J. Logel

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.

Biological stability of mRNA isolated from human postmortem brain collections

RNA isolated from frozen human postmortem brain tissue was evaluated for its utility in molecular biological studies. Samples varying in postmortem interval, delay period before freezing, and long-term freezer storage were analyzed. It was found that storage of human postmortem brain at -70 degrees C for more than 5 years may compromise its use for oligo-dT primed library construction and in vitro expression studies. Although biological competency of the messenger RNA may be affected by long-term freezer storage of human brain, enough full-length or partial transcripts remained for amplification by the polymerase chain reaction. We conclude that human postmortem brain collections will continue to be valuable resources for the study of gene expression and isolation of nucleotide sequences.

Comparison of polymorphisms in the α7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects

The hypothesis that the 15q13‐15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The α7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first‐degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty‐one variants were found in the exons, but non‐synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal.

[3H]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.

Multiple genes in the 15q13-q14 chromosomal region are associated with schizophrenia

Objective The chromosomal region, 15q13-q14, including the &agr;7 nicotinic acetylcholine receptor gene, CHRNA7, is a replicated region for schizophrenia. This study fine-mapped genes at 15q13-q14 to determine whether the association is unique to CHRNA7. Methods Family-based and case–control association studies were performed on Caucasian-non-Hispanic and African-American individuals from 120 families as well as 468 individual patients with schizophrenia and 144 well-characterized controls. Single-nucleotide polymorphism (SNP) markers were genotyped, and association analyses carried out for the outcomes of schizophrenia, smoking, and smoking in schizophrenia. Results Three genes were associated with schizophrenia in both ethnic populations: TRPM1, KLF13, and RYR3. Two SNPs in CHRNA7 were associated with schizophrenia in African-Americans, and a second SNP in CHRNA7 was significant for an association with smoking and smoking in schizophrenia in Caucasians. Conclusion Results of these studies support association of the 15q13-q14 region with schizophrenia. The broad positive association suggests that more than one 15q gene may be contributing to the disorder, either in combination or through a regulatory mechanism.