Smoking and mental illness
Introduction
A major conundrum in tobacco research today is the neurobiology of tobacco use in the mentally ill. The incidence of smoking in individuals suffering from various forms of mental illness is inordinately high, approximately 60% overall compared to 25% in the general population. It is estimated that of the total number of smokers in the US today, 30% have some form of mental illness. This population purchases the majority of cigarettes sold, since they are also the heaviest smokers, and yet we know very little about any differences in the biology of smoking in this population that might account for their increased rate of tobacco use. This review focuses on what is known about the receptor populations that respond to nicotine in a common mental illness, schizophrenia.
Section snippets
The mentally ill population
Individuals suffering from a mental illness fall into several major groups. When the phenotypes are parsed, differences can be seen in the extent to which each group smokes and also in the use of alcohol. Although the groupings can be subdivided endlessly by phenotype, four major groups will be considered: schizophrenia, bipolar disorder, depression, and other. The last group, “other” includes posttraumatic stress disorder (PTSD), attention-deficit disorder (ADD), panic disorder, and anxiety.
Smoking incidence
The incidence of smoking is higher in all of the mentally ill groups than in the general population Glassman, 1993, Dalack et al., 1999, Foulds, 1999, George and Krystal, 2000. It is estimated that 25% of the general population in the US are currently smoking tobacco (Anonymous, 1999). Active smoking cessation programs and the pressure of smoking bans in many buildings assure that the incidence of smoking is likely to continue declining in general. The incidence of smoking in schizophrenia,
What are the underlying biological etiologies of smoking in the mentally ill?
The reasons for the high incidence of smoking in the mentally ill are likely to be as complex as the illnesses themselves. Although there are some common phenotypic symptoms in schizophrenia and the affective disorders, there are also major differences. Genetic evidence, discussed below, suggests commonality at some loci and not at others. Smoking cessation in all the disorders leads to a worsening of symptoms Glassman et al., 1990, Greeman and McClellan, 1991, Dalack et al., 1999 and it has
Direct assay of behavioral phenotypes in schizophrenia and bipolar disorder
The use of behavioral phenotypes in the study of schizophrenia was first proposed by Peter Venables in 1964. Venables suggested that sensory overload, which he referred to as “flooding,” pointed to a defect in important brain mechanisms regulating perception of sensory stimuli. The failure of such an inhibitory filter for sensory input could possibly lead to the paranoia and delusions frequently seen in schizophrenia. This has stimulated the investigation of several behavioral paradigms in
Normalization of sensory deficits by nicotine
Several of these sensory deficits, seen in schizophrenics and their first-degree relatives, are normalized by nicotine, suggesting that the high incidence of tobacco use in the mentally ill is an attempt at self-medication Adler et al., 1998, Leonard et al., 1998a, Leonard et al., 2000. Nicotine, administered either as gum or in cigarettes, normalizes the P50 deficit in both schizophrenics and their nongating relatives Adler et al., 1992, Adler et al., 1993. An effect on desensitization of
Effects of neuroleptic treatment on auditory sensory gating and eye tracking
Typical (haloperidol) and atypical (clozapine) neuroleptic medication have differing effects on sensory-processing measures. Haloperidol, thought to act principally as a dopamine D2 receptor antagonist (Farde et al., 1992), has no effect on the auditory-evoked potential deficits seen in schizophrenics and their first-degree relatives Freedman et al., 1983, Adler et al., 1990. The atypical neuroleptic clozapine, however, normalizes the P50 deficit (Nagamoto et al., 1996). Clozapine has also been
Nicotinic receptors in animal models of sensory processing
Processing of sensory information also occurs in animals, where invasive pharmacological techniques can be used. The work described above suggested that the nicotinic acetylcholine receptors might be involved in the brain pathways active in sensory processing. Using a paradigm of paired auditory stimuli, similar to that used in the human experiments, gating of the second or test response was observed in anesthetized rats Adler et al., 1986, Bickford-Wimer et al., 1990. Although an antagonist of
Human genetics of auditory gating
The studies in inbred mouse strains suggested that inhibition of auditory responses is inherited in these animal models. Auditory-gating deficits are also inherited in human subjects. While gating deficits are present in more than 80% of schizophrenic subjects, they are also present in about 50% of the first-degree relatives of schizophrenics and at a lower level in the general population (Waldo et al., 1991). Not all of the first-degree relatives have schizophrenia, suggesting that the
Expression of the low-affinity nicotinic acetylcholine receptor in schizophrenia
The correlation of low levels of α7 receptor expression with loss of auditory gating in the mouse models suggested that low levels of α7 expression might also be found in schizophrenia. Using receptor autoradiography, we measured binding of [125I]-α-bungarotoxin in postmortem hippocampus isolated from both schizophrenic and control subjects, matched for smoking history. Binding was found on both the cell somata and on cellular processes of large nonprincipal cells in both the dentate hilar
High-affinity nicotinic receptor expression is also decreased in schizophrenia
In human brain, [3H]-nicotine binding, which measures high-affinity nicotinic acetylcholine receptors, is increased in smokers compared to nonsmokers Benwell et al., 1988, Breese et al., 1997b, Perry et al., 1999. In subjects who had quit smoking for some time before death, receptor levels had returned to control levels. Receptor number is correlated with the packs of cigarettes used per day, but not with the length of time subjects have smoked in their lifetime (Breese et al.,1997b),
Polymorphism in the human α7 gene
We isolated both cDNA (GenBank accession: U40583) and genomic clones for the human α7 nicotinic receptor subunit gene (Gault et al., 1998). The gene is coded for by 10 exons with a gene size of approximately 75 kb. A putative promoter region of 2.6 kb was also isolated. Generation of a yeast artificial chromosome (YAC) map across the linkage region on chromosome 15q14 and mapping of noncoding polymorphisms in the gene revealed that the human α7 gene is partially duplicated. Exons 5–10 are
Discussion
Progress has been made in understanding the biological basis of smoking in the mentally ill, at least for schizophrenia in which the incidence of smoking is the most prevalent. Schizophrenics appear to have decreased expression of both high- and low-affinity nicotinic receptors. Further, nicotinic receptor up-regulation, seen in human tobacco use, may not be present in these patients. Expression of the α7 nicotinic receptor subunit has been studied more thoroughly than other subunits, since it
References (139)
- et al.
Neurophysiological studies of sensory gating in rats: effects of amphetamine, phencyclidine, and haloperidol
Biol Psychiatry
(1986) - et al.
Sensory physiology and catecholamines in schizophrenia and mania
Psychiatry Res
(1990) - et al.
10 Years of studies on P50 sensory gating—a review and considerations for future studies
Schizophr Res
(1991) - et al.
Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics
Biol Psychiatry
(1992) - et al.
The opioid antagonist naltrexone inhibits activity and alters expression of alpha 7 and alpha 4 beta 2 nicotinic receptors in hippocampal neurons: implications for smoking cessation programs
Neuropharmacology
(2000) - et al.
Neurophysiological assessment of sensory gating in psychiatric inpatients: comparison between schizophrenia and other diagnoses
Biol Psychiatry
(1987) - et al.
Sensitization of the mesoaccumbens dopamine response to nicotine
Pharmacol, Biochem Behav
(1998) Genetics of schizophrenia and the new millennium: progress and pitfalls
Am J Hum Genet
(2001)- et al.
[3H]Nicotine binding in peripheral blood cells of smokers is correlated with the number of cigarettes smoked per day
Neuropharmacology
(2000) - et al.
Auditory sensory gating in hippocampal neurons: a model system in the rat
Biol Psychiatry
(1990)