensitive, Haloperidol-Sensitive, [3H](+)SKF-10047-Binding Protein Partially Purified from Rat Liver and Rat Brain Membranes: An Opioid/Sigma Receptor? Synapse, 25, pp. 117-124, 1997.

Beneficial Effect of the Sigma Selective Ligand PRE-084 and Neurosteroids on the Impairment of Learning Induced after the Central Administration of ß25-35-Amyloid Peptide

PRE-084, a sigma ligand discovered at the NIDA IRP, improves learning and memory impairment induced by ß-amyloid peptide known to be related to Alzheimer's disease. As a continuing effort to demonstrate the memory-improving effect of a selective sigma receptor ligand PRE-084, discovered at the NIDA IRP, we examined if PRE-084 might affect the mnemonic deficit induced by the central injection of ß25-35- amyloid peptide which is known to be related to the Alzheimer's disease. PRE-084, like certain neurosteroids, dramatically improved the learning and memory impairment induced by the amyloid peptide. Maurice, T, Su, T-P, and Privat, A. Neuroscience, In Press.

Brain Imaging Section

Sex Difference in Up-regulation of Nicotinic Acetylcholine Receptors in Rat Brain

Male and female rats exhibit different neurochemical and pharmacologic responses to chronic nicotine. Recent declines in tobacco smoking have been less pronounced in women than in men and prompted an evaluation of sex differences in the effects of chronic nicotine administration and withdrawal on nicotinic acetylcholine receptor (nAChR) binding in the rat. Rats received nicotine or saline once a day for 15 days, and were killed either 1 or 20 days after discontinuing the chronic treatment. Male but not female rats receiving chronic nicotine had higher receptor densities than corresponding control groups; up-regulation of nAChRs was not seen 20 days after withdrawal. Further, in groups showing no up-regulation (controls and rats withdrawn for 20 days), nAChR densities were higher in female rats than males. The findings underscore the importance of sex differences in pharmacological responses as well as in basal neurochemical parameters. Koylu, E., Demirgoren, S., London, E.D., and Pogun, S. Life Sci., 61, pp. 185-190, 1997.

A New Detection Method for Measuring Binding to Central Nicotinic Acetylcholine Receptors in Living Animals Using a Simple Probe System

Central nicotinic acetylcholine receptors (nAChRs) are fundamental to brain function, and are affected by several neuropathological processes. Expensive imaging technologies that have been applied to the in vivo study of neurotransmitter receptors, such as nAChRs, in human subjects are not available to many investigators, but simpler radiation detector devices, called "probes", could be an alternative in vivo imaging method. NIDA researchers have now successfully used a simple probe procedure for labeling and monitoring nAChRs in the mouse brain using a radioiodinated analogue of the high affinity nicotinic agonist epibatidine, [125I]IPH. Intravenously administered [125I]IPH was taken up rapidly by nAChRs in the brain as verified by dissection experiments. Radioactivity had dissipated within 24 hours indicating no accumulation within the brain indicating that repeated studies can be performed with this radioligand on successive days. Liu, X., Musachio, J.L., Wagner, H.N. Jr., Mochizuki, T., Dannals, R.F., and London, E.D. External Monitoring of Cerebral Nicotinic Acetylcholine Receptors in Living Mice. Synapse, 24, pp. 378-380, 1997.

Exploitation of PET and SPECT Imaging Technology to Assess Specific Neurotransmitter Systems Holds Promise in Elucidating the Mechanisms Involved in Substance Abuse Disorders

An understanding of the neurobiological substrates of the maladaptive behaviors associated with substance abuse is essential for the development of effective treatments for this disorder. Noninvasive brain imaging provides a powerful approach to obtain the relevant information. It permits the in vivo assessment of brain structure and function, under different conditions that characterize various stages of an addictive cycle. Ernst, M., and London, E.D. Brain Imaging Studies of Drug Abuse: Therapeutic Implications. Semin. Neurosci., 9, pp. 120-130, 1997.

