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  • Review Article
  • Published:

Translational research in medication development for nicotine dependence

Nature Reviews Drug Discovery volume 6, pages 746–762 (2007)Cite this article

Key Points

  • Nicotine dependence is a major public health problem. Food and Drug Administration (FDA)-approved medications include nicotine-replacement therapies, bupropion and varenicline. Yet, only about 1 in 4 smokers are able to quit and remain abstinent for 1 year or more.

  • Significant progress in elucidating the molecular neurobiology of nicotine dependence has identified several mechanistic targets for translational research in medication development. These include, but are not limited to, dopaminergic, GABA (g-aminobutyric acid)-mediated, glutamatergic and opioid processes; intracellular signalling molecules (CREB (cyclic AMP response element binding), ΔFosB); and nicotinic cholinergic receptors.

  • The lack of validated animal and human laboratory paradigms that have demonstrated predictive clinical validity is a major obstacle to the development of improved medications for nicotine dependence. Scientists in academic institutions and industry can and should contribute to medication development for drug dependence by addressing this critical gap.

  • In animals and humans, the reinforcing value of drugs of abuse, including nicotine, can be assessed using self-administration models. Reward, a concept related to but different from reinforcement, can be measured in animals using conditioned place preference and intracranial self-stimulation paradigms. In humans, drug reward is measured using self-report assessments.

  • The negative-reinforcing effects of drugs of abuse focus on the alleviation of physiological, affective and neurocognitive signs of drug withdrawal in dependent subjects. Although many models exist to assess these variables, few have been tested for predictive clinical validity for medication screening.

  • Relapse is a central concept in drug dependence. In animals this is typically assessed using reinstatement models. Novel paradigms are also being developed for assessing medication effects on relapse in the human laboratory setting.

  • Animal and human laboratory models require further validation if they are to be used to optimize medication development. Ideally, these models should provide an early indication of the likely efficacy of a medication before proceeding to more costly clinical trials. One opportunity to address model validation would be to examine medications with proven efficacy for smoking cessation across each of the animal and human laboratory models.

Abstract

A major obstacle to the development of medications for nicotine dependence is the lack of animal and human laboratory models with sufficient predictive clinical validity to support the translation of knowledge from laboratory studies to clinical research. This Review describes the animal and human laboratory paradigms commonly used to investigate the pathophysiology of nicotine dependence, and proposes how their predictive validity might be determined and improved, thereby enhancing the development of new medications.

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Figure 1: An illustration of the substantial lack of comparison of treatment-relevant compounds across animal behavioural pharmacological and human laboratory paradigms.

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Acknowledgements

The authors are grateful to A. Chausmer of the Division of Basic Neuroscience and Behavioural Research at the National Institute on Drug Abuse for helping to organize us as a group, and for reading and commenting on the manuscript. We also thank P. Olausson, R. Ray, M. Sofuoglu and A. Strasser for their helpful input, and M. Foster for her assistance with the manuscript preparation. This work was supported in part by Transdisciplinary Tobacco Use Research Center grants from the National Cancer Institute, the National Institute on Drug Abuse, and National Institute on Alcohol Abuse and Addiction (P50CA84718 to C.L.; P50AA15632 to S.O.M.; P50DA013333 to D. Hatsukami, which partially supports M.G.L.), and by other grants (KO5AA014715 to S.O.M.; R01DA020136 to M.G.L.).

Author information

Authors and Affiliations

  1. Department of Psychiatry and Abramson Cancer Center, University of Pennsylvania, 3535 Market Street, Suite 4100, Philadelphia, 19104, Pennsylvania, USA

    Caryn Lerman

  2. Minneapolis Medical Research Foundation, 914 South 8th Street, Minneapolis, 55404, Minnesota, USA

    Mark G. LeSage & William A. Corrigall

  3. WPIC University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, 15213, Pennsylvania, USA

    Kenneth A. Perkins

  4. Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, 06519, Connecticut, USA

    Stephanie S. O'Malley

  5. Department of Psychiatry, Translational Research Laboratories, Room 2223 University of Pennsylvania, 125 South 31st Street, Philadelphia, 19104, Pennsylvania, USA

    Steven J. Siegel

  6. Department of Medicine, University of California San Francisco, BOX 1220, San Francisco, 94110, California, USA

    Neal L. Benowitz

  7. Department of Psychiatry, University of Minnesota, F282/2A West, 2450 Riverside Avenue, South Minneapolis, 55454, Minnesota, USA

    William A. Corrigall

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  1. Caryn Lerman
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  2. Mark G. LeSage
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  3. Kenneth A. Perkins
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  4. Stephanie S. O'Malley
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  5. Steven J. Siegel
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  6. Neal L. Benowitz
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  7. William A. Corrigall
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Corresponding authors

Correspondence to Caryn Lerman or William A. Corrigall.

