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Neurobiological substrates of nicotine addiction

Institution: Scripps Research Institute
Investigator(s): Athina Markou, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0004 Award: $742,393
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Almost 10 years ago the United States Surgeon General recognized tobacco smoking as the number one cause of death in the USA that could be prevented, if individuals quit smoking (US Department of Health and Human Services 1988). In the same report, it was also shown that nicotine is the main ingredient in cigarettes that leads to the habit of smoking because the individual gradually become addicted to nicotine and, therefore, tobacco smoking is continued in order to continue the administration of nicotine. In that sense, nicotine is considered to be as addictive as other drugs of abuse such as morphine or heroin, amphetamines and alcohol. The fact that nicotine is addictive is indicated by the fact that smokers frequently fail to quit. As high as 80% of individuals who attempt to quit, resume smoking within one year, even though these individuals are often fully aware of the potential harmful effects of smoking on health. One of the reasons that quitting smoking is difficult is because when a heavy habitual smoker stops smoking, then he/she suffers from several withdrawal symptoms, such as depression anxiety, irritability, restlessness and increased appetite. These symptoms make the person crave and desire tobacco smoking in order to relieve the suffering which results from these symptoms, and `'cure" the nicotine withdrawal symptoms. In the brain, nicotine produces its effects by attaching to and "activating ' specific sites called receptors. The purpose of the present studies is to investigate to which receptors nicotine attaches in order to produce the pleasurable effects that habitual tobacco smokes experience. Other experiments will explore which of these receptors have changed their normal function during repeated tobacco use, so that when nicotine is no longer available in the brain to attach to these receptors, these receptors' actions lead to a series of events that produce the aversive symptoms experienced during nicotine withdrawal. Another series of experiments will investigate whether repeated failed attempts to quit smoking lead to an increased severity in the withdrawal symptoms, thus making it harder for people to quit smoking. The same experiments will also test whether the longer an individual has been a smoker, the harder it is to quit smoking; because for these individuals the pleasurable effects of nicotine are greater compared to the pleasurable effects of nicotine experienced by an individual that just started smoking. Further, other experiments will test whether the more times an individual has tried to quit smoking and failed, the harder it is to quit smoking, because again, for this individual, nicotine has stronger and more powerful pleasurable effects than for non smokers. Finally, other studies will investigate which parts of the brain are involved specifically in the production of nicotine withdrawal symptoms. All of the studies described above will use animal subjects. Such experiments are the types of experiments that will enable us to study exactly which parts of the brain and which receptors are responsible for the development of nicotine addiction, and for the aversive symptoms of nicotine withdrawal. These studies are expected to provide us with valuable information that will help us design effective treatment programs the may involve both behavioral and pharmacological techniques to help people to quit smoking, and thus avoid the detrimental effects of tobacco smoking on health.