Comparison of LAAM, Morphine and Methadone in Suppression of the Opioid Withdrawal Syndrome

The effectiveness of LAAM treatment for opiate addiction is likely due to its own rapid onset of action and efficacy as well as to the equivalent efficacies and higher potencies of its nor and dinor metabolites. nor-LAAM and dinor-LAAM are active metabolites of the opiate l-alpha acetylmethadol, more commonly known as LAAM, and they are thought to primarily contribute to the prolonged actions of the parent compound. nor-LAAM, dinor-LAAM and LAAM were given intravenously to dogs to determine acute, single dose effects and their ability to suppress withdrawal. LAAM as well as its metabolites produced dose-dependent antinociception, decreases in body temperature, and pupillary constriction with dinor-LAAM being 1.5 - 3 times and nor-LAAM 6 - 12 times as potent as LAAM. Five hours after administering LAAM or either metabolite, a naltrexone injection produced withdrawal indicating the presence of acute physical dependence. In dogs physically dependent on morphine, nor-LAAM was 9 times as potent as either LAAM or dinor-LAAM in suppressing spontaneous withdrawal. The efficacies of LAAM and its demethylated metabolites in the dog for producing acute opiate effects were comparable to those of morphine and methadone. There was a trend, however, for LAAM to suppress the expression of abstinence more fully than either metabolite. Of additional interest was the finding that LAAM had a rapid onset of action in the dog, which did not differ from its active metabolites, demonstrating that the parent compound was pharmacologically active. Vaupel, D.B., and Jasinski, D.R. l-a-acetylmethadol, l-a-acetyl-N-normethadol and l-a- acetyl-N,N-dinormethadol: Comparisons with Morphine and Methadone in Suppression of the Opioid Withdrawal Syndrome. J. Pharmacol. Exp. Therap., 283, pp. 833-842, 1997.

Imaging Nicotinic Acetylcholine Receptors with Fluorine-18-FPH, An Epibatidine Analog

Successful imaging of nicotinic acetylcholine receptors (nAChRs) in the baboon brain suggests the radiotracer [18F]-FPH has the potential for imaging these receptors in the human brain. In vivo studies in mice with [3H]epibatidine, a high affinity nicotinic ligand, previously demonstrated a high brain uptake of the tracer, a regional distribution consistent with that of nAChRs, a slow clearance from brain and low nonspecific binding. This study characterized the in vivo distribution and kinetics of [18F]FPH, a fluorinated epibatidine radiotracer, binding to nAChRs in the baboon brain using positron emission tomography. Radioactivity was in the thalamus and hypothalamus/midbrain, intermediate in the neocortex and hippocampus and lowest in the cerebellum and this regional binding pattern was highly correlated with the known densities of nAChRs measured inv vitro in human and rat brain. [18F]FPH appears to be a suitable tracer to study nAChRs in the human brain. Villemagne, V.L., Horti, A., Scheffel, U., Ravert, H.T., Finley, P., Clough, D., London, E.D., Wagner, H.N. Jr., and Dannals, R.F. J. Nucl. Med., 38, pp. 1737-1741, 1997.

Importance of the Prefrontal Dopamine Pathway Emerges from Study of Autistic Children

Using positron emission tomography, the accumulation of [18F]Fluorodopa was measured in the head of the caudate nucleus, putamen, ventral tegmental complex, and prefrontal and occipital cortices of 14 autistic (13.12.4 years; 8 males/6 females) and 10 healthy children (14.92.0 years; 7 males/3 females). Autistic children showed abnormally low dopaminergic activity only in the anterior medial prefrontal cortex, a region involved in cognitive and emotional processes. This finding stresses the importance of studies that address the development and maintenance of the medial prefrontal dopamine pathway and its role in cognitive tasks known to be altered in autism and mediated by the prefrontal cortex. Ernst, M., Zametkin, A.J., Matochik, J.A., Pascualvaca, D., and Cohen, D.M. Low Medial Prefrontal Dopaminergic Activity in Autistic Children. The Lancet, 350, p. 638, 1997.

