Review
Cocaine pharmacology and current pharmacotherapies for its abuse

https://doi.org/10.1016/j.bmc.2004.06.018Get rights and content

Abstract

Cocaine abuse continues to be prevalent and effective therapies for cocaine craving and addiction remain elusive. In the last decade immunopharmacotherapy has been proposed as a promising means to alleviate this illness. By using the organism's natural immune response, an anti-cocaine vaccine promotes the production of cocaine-specific antibodies that sequester the drug before their passage into the brain, where it exerts its reinforcing and thus addictive effects. A series of studies demonstrating the cocaine-blocking properties of various immunogenic conjugates will be reviewed in the context of the neuropsychopharmacological profile of the drug.

Introduction

Cocaine abuse has produced a major epidemic health problem in North America in the 1980s, and has since become a serious medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine.1

The abuse of cocaine is maintained by the drug's effects on brain reward systems, and mediated at least in part by its dopaminergic action. The patterns and consequences of use are best understood by considering the pharmacokinetics (rapid absorption and delivery to the brain, relatively short half-life) and the pharmacodynamics (intense central and peripheral neural stimulation). Cocaine is used therapeutically as a topical and local anesthetic. Toxicity occurs primarily in cocaine abusers, but also occasionally after therapeutic dosing. Medical complications reflect primarily excessive central nervous system (CNS) stimulation and excessive vasoconstriction, the latter resulting in severe hypertension and/or organ ischemia with associated organ injury. Most deaths that result from medical complications of cocaine intoxication are sudden and occur before medical intervention is possible. Other complications of cocaine abuse with severe personal and social consequences include traumatic deaths and injuries, and reproductive disturbances, as well as transmission of infectious diseases, especially AIDS. Cocaine addiction represents a serious social and health problem, which has led the National Institute on Drug Abuse (NIDA) to urge the scientific research community for the development of an effective pharmacological treatment for this condition. However, pharmacotherapies of cocaine addiction that typically target the monoaminergic neurochemical substrates implicated in its reward properties, have as yet been unsuccessful, and often generate adverse side effects.2

Over the last decade, an alternate line of research has emerged aimed at treating cocaine addiction using immunological reagents and the immune system to peripherally block the effects of the drug. This approach addresses key components that constitute an effective treatment venue, such as a significant decrease of the rapidity of cocaine permeation into the brain while circumventing unwanted side effects. Early work demonstrated that antibodies specific for haptenic drugs were feasible and that they were useful in the attenuation of their effects.3 In this study, a rhesus monkey trained to self-administer heroin and cocaine was immunized with a morphine hemisuccinyl-bovine serum albumin conjugate, that resulted in the gradual and selective extinction of heroin self-administration. Twenty years later, interest in this area was renewed with the first successful report describing effective blockade of the psychostimulant effects of cocaine by active immunization in rats.4 The approach is based on the premise that cocaine by itself is not an immunogenic molecule, and as such cannot produce an immune response. However, if conjugated with an immunogenic carrier molecule, administration of the conjugate would induce the immune system to produce antibodies against cocaine. Therefore, anti-cocaine antibodies induced by a cocaine vaccine, by inhibiting the entry of cocaine into the brain, will inhibit the ability of cocaine to interact with all of its targets in the CNS. The specificity of the cocaine vaccine for the drug, rather than for its target, should also minimize interference with other therapies. Also, a therapeutic vaccine based on active immunization has the potential to provide long-lasting clinical efficacy for relapse prevention after administration and to have minimal problems with compliance in humans who are motivated to stop using cocaine.

The advent of new technologies for monoclonal antibody production and for creating highly specific human antibodies has brought these proteins into the realm of clinical evaluation. This alternative offers the immunotherapeutic application of passive transfer for the treatment of cocaine overdose. Other groups, as well as our own group, have explored alternate protein-based therapies involving the destruction of cocaine before it has a chance of reaching the brain such as murine monoclonal catalytic antibodies,[5], [6], [7] and cocaine metabolism enhancement with butyrylcholinesterase.8

This review focuses primarily on the development and testing of the immunotherapeutic reagents reported over the last decade. First, a general overview of cocaine neuropharmacology and pharmacotherapeutic research to date will be presented. Next, we offer a perspective on the challenges to be faced in the successful application of the immunotherapeutic technologies thus far developed. Finally, other protein-based, nonpharmacological cocaine blockers will be explored.

Section snippets

Cocaine pharmacology

Cocaine is obtained from coca leaves (containing between 0.6% and 1.8% alkaloidal cocaine) using a relatively simple method by which it is extracted from the leaves with an organic solvent (often kerosene), resulting in a coca paste containing about 80% cocaine. The alkaloids are passed through an acidic aqueous solution based on hydrochloric acid; the solution is neutralized and the cocaine is extracted by recrystalization. Cocaine hydrochloride (HCl) is the pharmaceutical form used as a local

Cocaine neuropharmacology

The two main health-hazards associated with cocaine consumption are the abuse of the drug and the toxicity/lethality as a result of overdose. The neuropharmacology of both of these conditions focuses on the actions of cocaine upon the discrete aspects of the CNS and disruptions of cerebral blood flow. The effects of cocaine on the CNS and on cerebral blood flow are complex and only partly understood. Cocaine alters synaptic transmission by interacting with the plasma membrane transporters for

