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Neuroscience 1997 Press Release

"Self-Limiting Action of Nicotine on Brain Reward Mechanisms." M.A. Bozarth, C.M. Pudiak, and R. KuoLee. Addiction Research Unit, Department of Psychology, University at Buffalo, Buffalo, New York 14260-4110.

Nicotine has long been presumed to be the active ingredient in tobacco smoke and to produce the effects some people find desirable when using tobacco products. Since publication of the 1988 Surgeon General’s Report on The Health Consequences of Smoking: Nicotine Addiction, nicotine has been viewed by many scientists and most public health workers as a highly addictive substance comparable to cocaine in its addictiveness. This assertion is based in part on apparent similarities in nicotine’s effects on brain reward mechanisms and in part on the widespread use of tobacco which continues despite public health warnings. The latter argument involves circular reasoning—persistent smoking behavior is argued to be motivated by nicotine addiction, while evidence for nicotine addiction comes from observed cases of persistent smoking behavior. Independent evidence for addiction must be obtained if addiction is to be used as an explanation of behavior. Furthermore, because human substance use is very complex—being influenced by many psychological and sociological factors as well as a substance’s pharmacological effects—the addiction liability attributable directly to a substance is more accurately assessed using preclinical studies. These tests with laboratory animals can determine the addiction liability of a compound based solely on its pharmacological properties without the confounding influence of psychological and sociological variables present in human studies. Various studies have investigated the effects of nicotine on brain reward processes in an attempt to determine how nicotine influences behavior. Indeed, these studies have found evidence for some similarities between nicotine’s effects and the effects of highly addictive drugs such as cocaine. But how similar are these substances?

Several animal models have been developed to study the rewarding properties of addictive drugs. One method involves voluntary intravenous self-administration. Laboratory animals quickly learn to self-administer highly addictive drugs such as cocaine and heroin. Tests with nicotine have been conflicting, with some investigators reporting intravenous nicotine self-administration when special testing conditions are used. However, interpretation of these findings is somewhat controversial, because no special testing conditions are necessary to demonstrate reward from highly addictive substances. Therefore, other tests of nicotine’s effect on brain reward processes are especially important in determining its potential addiction liability.

The effects of direct electrical activation of brain reward pathways have been studied for over 40 years. Laboratory animals will a press lever thousands of times an hour to receive brief pulses (e.g., 0.5 sec) of stimulation through electrodes implanted in certain brain regions. Compounds that pharmacologically active brain reward processes, such as cocaine and heroin, enhance the rewarding effects of this electrical stimulation. Therefore, the facilitation of brain stimulation reward (BSR) provides a measure of a substance’s effects on brain reward mechanisms.

Previous studies have shown that nicotine’s effect on BSR is similar to the effects of caffeine and several over-the-counter medicines used as decongestants (i.e., pseudoephedrine), allergy treatments (i.e., diphenhydramine, tripelennamine), and sleep aids (i.e., diphenhydramine). The effect of cocaine is distinctively different, producing an effect 2½ times greater than that seen with these other compounds.

Studies reported at this year’s Neuroscience meeting have attempted to enhance nicotine’s BSR facilitation. These tests involved giving nicotine repeatedly and measuring its effect on responding for electrical brain stimulation. The first study injected laboratory rats with the same dose of nicotine daily for 21 days. The selected dose has been previously shown to produce maximum facilitation of BSR when given acutely. No enhancement of nicotine’s facilitation of BSR was seen with repeated injections. Therefore, nicotine does not appear to have a stronger effect on brain reward mechanisms with repeated exposure, despite the popular belief that nicotine’s rewarding effect becomes stronger with repeated nicotine use. In the second study laboratory rats were administered increasing doses of nicotine in an attempt to emulate the increasing nicotine exposure seen as humans develop smoking behavior (i.e., progress from several to 20 or more cigarettes per day). Rats were initially given the dose of nicotine previously found to produce maximum facilitation of BSR for 5 days. The nicotine dose was then doubled for the next 5 days and doubled again for the last 5 days. Nicotine initially facilitated BSR but doubling the dose produced no further enhancement of nicotine’s effect. Surprising, when the dose was doubled again during the last 5 days of testing, animals actually showed no facilitation of BSR during the 30-minute test. This escalating dose study demonstrated that successively increasing nicotine exposure fails to increase nicotine’s effect on brain reward mechanisms. In fact, the highest dose of nicotine did not appear to facilitate BSR. Finally, a single injection of the highest dose of nicotine tested was administered and BSR was continuously monitored for 3 hours. This dose of nicotine was well above nicotine levels achieved by human tobacco use, as evidenced by the fact that animals experienced mild convulsions immediately following nicotine administration. Nicotine initially elevated BSR thresholds but showed a delayed facilitation of BSR beginning 75 minutes after injection. This delayed facilitatory action was comparable to that seen sooner after the administration of smaller nicotine doses.

These and previous studies suggest that nicotine’s maximum effect on brain reward mechanisms is modest, comparable to caffeine and to several commonly used over-the-counter medicines. This action is distinctively different than the effect produced by highly addictive substances like cocaine. The similarities reported between nicotine and cocaine are superficial, not taking into consideration important differences in the magnitudes of their actions on brain reward mechanisms. Thus, nicotine may activate brain reward mechanisms but not with the efficacy of truly addictive drugs.

Nicotine appears to have a "self-limiting" effect on brain reward mechanisms. Unlike cocaine where increased doses produce increased effects, nicotine’s ability to activate brain reward mechanisms seems to be limited by some neurophysiological process. This "self-limiting" action may actually prevent primary addiction to nicotine. Nicotine’s modest effect on brain reward mechanisms could explain the failure of preclinical models to demonstrate a strong rewarding effect of nicotine comparable to that seen with highly addictive drugs and points to the importance of other factors in human tobacco use.

 

Note: Data reported here are from the Nicotine Evaluation Program supported by a grant from the Philip Morris Research Center (Richmond, VA).


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