Functional Interactions Between Sex and Brain Development May Contribute to Attention-Deficit /Hyperactivity Disorder (ADHD) Pathophysiology

Using positron emission tomography and [18F]fluorodeoxyglucose (FDG), glucose cerebral metabolic rates (CMRglc) were compared between 10 Attention-Deficit/Hyperactivity Disorder (ADHD) (14.101.91 years) and 11 normal girls (14.31.70 years). Lateralization of normalized CMRglc differed significantly between ADHD and control girls in parietal and subcortical regions. The sylvian area of the parietal region and the anterior putamen of the subcortical region were the main contributors to this effect. Normalized CMRglc of the hippocampus was higher in ADHD than in control girls. Sexual maturation correlated negatively with global CMRglc. This study suggested that (1) functional interactions between sex and brain development may contribute to ADHD pathophysiology, and that (2) sexual maturation should be controlled in future CMRglc studies of adolescent girls. Ernst, M., Cohen, R.M., Liebenauer, L.L., Jons, P.H., and Zametkin, A.J. Cerebral Glucose Metabolism In Adolescent Girls With Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 36, pp. 1399-1406, 1997.

Dextroamphetamine Facilitates Activation of Task-Related Regional Glucose Metabolism in the Brain and Reduces Activation of Glucose Metabolism Activated by Irrelevant Stimuli

The effects of intravenous dextroamphetamine on cerebral glucose metabolism were assayed by positron emission tomography (PET) and [18F]fluorodeoxy-glucose (FDG) in 13 healthy adults during the performance of a continuous visual attention task. Subcortical, limbic, frontal and cerebellar regional cerebral metabolic rates for glucose metabolism (rCMRglc) were significantly increased after dextroamphetamine, while rCMRglc of the temporal cortex significantly decreased. These rCMRglc changes reflect both the direct pharmacological effect of dextroamphetamine on monoaminergic neurotranmitter systems as well as enhancement of the activation of the neural network mediating the performance of the continuous attention task. Ernst, M.E., Zametkin, A.J., Matochik, J., Schmidt, M., Jons, P.H., Liebenauer, L.L., Hardy, K.K., and Cohen, R.M. Intravenous Dextroamphetamine and Brain Glucose Metabolism. Neuropsychopharmacology, 17, pp. 391-401, 1997.

Newly Synthesized Radiotracer [18F]FPH Labels Nicotinic Acetylcholine Receptors in the Central Nervous System will Benefit the Localization and Quantitation in Pathological States

Visualization of central nicotinic acetylcholine receptors (nAChRs) using modern imaging techniques has been hampered by the lack of a radioligand with suitable in vivo binding properties. This has led to the synthesis of a highly potent 18F labeled analog of epibatidine ([18F]FPH) and the assessment of its in vivo binding, kinetics and pharmacology in mouse brain. The rapid association of the tracer to nAChRs in receptor-rich areas and rapid egress from receptor-poor areas yielded high ratios of specific-to-nonspecific binding. [18F]FPH and PET should prove useful for the localization and quantitation of nicotinic AChRs in normal physiological conditions and pathological states. Horti, A., Scheffel, U., Stathis, M., Finley, P., Ravert, H.T., London, E.D., and Dannals, R.F. Fluorine-18-FPH for PET Imaging of Nicotinic Acetylcholine Receptors. J Nuc Med, 38, pp. 1260-1265, 1997.

Preclinical Pharmacology Branch
Psychobiology Section

A Novel Photoaffinity Label for the Dopamine Transporter Based on N-Substituted-4', 4"-Difluoro-3a-(diphenylmethoxy)tropane

DIR scientists have recently synthesized a novel photoaffinity label based on an N-butylphenyl- 4,4- difluorobenztropine analog that demonstrates high affinity and selectivity for the dopamine transporter. This compound combines structural features of both cocaine and GBR 12909 and was radiolabeled with 125I. In collaboration with Roxanne Vaughan, using immuno-precipitation techniques it was discovered that this compound photolabels the dopamine transporter and is currently being used in DAT topologic characterization studies. A rapid communication on this finding was recently published. Agoston, G.E., Vaughan, R., Lever, J.R., Izenwasser, S., Terry, P.D. and Newman, A.H. Bioorg. Med. Chem. Lett. 7, pp. 3027-3032, 1997.

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