AIDS, DRUGS OF ABUSE, AND THE NEUROIMMUNE AXIS

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY

Editorial Board:

NATHAN BACK, State University of New York at Buffalo

lRUN R. COHEN, The Weizmann Institute of Science

DAVID KRITCHEVSKY, Wistar Institute

ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research

RODOLFO PAOLETTI, University of Milan

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Volume 402 AIDS, DRUGS OF ABUSE, AND THE NEUROIMMUNE AXIS

Edited by Herman Friedman, Toby K. Eisenstein, John Madden, and Burt M. Sharp

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AIDS~ DRUGS OF ABUSE~ AND THE NEUROIMMUNE AXIS

Edited by

Herman Friedman University of South Florida College of Medicine Tampa, Florida

Toby K. Eisenstein Temple University School of Medicine Philadelphia, Pennsylvania

John Madden Emory University Atlanta, Georgia

and

Burt M. Sharp Minneapolis Medical Research Foundation Minneapolis, Minnesota

PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging-in-Publication Data

AIDS, drugs of abuse, and the neuroimmune axis! edited by Herman Friedman ... ret al.].

p. em. -- (Advances in experimental mediclne and biology 402)

"Proceedings of the Third Annual Symposium on AIDS, Drugs of Abuse. and the NeurOlmmune Axis, held November 9-11, 1995. in San Diego. California"--T.p. verso.

Includes bibl iographical references and index. ISBN -13: 978-1-4613-8038-2 e-ISBN -13: 978-1-4613-0407-4 DOl: 10.1007/978-1-4613-0407-4

v.

1. AIDS (Disease)--Etiology--Congresses. 2. AIDS (Disease)--Risk factors--Congresses. 3. Neuroimmunology--Congresses. 4. Drug abuse--Immunological aspects--Congresses. 5. Drugs of abuse­-Immunology--Congresses. 6. Immunosuppression--Congresses. I. Friedman, Herman, 1931- II. Symposium on AIDS, Drugs of Abuse, and the Neuroimmune Axis (3rd 1995 San Diego, Calif.) III. Series.

[DNLM, 1. Immune System--drug effects--congresses. 2. Immunosuppression--congresses. 3. Neuroimmunomodulation--drug effects--congresses. 4. Acquired Immunodeficiency Syndrome­-immunology--congresses. 5. Substance Abuse--complications--congresses, 6. Street Drugs--congresses. WI AD559 v.402 1996 !

OW 504 A288 1996J RC607.A26A3457337 1996 616.97'92071--dc20 DNLM/DLC for Library of Congress 96-25725

CIP

Proceedings of the Third Annual Symposium on AIDS, Drugs of Abuse and the Neuroimmune Axis, held November 9 - 11, 1995, in San Diego, California

ISBN- 13:978-1-4613-8038-2

© 1996 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1996

A Division of Plenum Publishing Corporation 233 Spring Street, New York, N. Y. 10013

