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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Dual Diagn. Author manuscript; available in PMC 2009 January 2.
Published in final edited form as:
J Dual Diagn. 2007 November 1; 3(3-4): 43–59.
doi:  10.1300/J374v03n03_05
PMCID: PMC2613326

Smoking, Genetics and Schizophrenia: Evidence for Self Medication


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., 1998;George and Krystal, 2000;Hakko et al., 2006;Leonard et al., 2000;CDC, 2005). Schizophrenics smoke high-tar cigarettes and extract more nicotine per cigarette than do control smokers (Olincy et al., 1997;Strand and Nyback, 2005). Smoking in schizophrenia may begin in the prodromal phase of the disorder (Weiser et al., 2003). Although many aspects of nicotine addiction in schizophrenia are similar to those of non-mentally ill smokers (Mansvelder et al., 2006;Ziedonis et al., 1994), it has been proposed that smoking in schizophrenia may also be a form of self-medication, as an attempt to correct underlying neuropathologies (Adler et al., 1990;Adler et al., 1993;Adler et al., 1998;Leonard et al., 2001;Kumari and Postma, 2005;Sacco et al., 2004). Growing evidence supports this hypothesis.

Nicotinic receptors are genetically linked to smoking and schizophrenia

Nicotine acts through a family of nicotinic acetylcholine receptors found in the brain and periphery (Leonard and Bertrand, 2001;Gotti et al., 2006). The neuronal nicotinic receptor gene family, as expressed in mammalian tissues, consists of 11 genes (α2-α7, α9, α10; β2-β4). The receptor assembles as a pentamer (Cooper et al., 1991). Upon ligand binding, the channel opens and fluxes Na+ and Ca++ (Vijayaraghavan et al., 1992). Receptors are of two classes, those consisting of both α and β subunits and homomers of α7 subunits. Nicotinic receptors are further characterized by those that bind nicotine with high affinity (principally α4β2*) and the low affinity α7* receptor (McGehee and Role, 1995;Leonard and Bertrand, 2001).

Both tobacco use (Heath and Martin, 1993;Bergen and Caporaso, 1999;Carmelli et al., 1992;Bierut et al., 2007;Saccone et al., 2007) and schizophrenia (Owen et al., 2004;Tsuang and Faraone, 1994;Badner and Gershon, 2002;Lewis et al., 2003;Harrison and Weinberger, 2005) have strong genetic components. Several nicotinic receptor genes have recently been associated with nicotine dependence (Saccone et al., 2007). Additionally, genetic linkage studies of smoking in schizophrenia show that these linkage sites coincide with replicated sites of linkage in schizophrenia as a disease (Faraone et al., 2004), suggesting a genetic overlap between smoking and schizophrenia. Faraone et al. found linkage of smoking in schizophrenia to the α2 (8p21), β2 (1q21), and α7 (15q14) nicotinic receptor subunits. The locus of the α7 subunit, 15q14, has also been linked to the P50 deficit in schizophrenia with a LOD score of 5.3 (Freedman et al., 1997). Linkage of this site to schizophrenia has been replicated in multiple studies (Freedman et al., 2001a;Freedman et al., 2001b;Leonard et al., 1998;Xu et al., 2001;Liu et al., 2001;Tsuang et al., 2001;Kaufmann et al., 1998;Stober et al., 2000;Riley et al., 2000). A linkage of smoking in schizophrenia to a dinucleotide repeat in intron 2 of the α7 gene, CHRNA7, was recently reported (De Luca et al., 2004), further supporting a role for the α7* receptor in smoking in schizophrenia.

Normalization of sensory processing and cognitive deficits by smoking in schizophrenia

Schizophrenics suffer from multiple sensory processing deficits including auditory sensory processing (P50 deficits) (Adler et al., 1991), eye-tracking deficits (Iacono et al., 1992;Ross et al., 1998;Holzman et al., 1973), pre-pulse inhibition (PPI) abnormalities (Braff et al., 2001;Meincke et al., 2004), and cognitive deficiencies (Barch et al., 2003;Cornblatt and Malhotra, 2001;Leger et al., 2000). Smoking has been found to improve all of these deficits in schizophrenic patients.