Final Report
As high as 80% of individuals who attempt to quit, resume smoking within one year, even though these individuals are often fully aware of the potential harmful effects of smoking on health. One of the reasons that quitting smoking is difficult is because when a heavy habitual smoker stops smoking, then he/she suffers from affective/emotional withdrawal symptoms, such as depression, anxiety, ittitability, restlessness and increased appetite. The purpose of the present project was to study the neurobiology of one of these negative affective/emotional aspects of nicotine withdrawal, namely depression; because we hypothesize that these negative affective aspects of withdrawal are the ones that a smoker finds the most difficult to withstand, and thus resumes smoking. Animal subjects are used to study one of the core symptoms of depression, anhedonia (i.e., diminished interest or pleasure in previously rewarding stimuli), that animals, including humans, experience during nicotine withdrawal. Our studies indicated that both the rewarding effects of nicotine and the negative affective aspects of nicotine withdrawal are dependent on the function of specific sites in the brain called nicotinic acetylcholine receptors to which nicotine binds. The results also indicated that treatment with an antidepressant drug combination reversed the affective aspects of nicotine withdrawal indicating that depression is one of the symptoms of nicotine withdrawal. It was also shown that during nicotine treatment, the subjects did not gain weight as fast as control subjects. Nevertheless, after the cessation of nicotine administration, these subjects gained weight fast and quickly reached the weight of the control subjects. The results also indicated that the longer a subject was exposed to nicotine, the longer lasting the affective aspects of withdrawal were. This result suggests that high exposure to nicotine will make it difficult for an individual to abstain from smoking. It was also shown that: a) a period of deprivation from nicotine (a weekend) resulted in the subjects self-administering more nicotine on Mondays than on any other day of the week; b) that animals will work harder (he, press a lever more times) to gain access to higher doses of nicotine, and; c) that presentation of environmental stimuli that were previously associated with nicotine administration prolonged the extinction of selfadministration behavior, even when this self-administration behavior did not lead to nicotine access. This pattern of results indicates that nicotine has rewarding properties and that animals, including humans, will work to gain access to nicotine. These studies are providing us with valuable information that will help us design effective treatment programs that may involve both behavioral and pharmacological techniques to help people quit smoking, and thus avoid. the detrimental effects of tobacco smoking on health.
Publications

Blockade of nicotine self-administration with nicotinic antagonists in rats
Periodical: Pharmacology Biochemistry and Behavior Index Medicus:
Authors: Watkins SS, Epping-Jordan MP, Koob GF, Markou A ART
Yr: 1999 Vol: 62 Nbr: 4 Abs: Pg: 743-751

In nicotine-dependent rats, a place aversion conditioning is induced by the administration of both nicotine and opiate receptor antagonists
Periodical: Behavioral Pharmacology Index Medicus:
Authors: Stinus L, BelahsenO, Markou A, Koob GF, Cador M ABS
Yr: 1998 Vol: 9 Nbr: Suppl 1 Abs: S83 Pg:

Effects of precipitated nicotine withdrawal on brain reward thresholds and somatic signs: central and peripheral mechanisms
Periodical: Neuroscience Index Medicus:
Authors: Watkins SS, Koob GF, Markou A ABS
Yr: 1998 Vol: 24 Nbr: Abs: Pg: 752

Naloxone precipitated nicotine withdrawal in rats: intracranial self-stimulation and conditioned place aversion
Periodical: Scientific Abstracts Index Medicus:
Authors: ABS
Yr: 1999 Vol: 27 Nbr: Abs: Pg:

Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects
Periodical: Journal of Pharmacology and Experimental Therapeutics Index Medicus:
Authors: Watkins SS, Stinus L, Koob GF, Markou A ART
Yr: 2000 Vol: 292 Nbr: 3 Abs: Pg: 1053-1064

Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal
Periodical: Nicotine and Tobacco Research Index Medicus:
Authors: Watkins SS, Koob GF, Markou A ART
Yr: 2000 Vol: Nbr: Abs: Pg:

Both nicotine- and amphetamine-withdrawal-induced elevations in brain reward thresholds are reversed by an antidepressant: opposite effects in control rats
Periodical: Behavioral Pharmacology Index Medicus:
Authors: Harrison AA, Markou A ABS
Yr: 1999 Vol: 10 Nbr: 1 Abs: S44 Pg:

Effects of acute nicotine and nicotine withdrawal on brain reward function: reversal of withdrawal by an antidepressant
Periodical: American College of Neuropsychopharmacology: Scientific Abstracts Index Medicus:
Authors: Markou A ABS
Yr: 1999 Vol: Nbr: Abs: 82 Pg:

Effects of clozapine on brain reward thresholds and somatic signs during nicotine withdrawal: relevance to depression
Periodical: Proceedings of the TRDRP Annual Investigator's Meeting Index Medicus:
Authors: Semenova S, Markou A ABS
Yr: 1999 Vol: Nbr: Abs: Pg: 33