109876'54321

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

PREFACE

This volume represents the Proceedings of the Symposium on AIDS, Drugs of Abuse and the Neuroimmune Axis. This meeting was held in San Diego, California, November 11-13, 1995. As in the previous symposia in this series, productive studies were reviewed concerning the relationship between the nervous and the immune systems in regards to the relationship between drugs of abuse and infections, especially infections by the immunode­ficiency virus that causes AIDS. In recent years, various investigators have begun to describe the role of illicit drugs and their endogenous counterparts on the brain-immune axis. It is widely recognized that the neuroendocrine system is intimately involved in the effects and manifestations of the interactions of drugs of abuse and the immune system. The meeting on which the chapters in this book are based brought together many biological scientists from an array of various scientific disciplines whose work is focused on the effects of drugs of abuse on the neuroendocrine-immune axis and its relationships to immunodeficiency caused by the AIDS virus. As in the past, the symposium was unique in focusing on the .brain-immune axis from the viewpoint of drugs of abuse rather than from the viewpoint of immunity or the brain itself. One ofthe aims of this series of conferences was to clarify the consequences of immunomodulation induced by drugs of abuse on susceptibility and pathogenesis of infectious diseases in various model systems, including those associated with the AIDS virus. The recreational use of drugs of abuse, such as morphine, cocaine and marijuana, as well as alcohol, by large numbers of individuals in this country and around the world has aroused serious concern about the consequences of use of such drugs. For example, it is widely known that marijuana is used by tens of millions of individuals in this country and abroad. Furthermore, use of cocaine, especially crack cocaine, is now considered to be epidemic, as well as the use of other illicit recreational drugs. Alcoholism is also considered a major problem in this country, as well as elsewhere, and it is estimated there are at least 10 million alcoholics in the U.S.A. alone. A significant proportion of those individuals hospitalized for infectious diseases are known to be alcoholics. Recently there have been reports of association between use of drugs such as marijuana and cancer. Such observations encourage laboratory studies aimed at determining the nature and mechanism of how these drugs affect the immune system, as well as the neuroendocrine system which, in tum, has effects on immunity.

There are now very strong concerns that if drugs of abuse are indeed immunosup­pressive, individuals who use such drugs may be prone to infectious diseases and develop increased mortality to such infections. Although many investigators believe that acute infections are not directly associated with use of drugs of abuse, there are suggestive clinical observations indicating that chronic diseases, including infections, may be more frequent in drugs abusers. It is also now widely accepted that many illicit drugs, including marijuana, morphine, and cocaine, as well as alcohol, detrimentally influence the immune response.

v

vi Preface

With the onset of the AIDS epidemic in the United States and worldwide, attempts have been made to search for possible "co-factors" which interact with the human immunodeficiency virus. It is known that approximately one fifth of all AIDS patients in this country are i.v. drug abusers and it has been shown that the AIDS virus is readily spread by contaminated needles or equipment used by such drug abusers. In addition, in many instances, these drugs are now known to be immunosuppressive. However, it is also well known that many AIDS patients are not Lv. drug abusers but are known to utilize other drugs such as marijuana and cocaine. Thus there is a probability that such drugs may indeed act as cofactors in AIDS progression, and therefore, there has been a concerted effort to examine in detail the mechanisms whereby such drugs may compromise the immune system in general.

It is widely acknowledged that the immune system of humans is continually exposed to a variety of environmental agents and toxic substances. Drugs of abuse are known to consitute one of many such groups of toxic agents. As reported in this symposium by various investigators, drugs of abuse may impact and modulate the function of the imm~ne system either directly or by effects on the neuroendocrine system. Although many of the drug-in­duced alterations in immune and neuroendocrine functions have been defined, there is still much to be learned concerning the molecular and cellular basis for these changes. Further­more, the acute and chronic public health implications of the effects of such drugs on immunity and increased risks for infections are not fully appreciated. The first section of this book contains summaries of presentations at the meeting concerning the effect of opiates, including morphine, on the brain-immune axis and the immune response, as well as effects on altering susceptibility to HIV infection, including AIDS in monkey models. On the other hand, there has been an explosion of interest concerning receptors for opiates on brain cells as well as on lymphoid cells. Pharmacological characterization of such opiate receptors has been well studied and some of the papers presented discuss such receptors and the antagonists for these receptors.

The second section of the symposium summarized newer information concerning cannabinoids and immunity. The first receptor for cannabinoids found on immune cells was recently described, as well as the ligand for such receptors. The effect of cannabionoids on immunity to infectious organisms as well as the effect of such cannabinoids on the biochem­istry and cytokine formation by immune cells was also discussed. The third section of the book summarizes some of the presentations concerning the effects of cocaine on immunity, including effects of cocaine on the function of immune cells, including macrophages, as well as production of cytokines by lymphocytes and macrophages treated with cocaine. The effect of alcohol on HIV infection, as well as summaries of effects of other drugs, including isobutyl nitrate, on immune cells is also presented. Studies concerning cytokines in immunity and AIDS as affected by drugs of abuse are also presented. There were several workshops presented at the symposium as well as a panel discussion concerning drugs of abuse and progression of AIDS.

