Historical and current perspective on tobacco use and nicotine addiction

Abstract

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.

Figure 1

An historical pathway and representative contributors to our present use and understanding of tobacco. 1490’s: At their first encounter with Native Americans in 1492, Christopher Columbus and his crew of Spanish sailors were given merchandise, including dried tobacco leaves that they discarded because they had no use for them. Later, members of Columbus’s crew were again given the highly prized leaves, and they were shown the process of smoking. 1560’s: As France’s ambassador to Portugal, Jean Nicot sent tobacco products to the French court as a potential medicinal treatment in 1561. The tobacco plant, Nicotiana, and the addictive substance, nicotine, derived their names from him. Early 1900’s: In the early 1900’s, Henry Dale isolated acetylcholine and demonstrated that it was the parasympathetic neurotransmitter that Otto Loewi had called, Vagusstoff. Mid-1900’s: In the 1950’s, Ernst Wynder contributed to an epidemiological study linking smoking to cancer. Wynder and colleagues also painted cigarette tar onto the skin of mice during the first study using tobacco to induce cancer in a laboratory setting. Later 1900s: Bridging from the 1960’s to the present, Jean-Pierre Changeux has made important contributions to our understanding of the molecular and cellular properties and roles of nAChRs. Using genetically engineered mouse models, he and his colleagues also contributed detailed information about the roles of specific nAChR subtypes in the mesolimbic dopamine system during the nicotine addiction process.

Figure 2

Didactic representation of Otto Loewi's most famous experiment, which was published in 1921. The idea for the experiment came to him in a dream. Two beating frog hearts were isolated in containers of Ringer’s solution. The vagus nerve was stimulated in one heart (A), slowing heart rate A. Fluid moved from container (A) and applied to the heart in container (B) slowed heart rate B. This demonstrated that a soluble substance released by the vagus nerve modulated the heart rate. He called the unknown substance Vagusstoff, and Henry Dale’s lab later identified the chemical to be acetylcholine.

Figure 3

Schematic representation of a generalized nAChR. (A) The arrangement of a single nAChR polypeptide subunit within the plasma membrane. The 4 transmembrane segments (M1–M4) of a nAChR subunit are oriented within the membrane, with both the amino and carboxyl ends being located extracellularly. (B) Many nAChRs are constructed from α and β subunits, with the most common nAChR subtype being the α4β2 nAChR in the mammalian brain. The α7 subunit forms the most common homomeric nAChR in the mammalian brain. More complex subunit combinations are possible, with more than one α and/or more than one β subunit combining to form other nAChR subtypes. Looking down on the receptor from above, the central water-filled cation-conducting pore is represented by the white circle in the center of the subunits. (C) A side cut-away view of the nAChR showing the subunits arranged around the central pore that passes through the membrane. There are 3 main conformational states of the nAChR: closed pore at rest, open pore with 2 acetylcholine (ACh) molecules bound to the agonist binding sites, and closed pore in the desensitized state with 2 ACh molecules bound.

Figure 4

Didactic representations of nAChR subtypes at different synaptic locations. (A) Fast, direct, nicotinic cholinergic synaptic transmission is shown with ACh (green circles) being released from the presynaptic terminal vesicles. Only nAChRs (purple) are represented on the postsynaptic bouton in this simplified picture. (B) A representation of presynaptic nAChRs (light blue) intermingling with other presynaptic macromolecules. The nAChRs are positioned so they can influence the release of synaptic vesicles. Evidence indicates that nAChRs initiate a direct and indirect increase of calcium in the presynaptic terminal. The calcium then enhances the release of the neurotransmitter. Low levels of ACh (green circles) are represented to have diffused near to this non-cholinergic synapse from more distant sources. (C) A representation of preterminal or axonal nAChRs (blue). The nAChRs are located in a position along the axon to indicate they could influence excitability along that fiber. Low levels of ACh (green circles) are represented to have diffused into the area from more distance sources.

Figure 5

Schematic representations of nicotine self-administration in rodents, the inverted U-shaped dose-response curve, and electrical intracranial self-stimulation. (A) Nicotine self-administration by a rodent (e.g., a rat) is commonly through an intravenous catheter located in the jugular vein. By an operant act (e.g., pushing a level), the rat activates a pump that delivers a small nicotine infusion that is distributed throughout the body and brain. (B) Nicotine dosing in both humans and animals follows an inverted U-shaped dose-response curve. At the lower concentrations, nicotine has little influence, but there is increasing pleasurable or rewarding influence activated with increasing dose. At higher nicotine concentrations, aversive influences come into play. Smokers and animals during self-administration titrate their nicotine intake to experience the rewarding effects, while avoiding the aversive actions. (C) Intracranial self-stimulation by a rat is induced by activation of an electrical stimulator with an electrode placed within discrete areas of the brain that influence the reward circuitry, including the mesocorticolimbic dopamine (DA) system and targets such as the NAc. By an operant act (e.g., pushing a level), the rat activates the stimulator to deliver a brief shock to the areas of the brain where the electrode is positioned. The technique allows the experimenter to measure changes in brain reward function. The protocol has been used to show that nicotine increases brain reward function (measured as an increase in the sensitivity to rewarding stimulation within the brain) whereas nicotine withdrawal decreases brain reward function.

Box 1 Figure I

A tobacco field of Nicotiana tabacum under a threatening sky. Photo credit: iStockphoto.com.