Smoking and mental illness.

Patients with mental illness have a higher incidence of smoking than the general population and are the major consumers of tobacco products. This population includes subjects with schizophrenia, manic depression, depression, posttraumatic stress disorder (PTSD), attention-deficit disorder (ADD), and several other less common diseases. Smoking cessation treatment in this group of patients is difficult, often leading to profound depression. Several recent findings suggest that increased smoking in the mentally ill may have an underlying biological etiology. The mental illness schizophrenia has been most thoroughly studied in this regard. Nicotine administration normalizes several sensory-processing deficits seen in this disease. Animal models of sensory deficits have been used to identify specific nicotinic receptor subunits that are involved in these brain pathways, indicating that the alpha 7 nicotinic receptor subunit may play a role. Genetic linkage in schizophrenic families also supports a role for the alpha 7 subunit with linkage at the alpha 7 locus on chromosome 15. Bipolar disorder has some phenotypes in common with schizophrenia and also exhibits genetic linkage to the alpha 7 locus, suggesting that these two disorders may share a gene defect. The alpha 7 receptor is decreased in expression in schizophrenia. [(3)H]-Nicotine binding studies in postmortem brain indicate that high-affinity nicotinic receptors may also be affected in schizophrenia.

[(3)H]Nicotine binding in peripheral blood cells of smokers is correlated with the number of cigarettes smoked per day.

The principal sites for biological action of tobacco products are thought to be the nicotinic acetylcholine receptors (nAChR). Nicotinic receptor subunit genes, therefore, represent an important gene family for study in nicotine addiction. They are localized in both brain and in the periphery. In brain these receptors appear to function as modulators of synaptic transmission; the function of peripheral receptors is not known. Nicotinic receptor levels in human brain are regulated by smoking in a dose-dependent manner. In peripheral blood, nicotinic receptors are present on both lymphocytes and polymorphonuclear cells (PMN). We have compared [(3)H]nicotine binding in PMN isolated from smokers and non-smokers. [(3)H]nicotine binding was increased in smokers and was correlated, as in brain, with tobacco use. Expression of both mRNA and protein in lymphocytes and PMN, for a subset of nicotinic receptor subunits, suggests that these cell types contain both alpha4beta2 and alpha3beta4 receptors.

Smoking and schizophrenia: abnormal nicotinic receptor expression.

Biological and genetic evidence suggests a role for the neuronal nicotinic receptors in the neuropathophysiology of schizophrenia. Nicotine normalizes an auditory evoked potential deficit seen in subjects who suffer from the disease. Nicotinic receptors with both high and low affinity for nicotine are decreased in postmortem brain of schizophrenics compared to control subjects. The chromosomal locus of the human alpha-7 gene (15q14) is linked to the gating deficit with a lod of 5.3, and antagonists of the alpha-7 receptor (alpha-bungarotoxin and methyllycaconitine) induce a loss of gating in rodents. We have cloned the human alpha-7 gene and found it to be partially duplicated proximal to the full-length gene. The duplication is expressed in both the brain and in peripheral blood cells of normal subjects, but is missing in some schizophrenic subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.

Tobacco smoking induces expression of very-high-affinity nicotine binding sites on blood polymorphonuclear cells.

The targets of nicotine in the central nervous system (CNS) have been identified as nicotinic acetylcholine (ACh) receptors. Because of their localization in the brain, no data are available about their in vivo modifications. However, nonneuronal nicotine binding sites have been identified on peripheral blood cells. The present study was designed to evaluate the effects of tobacco smoking on granulocyte nicotine binding sites. Binding assays were performed on granulocyte membranes using (-)(3H)nicotine and were analyzed by the Scatchard method in nonsmokers (n=10), smokers (n=10), and ex-smokers (n=10). In nonsmokers, a single-affinity binding site was detected with Kd = 1.08 +/- 0.05 x 10 -9 M. In contrast, in smokers, two different classes of binding sites were identified: one with Kd1 = 2.80 +/- 0.81 x 10 -11 M and another with Kd2 = 3.92 +/- 0.58 x 10 -9 M, similar to the binding site in nonsmokers. Moreover, a twofold increase in nicotine binding-site density was observed in smokers. Ex-smokers recovered a single class of binding sites similar to those observed in nonsmokers when they had stopped smoking for more than 1 yr, whereas recent ex-smokers (1 to 8 mo) displayed a pattern similar to that in smokers, as demonstrated by the persistence of two classes of nicotine binding sites. Chronic nicotine exposure induces modifications of nicotine binding sites on granulocytes. It is noteworthy that the persistence of such alterations corresponds to the very high rate of relapse into smoking observed during the early stages of tobacco cessation. Consequently, monitoring of nicotine binding sites could constitute an interesting approach to understanding the pharmacologic mechanisms involved in tobacco dependence.