It is the hope of the organizers of this series of conferences, including the conference in San Diego on which this proceedings is based, as well as the editors of the proceedings that these publications will further inspire interest in this rapidly developing field of biomedical science and result in a better understanding of the impact of drugs of abuse on the brain-immune axis and their relationship to immunodeficiency, especially that caused by the AIDS virus. It is anticipated that future meetings on the subject will be held periodically and publication of the proceedings of these conferences will continue to stimulate interest in the field of the brain-immune axis and substance abuse. The authors thank the organizing committee and its administrator, Ms. Suzanne Ingalls, for invaluable assistance that contrib­uted to the success of the symposium. The editors also thank Ms. Ilona Friedman for invaluable assistance as editorial coordinator and managing editor for preparation of this volume of the symposium proceedings. We also thank the National Institute for Drug Abuse

Preface vii

for financial support and Dr. Charles Sharp, Project Director ofNIDA for Immunology, for continuing interest and valuable advice.

H. Friedman T. K. Eisenstein J. Madden B. M. Sharp

CONTENTS

1. AIDS, Drugs of Abuse and the Neuroimmune Axis: Introduction and Perspectives .................................................. .

Herman Friedman

2. The Effect of Novel Opioids on Natural Killer Activity and Tumor Surveillance in Vivo ....................................................... 5

Daniel J. J. Carr, Mace Scott, Linda L. Brockunier, Jerome R. Bagely, and Charles P. France

3. Kappa Opioid Receptors on Immune Cells as Studied by Fluorescent Ligands .. 13 Jean M. Bidlack, Diane M. P. Lawrence, and Tracey A. Ignatowski

4. Presence of Opiate Alkaloid-Selective ~3 Receptors in Cultured Astrocytes and in Brain and Retina ................... _. . . . . . . . . . . . . . . . . . . . . . . . .. 23

M. H. Makman, K. Dobrenis, S. Downie, W. D. Lyman, and B. Dvorkin

5. Opiates, Glia, and Neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 29 Chun C. Chao, Shuxian Hu, and Phillip K. Peterson

6. Morphine Affects the Brain-Immune Axis by Modulating an Interleukin-l Beta Dependent Pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 35

Sulie L. Chang, Roberta L. Moldow, Steve D. House, and James E. Zadina

7. Opioid Dependency and the Progression of Simian AIDS: Mortality and Behavioral Observations ........................... ',' . . . . . . . . . . .. 43

Keith F. Killam, Jr., Linda F. Chuang, and Ronald Y. Chuang

8. Endogenous Opioids and HIV Infection ............................... " 53 Kamaraju S. Sundar, Lakshmi S. Kamaraju, James McMahon,

Robert A. Bitonte, Sastry Gollapudi, William H. Wilson, Ling-yuan Kong, John S. Hong, and James E. Lee

9. Methionine Enkephalin Used in Combination with Azidothymidine in Murine Retrovirus Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59

Steven Specter, Nicholas Plotnikoff, Jeong-1m Sin, and Darlene Goodfellow

10. On the Evolution of Opioid Mechanisms and Immune Defenses ............ " 63 Fernando L. Renaud and Enid Z. Tomei

ix

x Contents

11. Purification and Characterization of a Secreted T-Cell J3-Endorphin Endopeptidase .................................... . . . . . . . . . . . .. 71

Afshin Safavi, Bonnie C. Miller, Louis B. Hersh, and G. Larry Cottam

12. Effects of Centrally Administered Opioid Agonists on Macrophage Nitric Oxide Production and Splenic Lymphocyte Proliferation . . . . . . . . . . . . . .. 81

Gabrielle M. Schneider and Donald T. Lysle

13. Prenatal Morphine Exposure Interacts with Adult Stress to Affect Type and Number of Blood Leucocytes .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 89

