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Neurobiological substrates of nicotine addiction

Institution: Scripps Research Institute
Investigator(s): Athina Markou, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0074 Award: $402,852
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 indicated that nicotine is the main component of cigarettes that leads to the habit of smoking because the individual gradually becomes 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 opiates, amphetamines and ethanol. The fact that nicotine is addictive is indicated by the fact that smokers frequently fail to quit, with as high as 80% of individuals attempting to quit, resuming smoking within a year, even though these individuals are often fully aware of the potential harmful effects of smoking on health. One of the reasons that quiting smoking is difficult is because when a heavy habitual smoker stops smoking then the person suffers from several withdrawal symptoms, such as depression, anxiety, irritability, restlesness and increased appetite. These symptoms make the person crave and desire tobacco smoking in order to alleviate the suffering resulting 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, and more specifically, on a type of receptor called acetylcholine receptor. This receptor is called acetylcholine receptor because a substance that is naturally found in the brain, called acetylcholine, normally attaches to these receptors. There are actually several subtypes of acetylcholine receptors. The purpose of the present studies is to investigate to which subtypes of acetylcholine receptors nicotine attaches in order to produce the pleasurable effects that habitual tobacco smokers experience. Other experiments will explore which of these acetylcholine receptor subtypes have changed their normal function during repeated nicotine administration, 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, and 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 strong and powerful pleasurable effects. Finally, other studies will investigate which parts of the brain that contain acetylcholine and opioid receptors (the receptors on which opiate drugs and endorphins attach) are involved in the production of the nicotine withdrawal symptoms. All of the studies described above will be done in rats because such invasive studies that require injection of small amounts of nicotine and other drugs directly into the brain, or administration of drugs that have not been studied sufficiently to determine whether they have toxic effects in humans, cannot be done in humans; and such invasive experiments are the types of experiments that will enable us to study exactly which parts of the brain and receptor subtypes are responsible for the development of nicotine addiction and for the aversive symptoms of nicotine withdrawal. These studies will hopefully provide us with valuable information that will help us design effective treatment programs that involve both behavioral and pharmacological techniques, to help people to quit smoking, and thus, avoid the detrimental effects of tobacco smoking on health.
Publications

Nicotine potentiation of brain stimulation reward reversed by DH E and SCH 23390, but not by eticlopride, LY 314582 or MPE in rats.
Periodical: Psychopharmacology Index Medicus:
Authors: Harrison, AA, Gasparini F, and Markou A ART
Yr: 2002 Vol: 160 Nbr: Abs: Pg: 56-66

Neuroadaptations to chronic exposure to drugs of abuse: Relevance to depressive symptomatology seen across phychiatric diagnostic categories.
Periodical: Neurotoxicity Research Index Medicus:
Authors: Markou A, and Kenny JP ART
Yr: 2002 Vol: 4 Nbr: 4 Abs: Pg: 297-313

Increased GABA neurotransmission via administration of gamma-vinyl GABA decreased nicotine self-administration in the rat.
Periodical: Synapse Index Medicus:
Authors: Paterson NE, and Markou A ART
Yr: 2002 Vol: 44 Nbr: Abs: Pg: 252 - 253

Increases in the duration of nicotine withdrawal following prolonged exposure to nicotine exposure or repeated withdrawal episodes in rats.
Periodical: Drug and Alcohol Dependence Index Medicus:
Authors: Skjei K, and Markou A ABS
Yr: 2001 Vol: 63 Nbr: 1 Abs: Pg: S147

Nicotine self-administration in rats:short-term abstinence, progressive ratio schedule, and extinction with or without conditioned stimuli.
Periodical: Drug and Alcohol Dependence Index Medicus:
Authors: Paterson NE and Markou A ABS
Yr: 2001 Vol: 63 Nbr: 1 Abs: Pg: S120

Clozapine treatment prevented the somatic signs and partially reversed the affective aspects of nicotine withdrawal in rats.
Periodical: Behavioral Pharmacology Index Medicus:
Authors: Semenova S, and Markou A ABS
Yr: 2001 Vol: 12 Nbr: Suppl 1 Abs: Pg: S94

Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats.
Periodical: Psychopharmacology Index Medicus:
Authors: Skjei KL, Markou A ART
Yr: 2003 Vol: 168 Nbr: Abs: Pg: 280-292

Cocaine-seeking behavior after extended cocaine abstinence in rats: role of conditioned stimuli.
Periodical: Psychopharmacology Index Medicus:
Authors: Semenova S, Markou A ART
Yr: 168 Vol: Nbr: 192-200 Abs: Pg:

Decreased prepulse inhibition during nicotine withdrawal in DBA/2J mice is reversed by nicotine self-administration.
Periodical: European Journal of Pharmacology Index Medicus:
Authors: Semenova S, Bespalov A, Markou A ART
Yr: 2003 Vol: 472 Nbr: Abs: Pg: 99-110

The antismoking and antidepressant agent bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal.
Periodical: Psychopharmacology Index Medicus:
Authors: Cryan JF, Bruijnzeel AW, Skjei KL, Markou A ART
Yr: 168 Vol: Nbr: 347-358 Abs: Pg:

Effects of bupropion on responding for nicotine and food under fixed-ratio and progressive ratio schedules of reinforcement in rats.
Periodical: Synapse Index Medicus:
Authors: Bruijnzeel AW, Markou A ART
Yr: 2003 Vol: 50 Nbr: Abs: Pg: 20-28