The P50 response is measured by electroencephalography as a wave that occurs with a 50 msec latency after an auditory stimulus. When a second stimulus is given 0.5 sec later, the response is inhibited or gated (Adler et al., 1991). Schizophrenics, however, fail to gate out the second response, suggesting that an inhibitory mechanism is aberrant in these patients (Adler et al., 1982;Freedman et al., 2000). The P50 deficit is inherited; approximately 50% of first degree relatives of schizophrenics also have the deficit (Waldo et al., 2000). Smoking transiently normalizes the P50 deficit, in both schizophrenic patients (Adler et al., 1993;Griffith et al., 1998), and their first-degree relatives (Adler et al., 1992).

Pre-pulse inhibition (PPI) is somewhat similar to effects seen in the P50 response. PPI measures the effects of a weak stimulus given prior to a strong stimulus on the response to the strong stimulus. A normal performance is a reduction in the amplitude of the second response (Graham, 1975), again implying an inhibitory mechanism. PPI is abnormal in schizophrenic subjects; the first stimulus does not inhibit the second response (Braff et al., 2001). As with the P50 deficit, PPI appears to be inherited (Anokhin et al., 2003). These two endophenotypes may have some causal factors in common, but they are inherited independently (Kumari et al., 2000) and, unlike the P50, PPI involves a motor response. Smoking has a positive effect on PPI deficits in schizophrenia (Kumari et al., 2001). PPI is impaired by smoking abstinence in schizophrenia and improved by acute smoking reinstatement, mediated by stimulation of nicotinic receptors (George et al., 2006).

Eye-tracking deficits are also inherited (Holzman et al., 1984) and improved by smoking in schizophrenia (Olincy et al., 1998;Larrison-Faucher et al., 2004;Avila et al., 2003). The eye-tracking abnormalities most often studied include smooth-pursuit (SPEM) and antisaccade responses. The first measures accuracy of eye movement following a moving target, and the latter measures an inhibitory response in which the subject is asked to generate an eye movement in opposite orientation to the target. Both SPEM and antisaccade performance were improved in schizophrenic patients on nicotine (Olincy et al., 2003;Klein and Andresen, 1991;Depatie et al., 2002;Avila et al., 2003). It has also been recently shown in an fMRI study that eye-tracking performance is improved through cholinergic stimulation of the hippocampus and cingulate gyrus (Tanabe et al., 2006).

Nicotine is known to improve cognitive function in animal studies (Levin and Simon, 1998;Levin et al., 2006). Cognitive deficits are common in schizophrenia including decreased attention and working memory (Barch et al., 2003;Cornblatt and Malhotra, 2001;Leger et al., 2000;Sharma and Antonova, 2003). Both attention (Lohr and Flynn, 1992) and working memory (Jacobsen et al., 2004;Myers et al., 2004;Sacco et al., 2005) are improved in schizophrenic patients by smoking. Withdrawal of schizophrenic smokers worsened a visuospatial working memory task (George et al., 2002).

These results are summarized in Table 1 and are consistent with a self-medication hypothesis. Schizophrenics may be attempting to treat these underlying endophenotypic deficits by smoking.

Table 1
Evidence for self-medication by smoking in schizophrenia

Animal studies show a link between the α7* receptor and sensory processing deficits

In animal studies, blockade of the α7* receptor with specific antagonists results in loss of auditory sensory gating, similar to that seen in schizophrenia (Luntz-Leybman et al., 1992). A mouse model of low levels of hippocampal Chrna7 expression exists in the DBA/2j mouse compared to the C3H strain with high levels of expression (Stevens et al., 1996). Treatment of these mice with 3–2,4 dimethoxybenzylidene anabaseine (DMXB-A), a specific agonist of the α7* receptor results in normalization of the sensory gating deficit (Simosky et al., 2001;Stevens et al., 1998).