James T. Martin, Sandra L. Nehlsen-Cannarella, Gary M. Gugelchuk, and Omar Fagoaga

14. Endogenous Cannabinoid Ligands ..................................... 95 R. Mechoulam, S. Ben Shabat, L. Hanus, E. Fride, M. Bayewitch, and

z. Vogel

15. Cannabinoids and Immunity to Legionella pneumophila Infection ............ 103 Thomas W. Klein, Cathy Newton, and Herman Friedman

16. Cannabinoids and Interleukin-6 Enhance the Response to NMDA in Developing CNS Neurons ........................................ III

D. L. Gruol, J. G. Netzeband, Z. Qiu, 1. L. Campbell, and K. L. Parsons

17. Cannabinoid Receptor Expression in Immune Cells ........................ 119 D. A. Dove Pettit, D. L. Anders, M. P. Harrison, and G. A. Cabral

18. Cannabinoids and Immunity to Viruses .................................. 131 Steven Specter

19. Alteration of Macrophage Functions by Cocaine .......................... 135 S. S. Lefkowitz, A. Vaz, 1. Lincoln, T. Cain, D. J. Brown, and

D. L. Lefkowitz

20. Divergent Effects of Cocaine on Cytokine Production by Lymphocytes and Monocyte/Macrophages: HIV-l Enhancement by Cocaine within the Blood-Brain Barrier ............................................. 145

A. M. Fiala, X.-H. Gan, T. Newton, F. Chiappelli, P. Shapshak, V. Kermani, M. A. Kung, A. Diagne, O. Martinez, D. Way, M. Weinand, M. Witte, and M. Graves

21. Effects on Mouse Thymocyte Biology: A Mini-Overview with Some New Evidence ..................................................... 157

David W. Ou, Mei-ling Shen, and Ken M. Anderson

22. Immunopathogenesis of HI V Infection: Role of Alcohol and HIV Peptides ..... 165 Madhavan P. N. Nair and Stanley A. Schwartz

Contents xi

23. HIV-l Neuropathogenesis and Abused Drugs: Current Views, Problems, and Solutions ..................................................... 171

P. Shapshak, K. A. Crandall, K. Q. Xin, K. Goodkin, R. K. Fujimura, W. B,radley, C. B. McCoy, I. Nagano, M. Yoshioka, C. Petito, N. C. J. Sun, A. K. Srivastava, N. Weatherby, R. Stewart, S. Delgado, A. Matthews, R. Douyon. K. Okuda, J. Yang, B. T. Zhang 1 , X. R. Cao, S. Shatkovsky, J. B. Fernandez, S. M. Shah, and J. Perper

24. Inhaled Isobutyl Nitrite Produced Lung Inflammation with Increased Macrophage TNF-a. and Nitric Oxide Production ..................... 187

L. S. F. Soderberg, L. W. Chang, and J. B. Barnett

25. Cytokine Action in the Nervous System at Pathophysiological versus Pharmacological Concentrations ................................ ' .. 191

Carlos R. Plata-Salaman

26. Behavioral and Neurophysiological Effects ofCNS Expression ofCytokines in Transgenic Mice ............................................... 199

Lisa H. Gold, Charles J. Heyser, Amanda J. Roberts, Steven J. Henriksen, Scott C. Steffensen, George R. Siggins, Frederick P. Bellinger, Chi-Shiun Chiang, Henry C. Powell, Eliezer Masliah, and lain L. Campbell

27. ILl Beta Impairs Relational but not Procedural Rodent Learning in a Water Maze Task .................................................... 207

Michael Gibertini

28. TNFa.: A Neuromodulator in the Central Nervous System ................... 219 Tracey A. Ignatowski, Bernice K. Noble, John R. Wright, Janet L. Gorfien,

and Robert N. Spengler

29. Drugs of Abuse as Possible Co-Factors in AIDS Progression: Summary of Panel Discussion ............................................... 225

H. Friedman

Index ................................................................. 229