Genetics of Smoking and Schizophrenia

Abstract

Schizophrenia is a common mental illness with a high prevalence of smoking. More than 80% of schizophrenics smoke compared to 25% of the general population. Both schizophrenia and tobacco use have strong genetic components, which may overlap. It has been suggested that smoking in schizophrenia may be a form of self-medication in an attempt to treat an underlying biological pathology. Smoking normalizes auditory evoked potential and eye tracking deficits in schizophrenia, as well as improving cognitive function. Nicotine acts through a family of nicotinic receptors with either high or low affinity for nicotine. The loci for several of these receptors have been genetically linked to both smoking and to schizophrenia. Smoking changes gene expression for more than 200 genes in human hippocampus, and differentially normalizes aberrant gene expression in schizophrenia. The α7* nicotinic receptor, linked to schizophrenia and smoking, has been implicated in sensory processing deficits and is important for cognition and protection from neurotoxicity. Nicotine, however, has multiple health risks and desensitizes the receptor. A Phase I trial of DMXB-A, an α7* agonist, shows improvement in both P50 gating and in cognition, suggesting that further development of nicotinic cholinergic drugs is a promising direction in schizophrenia research.Schizophrenia and smoking are closely connected. The prevalence of tobacco use in schizophrenia is inordinately high. Only 25% of the general population now smokes, but more than 80% of schizophrenics use tobacco products (de Leon and Diaz, 2005;Diwan et al

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

“…Postmortem evaluations of the brains of patients with schizophrenia show reduced expression of the low-affinity α7 nAChRs in multiple brain regions including the hippocampus, reticular nucleus of the thalamus, and cortex (Court et al, 1999; Freedman et al, 1995; Guan et al, 1999; Kunii et al, 2015; Leonard et al, 2007; Olincy and Stevens, 2007). However, the mRNA and protein levels of α7 nAChR were found to be similar between smokers with schizophrenia and healthy smokers indicating an aberrant assembly or trafficking of these receptors in schizophrenia that may be corrected by smoking (Mexal et al, 2010).…”

“…However, there have been two overarching theories proposed to explain widespread smoking behavior among subjects with schizophrenia. The first one is the self-medication hypothesis that posits that excessive nicotine use represents a form of self-medication strategy to alleviate the negative and cognitive symptoms of the disorder (Adler et al, 1998; Kumari and Postma, 2005; Leonard et al, 2007; Sacco et al, 2004). The remediation of schizophrenia symptoms by nicotine is proposed to involve modulation of neurotransmitter signaling that is implicated in schizophrenia pathology (Kumari and Postma, 2005).…”

Nicotinic ACh receptors as therapeutic targets in CNS disorders

“…Schizophrenia has both genetic and environmental etiologies, and has been previously genetically linked to dysfunction in the hippocampal nAChR system [132]. In contrast to ASD, the schizophrenia patient population exhibits a much higher prevalence for smoking than the general population which some consider to be a form of self-medication as it may normalize some of the cognitive and sensory deficits [133, 134]. Nicotine exposure (either through smoking, nicotine gum, nasal spray, or the patch) appears to improve or normalize sensory deficits in schizophrenia [134]; however due to the adverse health effects and toxicity of nicotine, other ligands acting on nAChRs may prove useful as a treatment option for symptoms related to schizophrenia.…”

Transcriptional Repression of the α7 Nicotinic Acetylcholine Receptor Subunit Gene (CHRNA7) by Activating Protein-2α (AP-2α)

“…Expression of the ␣7 neuronal nicotinic acetylcholine receptor, ␣7*nAChR, is decreased in post-mortem hippocampus, cortex, and reticular nucleus of the thalamus in schizophrenia (55)(56)(57)(58), suggesting that smoking may be a form of self-medication (59,60). The ␣7*nAChR is a major pharmacological target in the development of treatments for schizophrenia and other neurological disorders (61).…”