Nicotinic receptor expression is low in postmortem brain of schizophrenic subjects

The expression of the CHRNA7 gene is low in schizophrenic postmortem hippocampus (Freedman et al., 1995). This finding has been replicated in cortex (Guan et al., 1999;Marutle et al., 2001) and in the reticular nucleus of the thalamus (Court et al., 1999). The CHRNA7 gene has been cloned (Peng et al., 1994;Breese et al., 1997a). The gene is partially duplicated; exons 5–10 were duplicated proximal to the full-length CHRNA7 gene, interrupting a partial duplication of a second gene (Gault et al., 1998). A transcript from the chimeric gene, CHRFAMA7, is expressed in the brain and periphery as mRNA. It does not appear to form a functional receptor, nor to interfere with expression of the full-length receptor (Villiger et al., 2002). Function of the duplicated gene remains unknown, but it is present in fewer copies in both schizophrenia and bipolar disorder (Gault et al., 1998;De Luca et al., 2006a;Perl et al., 2006). A 2bp deletion in the duplicated gene, CHRFAMA7, has been associated with risk for the P50 deficit (Raux et al., 2002).

High affinity nicotinic receptors, principally the α4β2* receptors, are also decreased in expression in schizophrenic hippocampus, as determined by [3H]-nicotine binding (Breese et al., 2000). In normal hippocampus, receptors in smokers increase in number by approximately 50% (Breese et al., 1997b). However, in schizophrenic subjects, this increase does not occur. Schizophrenic smokers have only slightly elevated receptor binding (Breese et al., 2000). A recent report shows a genetic interaction between the α4 and β2 subunits and schizophrenia (De Luca et al., 2006b), again suggesting a link between nicotinic receptors and the disorder. There is also recent evidence in animal studies that the α4β2* receptor may contribute to the effects of nicotine on sensory gating in a mouse model (Radek et al., 2006).

Consequences of decreased levels of nicotinic receptors in schizophrenia

The functions of nicotinic receptors are several. Stimulation of the receptors by acetylcholine, the endogenous ligand, or nicotine opens the channel allowing Ca++ influx (Mansvelder and McGehee, 2002;McGehee and Role, 1996;Vijayaraghavan et al., 1992). This results in release of a large number of different neurotransmitters, including dopamine, glutamate, acetylcholine, serotonin, and GABA (Dajas-Bailador and Wonnacott, 2004;Wonnacott, 1997;Rousseau et al., 2005;Guo et al., 1998;Zhu and Chiappinelli, 2002). The α7* receptor can also have a post-synaptic localization in or near the NMDA post-synaptic density (PSD) (Conroy et al., 2003;Shoop et al., 1999;Levy and Aoki, 2002) where Ca++ influx can have downstream affects on gene expression. It is the modulation of these neurotransmitter systems by chronic nicotine stimulation that likely results in addiction to tobacco products. For schizophrenic smokers, decreased nicotinic receptors can lead to changes in overall neurotransmitter release and also changes in gene expression, compared to control smokers (Leonard, 2003). A microarray study of global gene expression in human hippocampus of control and schizophrenic smokers and non-smokers showed that 277 genes were significantly changed in expression in smokers. The most significantly changed group of genes were those playing a role in the NMDA-PSD. More importantly, in schizophrenic smokers, 77 genes were differentially regulated by smoking (Mexal et al., 2005). The differential regulation fit specific patterns showing that gene expression was abnormal in schizophrenic non-smokers, compared to control subjects (either up- or down-regulated). In schizophrenic smokers, the expression was brought to control levels, or normalized. If the expression of a specific gene was up-regulated in schizophrenic non-smokers, in schizophrenic smokers expression was decreased to control levels. If the expression was decreased in schizophrenic non-smokers, compared with controls, it was increased to control expression values in schizophrenic smokers (Mexal et al., 2005). The microarray results were confirmed by real-time quantitative PCR (qRTPCR). These results are consistent with a self medication model for smoking in schizophrenia (Table 1); smoking is normalizing gene expression for a large number of genes, several of which lie in the NMDA-PSD, the most prevalent excitatory synapse in brain.

Alternatives to smoking for schizophrenia

Smoking improves psychiatric symptoms in schizophrenia (Glynn and Sussman, 1990), particularly negative symptoms (Smith et al., 2002;Dalack et al., 1999). However nicotine is obviously not a good drug for schizophrenia. Besides its adverse health risks, nicotine quickly desensitizes its receptors (Alkondon et al., 2000;Benwell et al., 1995;Dani et al., 2000;Grady et al., 1994;Griffith et al., 1998;Marks et al., 1994;Quick and Lester, 2002), abrogating its effects. The α7* receptor has been selected as a major target for drug development for cognitive deficits in schizophrenia by the NIMH Committee on Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) (Bromley, 2005;Psychiatric News, 2006). Recently several new agonists have been introduced, including 3–2,4 dimethoxybenzylidene anabaseine (DMXB-A), a derivative of a marine worm toxin (Martin et al., 2004;Kem, 2000). In animal models, DMXB-A was found to normalize aberrant auditory gating (O’Neill et al., 2003;Stevens et al., 1998) and to have effects on cognition (Arendash et al., 1995;Bjugstad et al., 1996;Kem, 2000;Hunter et al., 1994). A Phase I trial of adjunct DMXB-A for schizophrenic non-smokers has been completed. Results show improvements in both the sensory processing P50 deficit and in cognition (Olincy et al., 2006). The major effect on cognition was on attention, as measured by the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). A Phase II trial is underway in which effects in schizophrenic smokers will be assessed. Such drugs may be effective for smoking in schizophrenia as well as for cognitive and sensory therapy. Clozapine, an atypical neuroleptic, results in decreased smoking in schizophrenia (McEvoy et al., 1995;George et al., 1995). Clozapine blocks the 5HT3 receptor, resulting in release of acetylcholine (Shirazi-Southall et al., 2002). Clozapine also normalizes the P50 deficit in schizophrenia (Nagamoto et al., 1996). Another antagonist of the 5HT3 receptor, tropisetron, was recently shown to normalize the P50 deficit (Koike et al., 2005). The hypothesis of the action of these drugs is that they act at nicotinic receptors by releasing endogenous acetylcholine.


While some aspects of nicotine addiction are likely to be similar across all chronic users of tobacco products, both biological and molecular evidence suggests that schizophrenics are smoking, at least partially, to self-medicate underlying neuropathology. Sensory processing deficits are normalized by smoking in schizophrenia. Low levels of nicotinic receptors in schizophrenia may lead to differences in neurotransmitter release and differential changes in gene expression in which abnormal expression is normalized by smoking. The development of drugs targeted to nicotinic receptors, particularly the α7* receptor, represents an important research endeavor.

Reference List

  • Adler GK, Smas CM, Fiandaca M, Frim DM, Majzoub JA. Regulated expression of the human corticotropin releasing hormone gene by cyclic AMP. Mol Cell Endocrinol. 1990;70:165–174. [PubMed]
  • Adler LE, Hoffer LD, Wiser A, Freedman R. Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psych. 1993;150:1856–1861. [PubMed]
  • Adler LE, Hoffer LJ, Griffith J, Waldo MC, Freedman R. Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psych. 1992;32:607–616. [PubMed]
  • Adler LE, Olincy A, Waldo MC, Harris JG, Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman R. Schizophrenia, sensory gating, and nicotinic receptors. Schiz Bull. 1998;24:189–202. [PubMed]
  • Adler LE, Pachtman E, Franks R, Pecevich M, Waldo MC, Freedman R. Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry. 1982;17:639–654. [PubMed]
  • Adler LE, Waldo MC, Nagamoto HT, Baker N, Franks R, Bickford-Wimer PC, Rose G, Gerhardt G, Drebing C, Johnson R, Stevens K, Johnson M, HOFFER L, Pecevich M, Pachtman E, Alpert J, LEYBMAN V, Freedman R. 10 Years of studies on P50 sensory gating - A review and considerations for future studies. Schizophrenia Research. 1991;4:329.
  • Alkondon M, Pereira EFR, Almeida LEF, Randall WR, Albuquerque EX. Nicotine at concentrations found in cigarette smokers activates and desensitizes nicotinic acetylcholine receptors in CA1 interneurons of rat hippocampus. Neuropharmacology. 2000;39:2726–2739. [PubMed]
  • Anokhin AP, Heath AC, Myers E, Ralano A, Wood S. Genetic influences on prepulse inhibition of startle reflex in humans. Neuroscience Letters. 2003;353:45–48. [PubMed]
  • Arendash GW, Sengstock GJ, Sanberg PR, Kem WR. Improved learning and memory in aged rats with chronic administration of the nicotinic receptor agonist GTS-21. Brain Research. 1995;674:252–259. [PubMed]
  • Avila MT, Sherr JD, Hong E, Myers CS, Thaker GK. Effects of nicotine on leading saccades during smooth pursuit eye movements in smokers and nonsmokers with schizophrenia. Neuropsychopharmacology. 2003;28:2184–2191. [PubMed]
  • Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Molecular Psychiatry. 2002;7:405–411. [PubMed]
  • Barch DM, Sheline YI, Csernansky JG, Snyder AZ. Working memory and prefrontal cortex dysfunction: Specificity to schizophrenia compared with major depression. Biological Psychiatry. 2003;53:376–384. [PubMed]
  • Benwell ME, Balfour DJ, Birrell CE. Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine. British Journal of Pharmacology. 1995;114:454–460. [PMC free article] [PubMed]
  • Bergen AW, Caporaso N. Cigarette smoking [Review] Journal of the National Cancer Institute. 1999;91:1365–1375. [PubMed]
  • Bierut LJ, et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet. 2007;16:24–35. [PMC free article] [PubMed]
  • Bjugstad KB, Mahnir VM, Kem WR, Socci DJ, Arendash GW. Long-term treatment with GTS-21 or nicotine enhances water maze performance in aged rats without affecting the density of nicotinic receptor subtypes in neocortex. Drug Development Research. 1996;39:19–28.
  • Braff DL, Geyer MA, Swerdlow NR. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology. 2001;156:234–258. [PubMed]
  • Breese CR, Adams C, Logel J, Drebing C, Rollins Y, Barnhart M, Sullivan B, DeMasters BK, Freedman R, Leonard S. Comparison of the regional expression of nicotinic acetylcholine receptor α7 mRNA and [125I]-α-bungarotoxin binding in human postmortem brain. J Comp Neuro. 1997a;387:385–398. [PubMed]
  • Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S. Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology. 2000;23:351–364. [PubMed]
  • Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, Leonard S. Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharm Ex Ther. 1997b;282:7–13. [PubMed]
  • Bromley E. A Collaborative Approach to Targeted Treatment Development for Schizophrenia: A Qualitative Evaluation of the NIMH-MATRICS Project. Schizophr Bull. 2005;31:954–961. [PubMed]
  • Carmelli D, Swan GE, Robinette D, Fabsitz R. Genetic influence on smoking-a study of male twins. N E J M. 1992;327:829–833. [PubMed]
  • CDC. Annual smoking-attributable mortality, years of potential life lost, and productivity losses--United States, 1997–2001. Morbidity and Mortality Weekly Report. 2005;54:625–628. [PubMed]