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Competing interests

C.L. has served as a consultant/advisor to Astra Zeneca, GlaxoSmithKline, Pfizer and Cephalon regarding medications for nicotine dependence.

M.L. has conducted research that has been funded by GlaxoSmithKline.

K.P. has previously consulted with GlaxoSmithKline, Elan and Pfizer.

S.O'M. has received research support, principally clinical supplies or contracts as a study site, from Alkermes, Bristol–Myers Squibb, Lipha–Merck, GlaxoSmithKline, Pfizer, Ortho–McNeil and Sanofi–Aventis, and has served as a consultant for Eli Lilly, Ortho–McNeil, GlaxoSmithKline, She is an inventor on patents held by Yale University for naltrexone for smoking cessation.

S.S. has served as a consultant to NuPathe developing drug delivery technologies and has conducted research related to nicotine receptor pharmacology that has been funded by AstraZeneca.

N.B. has served as a consultant to several pharmaceutical companies that market smoking cessation medications, specifically Pfizer and GlaxoSmithKline.

W.C. is the sole proprietor of a science consulting business in which a current contract with the National Institute on Drug Abuse includes activities related to the Transdisciplinary Tobacco Use Research Centers and the National Cooperative Drug Discovery Groups (in the case of the latter, he has reseach discussions with the pharmaceutical industry partners involved in the initiative, but not for additional remuneration). In addition, he has served as a consultant/advisor to, and/or conducted research funded by Cantab, GlaxoSmithKline, Pfizer and Pharmacia.

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FURTHER INFORMATION

National Cooperative Drug Discovery Groups for the Treatment of Mental Disorders, Drug or Alcohol Addiction

NIH Roadmap for Medical Research

Solicitation of Assays for High Throughput Screening (HTS) in the Molecular Libraries Screening Centers Network

Glossary

Partial agonist

A full agonist produces the system maximal response, whereas a partial agonist produces a maximal response that is below that of the system maximum (and that of a full agonist). As well as producing a submaximal response, partial agonists antagonize full agonists.

Face-valid model

A model that looks or appears to be a valid representation of what it purports to measure.

Translational research

The term is generally used to describe research efforts intended to apply advances in basic science to the clinical research setting. For drug discovery and development, the term refers to research intended to progress basic science discoveries into medications.

Sensitization

The phenomenon in which the biological or behavioural response to a drug increases with successive exposures to it. Sensitization may be elicited by repeated drug treatment itself or by coupling the drug with a particular environment.

CREB

This is an acronym for cyclic AMP response element binding and refers to proteins that increase or decrease the transcription of certain genes. CREB has been associated with many functions, including the formation of long-term memories, neuronal survival and cancers.

ΔFosB

Like CREB, this is also a transcription factor. It has been found to accumulate in neurons in the synaptic field of dopamine neurons following exposure to different dependence-producing drugs, and persists for protracted periods of time, suggesting that it may be important in sustaining changes in gene expression.

Intracranial self-stimulation

Also called brain-stimulation reward, this refers to the phenomenon in which animals will perform an operant task to receive an electrical current delivered through electrodes implanted in certain parts of their brains, such as the lateral hypothalamus.

Stroop colour-word test

This task measures how well an individual resists interference between incongruent stimuli. In the standard test, words can be congruent (for example, the colour green presented in green text) or incongruent (for example, the colour green presented in blue text). This task has been adapted to measure interference from words relating to drugs (for example, ashtray) or mood-related words (for example, sad).

Event-related potentials

Event-related potentials are positive and negative electroencephalogram voltage deflections in response to specific stimuli, for example, visual, auditory or somatosensory.

Five-choice serial reaction time task

A task used in animal behavioural pharmacological studies that approximates continuous performance tests in humans. Subjects are required to track a light stimulus at the rear of one of five holes in a response board. Nose poke behaviour in the correct hole produces food reward in a separate food hopper. Errors of commission, omission and premature responding are punished with a form of task reset.

Continuous performance task

This task measures sustained attention and vigilance. Subjects view a series of target (requiring a response) and non-target (not requiring a response) stimuli, such as letters, numbers or figures.

Fear-conditioning models

In these approaches, a neutral stimulus that is paired repeatedly with an aversive stimulus can elicit a fear response measurable in animals as physiological (for example, heart rate) and behavioural (for example, immobility) changes, and in humans with self-report and galvanic skin response.

Startle response

A physiological response, such as eye blink or bulk muscle contraction, to the presentation of an unexpected, brief stimulus, typically a quantifiable one such as a flash of light or audible tone.

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Lerman, C., LeSage, M., Perkins, K. et al. Translational research in medication development for nicotine dependence. Nat Rev Drug Discov 6, 746–762 (2007). https://doi.org/10.1038/nrd2361

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