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 Humans Service 1988). Cessation of tobacco smoking in individuals dependent on nicotine leads to a withdrawal syndrome characterized by both emotional and somatic signs of withdrawal. Nicotine withdrawal in humans includes somatic symptoms, such as bradycardia, insomnia, gastrointestinal discomfort, and increased appetite leading to weight gain, as well as emotional symptoms like depressed mood, irritability, anxiety, frustration, difficulty concentrating and craving for tobacco (American Psychiatric Association 1994). Interestingly, the above mentioned emotional symptoms are common to both nicotine withdrawal and schizophrenia. A high proportion of schizophrenia patients (88%) are heavy smokers compared to the general population (25-30%). It has been speculated that schizophrenia patients smoke in order to alleviate a cluster of symptoms, called negative symptoms of schizophrenia (similar to symptoms of depression), that are not readily treated by the majority of antipsychotic drugs available today. These negative symptoms of schizophrenia, which are a subset of the symptoms that schizophrenics exhibit, are similar to the depressive symptomatology characterizing nicotine withdrawal.
The neurobiology of nicotine withdrawal is proposed to involve alterations in several neurotransmitters systems, that are hypothesized to contribute to the negative affective state associated with nicotine withdrawal, and potentially to the negative symptoms of schizophrenia. These systems include the dopaminergic, noradrenergic, serotonergic and cholinergic systems. Thus, it seems fruitful to explore the potential role of these neurotransmitter systems in nicotine withdrawal using different selective receptor blockers. These receptor blockers have been selected based on: a) a theoretical rationale about possible overlapping neuronal mechanisms underlying the negative symptoms of schizophrenia and nicotine withdrawal; b) clozapine’s receptor profile, because clozapine is the most effective treatment against the negative symptoms of schizophrenia (although there is considerable room for improvement); and c) preliminary data indicating some efficacy of clozapine against nicotine withdrawal. Nicotine withdrawal is characterized by the symptom of anhedonia (“diminished interest or pleasure” in rewarding stimuli). A model of “diminished interest or pleasure” will be used in the proposed studies. This model utilizes the intracranial self-stimulation paradigm, which provides a valid, reliable and quantitative measure of the emotional aspects of nicotine withdrawal (that is, reward thresholds). Elevations in thresholds are interpreted as a decrease in the reward value of the stimulation, and are considered a measure of the symptom of “anhedonia”. The goal of the proposed studies is to explore the biological mechanisms that may mediate the emotional and somatic symptoms of nicotine withdrawal.
The results of these experiments will have important implications about the treatment of nicotine withdrawal in psychiatric and non-psychiatric populations, and about the links of cigarette smoking to schizophrenia. The goals of the studies proposed in the present application are consistent with the priorities of the Tobacco-Related Disease Research Program. |