Addicted to Nicotine
A National Research Forum

Section IV: Biology of Nicotine Addiction
Neil E. Grunberg, Ph.D., Chair

NICOTINE REINFORCEMENT IN ANIMALS AND HUMANS

Kenneth A. Perkins, Ph.D.
Western Psychiatric Institute and Clinic
University of Pittsburgh Medical Center

Introduction

Research on the effects of nicotine, such as acute mood responses or changes in brain function, is important in order to understand the consequences of tobacco smoking. However, to fully comprehend how these changes may help explain nicotine dependence or addiction, it is necessary to link these changes to tobacco use behavior or nicotine self-administration. The degree to which a drug is self-administered, more than an inert substance (e.g., placebo, saline solution), is generally taken as the measure of its reinforcing value. Examination of factors that alter nicotine self-administration behavior is critical to improving our understanding of how tobacco smoking is initiated and maintained, as well as evaluating potential interventions to help people quit smoking.

In most animal and human self-administration studies, nicotine is administered following a specific simple response (e.g., bar press, squeeze on a nasal spray bottle), and if this response subsequently increases in frequency, then nicotine is said to be reinforcing. Because tobacco smoke contains several thousand compounds besides nicotine, studies of smoking behavior are often limited in what they can reveal about the reinforcing effects of nicotine itself. However, procedures have been developed by which the drug nicotine can be administered to animals by intravenous infusion, isolating the influence of nicotine on behavior. Similarly, novel methods of administering nicotine to humans in the absence of tobacco smoke have been developed, enabling researchers to clarify the degree to which nicotine per se is reinforcing in humans.

What We Know

Both animals and humans will self-administer nicotine significantly more than placebo, demonstrating the reinforcing value of nicotine. As an example, among smokers trying to quit smoking, those given access to nicotine nasal spray will use it significantly more than those given access to placebo nasal spray. Since the only difference between the sprays is the presence of the drug nicotine, then nicotine must be what is reinforcing their spray use. Other evidence comes from the observation that tobacco cigarettes with the nicotine removed have not succeeded in the marketplace. Despite demonstrations from a number of different studies that nicotine is reinforcing, some have questioned whether nicotine is as dependence producing as other drugs. Recent animal and human studies indicate that the amount of self-administration behavior is at least as great, and the onset of dependence is at least as likely, if not more so, with nicotine use as with exposure to other drugs.

Animals and humans also vary their self-administration of nicotine in orderly ways to maintain steady intake following systematic manipulations of dose, response requirement, and availability of alternative reinforcers. For example, if the available nicotine dose is lowered, animals will often increase their rate of responding correspondingly to try and maintain the same amount of nicotine intake. Lack of effect of this dosing manipulation on responding for other reinforcers, such as food, shows that this behavior is specific to nicotine reinforcement. Similarly, if smokers switch to a lower nicotine yield cigarette brand, they almost invariably increase the frequency or intensity of their smoking to try and extract as much nicotine as they previously received from their higher yield brand.

Furthermore, animal research shows that nicotine self-administration varies according to a number of individual difference factors, such as species strain, and as a result of short- or long-term environmental experiences, such as consumption of alcohol, food deprivation, stress, and presentation of stimuli specifically paired with nicotine availability (e.g., lights). Although often not as clearly demonstrated, other research suggests that similar factors influence human nicotine self-administration. These factors include individual differences such as heredity and gender, as well as environmental experiences such as chronic or acute alcohol use, stress, and cues associated with smoking (e.g., being in the presence of a lit cigarette).

Finally, nicotine self-administration procedures have proven valuable in examining the potential effectiveness as well as addictiveness of pharmacological treatments for smoking cessation. For example, providing nicotine gum, patch, or spray subsequently reduces amount of smoking behavior in the lab among smokers, even those not trying to quit. Similarly, a drug that blocks nicotine's effects in the brain, mecamylamine, has been found to reduce nicotine self-administration in animals, to reduce nicotine's subjective effects in humans, and to aid in smoking cessation. It seems unlikely that any drug that fails to decrease nicotine self-administration over time will be promising as a treatment for smoking. On the other hand, controlled clinical research has shown that humans generally do not self-administer nicotine gum or patch substantially more than placebo gum or patch, probably because of the very slow rate of nicotine delivery from these products compared with smoking. This observation is an important piece of evidence indicating that gum and patch are unlikely to be abused.

What We Need To Know More About

Despite this recent progress, more data are needed regarding factors that influence nicotine self-administration in animals and humans. For example, What specific acute interceptive (subjective) and behavioral effects of nicotine are most reinforcing in animals and humans? Nicotine has a wide array of effects, and it is likely that only a subset of these effects is critical to maintaining self-administration, although what these effects are is not known. It is not even clear to what degree positive reinforcing effects (e.g., pleasurable mood) versus negative reinforcing effects (e.g., relief of withdrawal) maintain nicotine self-administration. Also, What is the minimum nicotine exposure (per cigarette and over what period of time) required in order to induce dependence, and similarly, What is the maximum exposure allowable that will still not likely lead to dependence? This information may be important in future regulation of nicotine-containing products, including cigarettes.

Research must address the behavior of nicotine self-administration as it directly relates to measures of brain functioning, such as neurotransmitter activity or nicotine receptor number and subtypes. Nicotine use is associated with a number of indices of brain function, but we need to know which of these are responsible for nicotine reinforcement and dependence and which are merely correlated with use.

Similarly, we need to know what differential effects of nicotine on mood or behavior or in brain function are related to individual differences in vulnerability to nicotine dependence. Heredity and environmental causes of variability in responding must act through specific mechanisms directly linked to nicotine effects, but these mechanisms are not clear. For example, some smokers may primarily self-administer nicotine for positive reinforcing effects while others may self-administer mostly for negative reinforcement, such as to relieve negative affect. The mechanisms responsible for these differential reinforcing effects between smokers need to be determined.

We also need to know what accounts for the striking persistence of nicotine use, even after lengthy periods of abstinence. To what degree do stimuli associated with nicotine intake (conditioned stimuli) contribute to the persistence of self-administration, and can these stimuli be sufficiently altered or eliminated to discourage self-administration?

Finally, we need to know how applicable to smoking in the natural environment are the observations of nicotine self-administration in the laboratory. For example, although human laboratory-based studies have shown that nicotine self-administration can be substantially reduced if the response requirement is increased sufficiently, it is not clear that such reductions would be as robust or long-lasting if this manipulation was instituted in the natural environment.

Recommended Reading

Anthony, J.C.; Warner, L.A.; and Kessler, R.C. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 2:244-268, 1994.

Corrigall, W.A.; Franklin, K.B.J.; Coen, K.M.; and Clarke, P.B.S. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology 107:285-289, 1992.

Perkins, K.A.; Grobe, J.E.; D'Amico, D.; Fonte, C.; Wilson, A.; and Stiller, R.L. Low-dose nicotine nasal spray use and effects during initial smoking cessation. Exp Clin Psychopharmacol 4:157-165, 1996.

Pich, E.M.; Pagliusi, S.R.; Tessari, M.; Talabot-Ayer, D.; van Huijsduijnen, R.H.; and Chiamulera, C. Common neural substrates for the addictive properties of nicotine and cocaine. Science 275:83-86, 1997.

Rose, J.E., and Corrigall, W.A. Nicotine self-administration in animals and humans: Similarities and differences. Psychopharmacology 130:28-40, 1997.

Zacny, J.P., and Stitzer, M.L. Cigarette brand-switching: effects on smoke exposure and smoking behavior. J Pharmacol Exp Ther 246:619-627, 1988.