The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice
Periodical: Psychopharmacology Index Medicus:
Authors: Paterson NE, Semenova S, Casparini F, Markou A ART
Yr: 2003 Vol: 167 Nbr: Abs: Pg: 257-264

Clozapine treatmnet attenuated somatic and affective signs of nicotine and amphetamine withdrawal in subsets of rats that exhibited hyposensitivity to the initial effects of clozapine.
Periodical: Biological Psychiatry Index Medicus:
Authors: Semenova S, Markou A ART
Yr: 0 Vol: Nbr: Abs: Pg:

THe GABAb receptor agonists baclofen and CGP44532 decrease nicotine self-administration in the rat.
Periodical: Psychopharmacology Index Medicus:
Authors: Paterson NE, FroestlW, Markou A ART
Yr: 0 Vol: Nbr: Abs: Pg:

The differential role of 7 nicotinic receptors in nicotine self-administration and nicotine withdrawal in the rat.
Periodical: Drug and Alcohol Dependence Index Medicus:
Authors: Markou A, Paterson N, Skjei K ABS
Yr: 2001 Vol: 63 Nbr: 1 Abs: Pg: S98

Nicotine withdrawal and antidepressants: serotonergic modulation or reward.
Periodical: European Neuropsychopharmacology Index Medicus:
Authors: Markou A ABS
Yr: 2001 Vol: 11 Nbr: Sup. 3 Abs: Pg: S140-141

The effect of blockade of NMDA and metabotropic glutamate5 receptors (mGluR5) in nicotine dependence.
Periodical: Behavioral Pharmacology Index Medicus:
Authors: Kenny PJ, Wright C, Casparini F, Markou A ABS
Yr: 2001 Vol: 12 Nbr: Abs: Pg: S52

Nicotine potentiation of brain stimulation reward reversed by DHE and SCH 23390, but not be eticlopride, LY 314582 or MPEP in rats.
Periodical: Behavioral Pharmacology Index Medicus:
Authors: Markou A, Harrion AA, Gasparini F ABS
Yr: 2001 Vol: 12 Nbr: Abs: Pg: S63

Nicotine self-administration in rats is decreased by cholinergic and GABAergic manipulations: short-term abstinence, progressive ratio schedule, and extinction with or without conditioned stimuli.
Periodical: Society for Research on Nicotine and Tobacco Conference Index Medicus:
Authors: Markou A ABS
Yr: 2001 Vol: Nbr: Abs: 15 Pg:

Nicotine self-administration in rats on a progressive ratio schedule: administration of the GABAb agonist CGP-44532 decreased breaking points.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Paterson NE, Markou A, Froestl' W ABS
Yr: 2001 Vol: Nbr: Abs: 26 Pg:

Effects of clozapine on nicotine and amphetamine withdrawal in rats.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Semenova S, van de Spijker WA, Markou A ABS
Yr: 2001 Vol: Nbr: Abs: 26 Pg:

Stimulation of metabotropic glutamate 2/3 receptors (mGluR2/3) precipitates nicotine withdrawal in rats: role of mGluR5 and NMDA receptors.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Kenny PJ, Wright C, Gasparini F, Markou A ABS
Yr: 2001 Vol: Nbr: Abs: 26 Pg:

The antidepressant bupropion increases brain reward function: reversal of reward deficits associated with nicotine withdrawal.
Periodical: American College of Neuropsychopharmacology: Scientific Abstracts Index Medicus:
Authors: Cryan JF, Skjei KL, Markou A ABS
Yr: 2002 Vol: Nbr: Abs: 153 Pg:

Characterization of nicotine intake, extinction, reinstatement and precipitated withdrawal using 23-hr access to nicotine self-administration.
Periodical: College on Problems of Drug Dependence Index Medicus:
Authors: O'Dell LE, Chen SA, Lerner K, Markou A, Balster RL, Koob GF ABS
Yr: 0 Vol: Nbr: Abs: Pg:

The antidepressent bupropion increased brain reward function and reversed nicotine withdrawal.
Periodical: International Behavioral Neuroscience Society Index Medicus:
Authors: Markou A, Skjei KL, Bruijnzeel A, Cryan JF ABS
Yr: 2002 Vol: Nbr: Abs: Pg: 31

Nicotine withdrawal decreased prepulse inhibition (PPI) and decreased sensitivity to self-administered nicotine in DBA/2J mice.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Semenova S, Bespalov A, Markou A ABS
Yr: 2002 Vol: Nbr: Abs: Pg: 27

The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and drug-naive mice.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Paterson NE, Semenova S, Gasparini F, Markou A ABS
Yr: 2002 Vol: Nbr: Abs: Pg: 27

Nicotine normalizes phencyclidine-induced disruption of prepulse inhibition in selected inbred strains of mice.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Spielewoy C, Chevrette J, Markou A ABS
Yr: 2002 Vol: Nbr: Abs: Pg: 27

The antidepressant bupripion enhances brain reward function and reverses nicotine withdrawal in the rat.
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Cryan JF, Bruijnzeel AW, Skjei KL, Markou A ABS
Yr: 2002 Vol: Nbr: Abs: Pg: 27

Characterization of the effects of bupropion on the reinforcing and incentive-motivational properties of nicotine and food in rats.
Periodical: College on Problems of Drug Dependence Index Medicus:
Authors: Bruijnzeel AW, Markou A ABS
Yr: 2003 Vol: Nbr: Abs: Pg: