Review
Historical Perspective
Historical and current perspective on tobacco use and nicotine addiction

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Although the addictive influence of tobacco was recognized very early, the modern concepts of nicotine addiction have relied on knowledge of cholinergic neurotransmission and nicotinic acetylcholine receptors (nAChRs). The discovery of the ‘receptive substance’ by Langley, that would turn out to be nAChRs, and ‘Vagusstoff’ (acetylcholine) by Loewi, coincided with an exciting time when the concept of chemical synaptic transmission was being formulated. More recently, the application of more powerful techniques and the study of animal models that replicate key features of nicotine dependence have led to important advancements in our understanding of molecular, cellular and systems mechanisms of nicotine addiction. In this review, we present a historical perspective and overview of the research that has led to our present understanding of nicotine addiction.

Introduction

Tobacco use spread around the world from its origins in the Americas (Box 1). Early anecdotal accounts of tobacco's captivating influence and of associated health consequences inspired research into its addictive properties. However, our present molecular and cellular concepts of nicotine addiction (see Glossary) arising from tobacco use are relatively recent. The specific investigation of nicotine addiction arose from a long history of basic cholinergic research. It is valuable, captivating and, for some of us, even romantic to look back at the early work that laid the foundation for our present understanding of nicotine addiction. The early discovery of autonomic cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) spurred physiological characterization of the neuromuscular junction (NMJ). Those studies served as guideposts, or they may more appropriately be called points-of-reference, for the more recent investigations that revealed surprisingly different and diverse mechanisms of nicotinic cholinergic transmission in the brain. Most commonly, humans self-administer nicotine using an exquisite dosing device, the cigarette. Acting directly and mainly through nAChRs, nicotine impinges upon neural circuitry that shapes short-term and long-term behavior. This review provides a compact summary of tobacco use and the scientific advances that led to the modern research into nicotine addiction. We hope this brief article and the referenced review publications and books will inspire both novices and experts to explore these fascinating historical events further.

Section snippets

Brief history of nicotinic cholinergic signaling

As tobacco use spread around the world (Box 1), interest in the active ingredients and their effects stimulated scientific investigation. Early in the 20th century, nicotine had been synthesized and the classic studies of drug action by John Newport Langley and his colleagues had begun [1]. These initial efforts with nicotine culminated in the 1905 study in which Langley refers to the ‘receptive substance’ that would eventually turn out to be nAChRs [2].

As the concepts of specific receptors,

Brief history and scientific advances of nicotine as an addictive drug

Although the modern concepts of tobacco or nicotine addiction are relatively recent, the captivating influence of tobacco was known by Native Americans and was quickly documented by Europeans [44]. For example, Francis Bacon, an English philosopher, statesman and Renaissance scientist, observed the spread of tobacco and wrote:

‘In our time the use of tobacco is growing greatly and conquers men with a certain secret pleasure, so that those who have once become accustomed thereto can later hardly

Concluding remarks

The decreasing cost of sequencing the human genome has brought human genetic diversity into the forefront of mental health and addiction research. Genome-wide association analysis of single nucleotide polymorphisms (SNPs) has already linked nAChRs to tobacco use and health problems. For example, the CHRNA5-CHRNA3-CHRNB4 gene cluster, which encodes the α5, α3 and β4 nAChR subunits, has been implicated in various aspects of nicotine dependence and cigarette-related health issues [136].

Acknowledgments

This work was supported by grants from the National Institutes of Health (NINDS NS21229 and NIDA DA09411). J.D. acknowledges the joint participation by the Diana Helis Henry Medical Research Foundation, through its direct engagement in the continuous active conduct of medical research in conjunction with Baylor College of Medicine, and the project Dopamine Signaling Dysfunction Precedes and Predicts Neuron Loss in an Animal Model of PD, and the Parkinson's Disease Program. We thank Mariella De

Glossary

Addiction
a state in which drug taking is out of control. Chronic exposure to drugs of dependence evoke changes in the central and peripheral nervous systems that cause the behavioral and somatic signs of withdrawal when drug taking is terminated abruptly.
Anhedonia
a state in which the ability of the individual to experience and respond to pleasurable stimuli is blunted.
Conditioned cues/stimuli
this refers to cues or stimuli that are paired repeatedly with the delivery of the addictive drug (or

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