Pharmacology of Nicotine and Tobacco Relevance to Schizophrenia

There has been an increasing understanding of the neurobiology of both schizophrenia and nicotine addiction in the past 20 years. For the purposes of this discussion, nicotine is assumed to be the active ingredient in tobacco and cigarette smoking that exerts psychopharmacological effects, though other components of tobacco smoke may also be active in this respect (Fowler et al. 1996a, 1996b). There are three possible reasons for the high comorbidity rates of nicotine addiction in schizophrenia: 1) self-medication of clinical and cognitive deficits associated with schizophrenia by tobacco use, 2) abnormalities in brain reward pathways in schizophrenia that make these patients

Table 5-1. Prevalence of cigarette smoking in individuals with schizophrenia


Patient population

Smoking prevalence rate (%)

O'Farrell et al. (1983) Masterson and O'Shea (1984) Hughes et al. (1986) el-Guebaly and Hodgins (1992) Menza et al. (1991) Goff et al. (1992) Ziedonis et al. (1994) de Leon et al. (1995) George et al. (1995)

Chong and Chou (1996) Diwan et al. (1998)

McEvoy and Brown (1999)

Kelly and McCredie (1999)

309 veteran inpatients in United States 100 schizophrenic inpatients in Ireland 277 psychiatric outpatients in United States 106 schizophrenic inpatients in Canada 126 psychiatric outpatients in United States 78 schizophrenic outpatients in United States 265 schizophrenic outpatients in United States 237 schizophrenic inpatients in United States 29 schizophrenic outpatients on clozapine in

United States 195 schizophrenic outpatients in China 63 schizophrenic veteran outpatients in United States

12 first-episode schizophrenic patients in United States

168 schizophrenic outpatients in Scotland Composite smoking prevalence

88 (n=207 schizophrenic patients) 83 (84% in males, 82% in females) 88 (n=24 schizophrenic patients) 61

56 (n=99 schizophrenic patients) 74 68

85 62.1

92 58 72.5


0 T3

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vulnerable to tobacco (and other drug) use, and 3) common genetic and environmental factors that are independently associated with smoking and schizophrenia. We briefly describe next the pharmacological effects of nicotine and how such effects may link nicotine addiction with schizophrenia.

Nicotine alters the function of neurotransmitter systems implicated in the pathogenesis of major psychiatric disorders, including dopamine, norepi-nephrine, serotonin (5-HT), glutamate, gamma-aminobutyric acid (GABA), and endogenous opioid peptides ( George et al. 2000b, 2000c; McGehee et al. 1995; Picciotto et al. 2000). Nicotine's receptor in the brain is the nicotinic acetylcholine receptor (nAChR), where stimulation of presynaptic nAChRs on neurons increases transmitter release and metabolism. Unlike most agonists, chronic nicotine administration leads to desensitization and inactivation of nAChRs (Collins et al. 1994; Picciotto et al. 2000), with subsequent upregulation of nAChR sites, a process that might explain why many smokers report that the most satisfying cigarette of the day is the first one in the morning. Mesolimbic dopamine (reward pathway) neurons possess presynaptic nAChRs and may be of particular importance in mediating the rewarding effects of nicotine through projections from the ventral teg-mental area (VTA) in the midbrain to anterior forebrain structures such as the nucleus accumbens and cingulate cortex. These are the same subcortical dopamine pathways that are implicated in the expression of the positive symptoms of schizophrenia. Similarly, there are nAChRs present presynap-tically on midbrain dopamine neurons that project from the VTA to the pre-frontal cortex (PFC) that evoke dopamine release and metabolism when activated by nicotine (during smoking). Dysregulation of PFC functioning has been demonstrated in schizophrenia, a finding possibly related to hypo-function of cortical dopamine and other transmitter systems (Knable and Weinberger 1997). It is this hypofunction of PFC dopamine that is thought to mediate the cognitive deficits and negative symptoms associated with schizophrenia and that may be ameliorated by cigarette smoking (George et al. 2000a, 2002a). Nicotine also stimulates glutamate release (McGehee et al. 1995) and could thereby alter abnormalities in central glutamatergic systems (e.g., hypofunction) associated with schizophrenia (Dalack et al. 1998).

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