Current pharmacotherapies

The development of pharmacotherapy for cocaine addiction is based on previous strategies designed to alleviate other chemical dependencies such as alcoholism and opiate addiction, focusing on the neurobiological and the behavioral bases of addiction.36 To date, no pharmacotherapy has been approved by the U.S. Food and Drug Administration for cocaine dependence, but two major classes of medications have been investigated: (1) dopaminergic agents and (2) antidepressants. Studies have been

Induction of the immune response

The importance of natural immunity has been widely recognized and defined by the generation or presence of protective, therapeutic antibodies to infectious or foreign agents.[83], [84], [85] Antibody responses make up the humoral response, and immune protection from disease can be passively transferred through serum containing antibodies. Antibodies represent a dominant class of serum proteins; reaching 10 mg/mL in the serum following immunization or during the course of severe chronic

Anti-cocaine haptens developed and preclinical studies

In the last 10 years, a new therapeutic strategy against cocaine abuse has been explored. This approach entails the synthesis of a therapeutic cocaine vaccine that induces the production of anti-cocaine antibodies. This immunogenic response is hypothesized to bind peripherally circulating cocaine, forming a large molecular complex, impenetrable through the blood–brain barrier, thus impeding its passage into the CNS, where the drug exerts its addictive effects. As a result, the reinforcing value

Other nonpharmacological cocaine-blocking agents

In addition to both active immunization and passive administration of monoclonal antibodies used to develop potential protein-based therapies for cocaine addiction, other approaches involving peripheral modifications to the cocaine molecule have been explored. One such approach entails the destruction of cocaine before it has a chance of reaching the brain. An alternative form of passive immunization is the passive transfer of monoclonal catalytic antibodies that bind cocaine and subsequently

Conclusion

Advances in our understanding of the underlying biology of cocaine addiction are affording new venues to procure the development of a still elusive effective therapy against this disease. Undoubtedly, the greatest challenge in this scientific endeavor is the inherent multifaceted nature of cocaine abuse with its complex psychosocial and neuropharmacological components. Immunotherapeutic strategies described herein offer a means with which to safely and effectively address relapse behavior, the

Acknowledgements

The authors would like to thank Prof. George Koob and his laboratory members for many years of pleasant and outstanding collaboration, Dr. Tobin Dickerson for his assistance in editing this manuscript and Mr. Edward Fishwick for his valuable contribution for the completion of this work. The work by the Janda laboratory reported in this review was supported in part by The Skaggs Institute for Chemical Biology and the National Institute on Drug Abuse Grants DA015700, DA08590, and DA016478.

Kim D. Janda was born 23 August 1957 in Cleveland, Ohio. He obtained his B.S. degree in clinical chemistry from the University of South Florida (1980) and his Ph.D. in organic chemistry from the University of Arizona (1984). He joined The Scripps Research Institute in 1985 as a postdoctoral fellow and, in 1987, was promoted to the faculty, where he is currently the Ely R. Callaway, Jr. Professor of Chemistry. His research interests include catalytic antibodies, polymer supported methodologies,

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    Kim D. Janda was born 23 August 1957 in Cleveland, Ohio. He obtained his B.S. degree in clinical chemistry from the University of South Florida (1980) and his Ph.D. in organic chemistry from the University of Arizona (1984). He joined The Scripps Research Institute in 1985 as a postdoctoral fellow and, in 1987, was promoted to the faculty, where he is currently the Ely R. Callaway, Jr. Professor of Chemistry. His research interests include catalytic antibodies, polymer supported methodologies, combinatorial chemistry/phage display systems, immunopharmacotherapy for the treatment of drug abuse and cancer, physiologically relevant reactivity of nicotine metabolites, protein–protein interactions, and quorum sensing. He is the recipient of an Alfred P. Sloan fellowship (1993–1995) and the Arthur C. Cope Scholar award (1999).

    Michael M. Meijler was born 12 December 1970 in Amsterdam, The Netherlands. He earned his M.Sc. degree in chemistry from the University of Amsterdam (1996), where he worked with Prof. Gerrit-Jan Koomen on the synthesis of brominated indole alkaloids. He interrupted his M.Sc. project in the winter of 1995 to work with the late Professor David Sigman at the University of California, Los Angeles, on the mechanism of DNA scission by chemical nucleases. He then moved to Israel to work with Professor Abraham Shanzer at the Weizmann Institute of Science on the synthesis and evaluation of siderophore analogs. After receiving his Ph.D. in 2002, he joined the group of Professor Kim D. Janda at The Scripps Research Institute, where his main research interests are in the area of bioorganic chemistry, and the interplay between synthetic organic chemistry, microbiology, and immunology.

    M. Rocı́o A. Carrera was born 29 December 1964 in Acapulco, Mexico. She earned her M.A. degree in psychology form the University of California San Diego (1991), working on the biological basis of ingestive behavior with Dr. Anthony J. Deutsch, specifically the satiety properties of cholecystokinin. She continued her training with Dr. George F. Koob at The Scripps Research Institute where she was aptly trained in neuropsychopharmacological assays to investigate the neural mechanisms of various drugs of abuse, including cocaine, heroin, cannabinoids, nicotine, and amphetamine. Currently she has a predoctoral fellowship from NIDA and is a graduate student in Professor Kim D. Janda's laboratory. Her research interests have spanned the field of immunopharmacotherapy, specifically with regards to cocaine abuse, her main research interest to date.

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