  • Conroy WG, Liu ZP, Nai Q, Coggan JS, Berg DK. PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons. Neuron. 2003;38:759–771. [PubMed]
  • Cooper E, Couturier S, Ballivet M. Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor. Nature. 1991;350:235–238. [PubMed]
  • Cornblatt BA, Malhotra AK. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. American Journal of Medical Genetics. 2001;105:11–15. [PubMed]
  • Court J, Spurden D, Lloyd S, McKeith I, Ballard C, Cairns N, Kerwin R, Perry R, Perry E. Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alpha-bungarotoxin and nicotine binding in the thalamus. J Neurochem. 1999;73:1590–1597. [PubMed]
  • Dajas-Bailador F, Wonnacott S. Nicotinic acetylcholine receptors and the regulation of neuronal signalling. Trends in Pharmacological Sciences. 2004;25:317–324. [PubMed]
  • Dalack GW, Becks L, Hill E, Pomerleau OF, Meador-Woodruff JH. Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia. Neuropsychopharmacology. 1999;21:195–202. [PubMed]
  • Dani JA, Radcliffe KA, Pidoplichko VI. Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas. European Journal of Pharmacology. 2000;393:31–38. [PubMed]
  • de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophrenia Research. 2005;76:135–157. [PubMed]
  • De Luca V, Likhodi O, Van Tol HHM, Kennedy JL, Wong AHC. Regulation of alpha 7-nicotinic receptor subunit and alpha 7-like gene expression in the prefrontal cortex of patients with bipolar disorder and schizophrenia. Acta Psychiatrica Scandinavica. 2006a;114:211–215. [PubMed]
  • De Luca V, Voineskos S, Wong G, Kennedy JL. Genetic interaction between alpha 4 and beta 2 subunits of high affinity nicotinic receptor: analysis in schizophrenia. Experimental Brain Research. 2006b;174:292–296. [PubMed]
  • De Luca V, Wong AHC, Muller DJ, Wong GWH, Tyndale RF, Kennedy JL. Evidence of association between smoking and alpha 7 nicotinic receptor subunit gene in schizophrenia patients. Neuropsychopharmacology. 2004;29:1522–1526. [PubMed]
  • Depatie L, O’Driscoll GA, Holahan ALV, Atkinson V, Thavundayil JX, Kin NNY, Lal S. Nicotine and behavioral markers of risk for schizophrenia: A double-blind, placebo-controlled, cross-over study. Neuropsychopharmacology. 2002;27:1056–1070. [PubMed]
  • Diwan A, Castine M, Pomerleau CS, Meador-Woodruff JH, Dalack GW. Differential prevalence of cigarette smoking in patients with schizophrenic vs mood disorders. Schizophrenia Research. 1998;33:113–118. [PubMed]
  • Faraone SV, Su J, Taylor L, Wilcox M. A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families. Human Heredity. 2004;57:59–68. [PubMed]
  • Freedman R, Adams CE, Adler LE, Bickford PC, Gault J, Harris JG, Nagamoto HT, Olincy A, Ross RG, Stevens KE, Waldo M, Leonard S. Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia. American Journal of Medical Genetics. 2000;97:58–64. [PubMed]
  • Freedman R, et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proceedings of the National Academy of Sciences of the United States of America. 1997;94:587–592. [PubMed]
  • Freedman R, Hall M, Adler LE, Leonard S. Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biological Psychiatry. 1995;38:22–33. [PubMed]
  • Freedman R, Leonard S, Gault JM, Hopkins J, Cloninger CR, Kaufmann CA, Tsuang MT, Farone SV, Malaspina D, Svrakic DM, Sanders A, Gejman P. Linkage disequilibrium for schizophrenia at the chromosome 15q13–14 locus of the alpha 7-nicotinic acetylcholine receptor subunit gene (CHRNA7) American Journal of Medical Genetics. 2001a;105:20–22. [PubMed]
  • Freedman R, Leonard S, Olincy A, Kaufmann CA, Malaspina D, Cloninger CR, Svrakic D, Faraone SV, Tsuang MT. Evidence for the multigenic inheritance of schizophrenia. American Journal of Medical Genetics. 2001b;105:794–800. [PubMed]
  • Gault J, Robinson M, Berger R, Drebing C, Logel J, Hopkins J, Moore T, Jacobs S, Meriwether J, Choi MJ, Kim EJ, Walton K, Buiting K, Davis A, Breese CR, Freedman R, Leonard S. Genomic organization and partial duplication of the human α7 neuronal nicotinic acetylcholine receptor gene. Genomics. 1998;52:173–185. [PubMed]
  • George TP, Krystal JH. Comorbidity of psychiatric and substance abuse disorders. Current Opinion in Psychiatry. 2000;13:327–331.
  • George TP, Sernyak MJ, Ziedonis DM, Woods SW. Effects of clozapine on smoking in chronic schizophrenic outpatients. Journal of Clinical Psychiatry. 1995;56:344–346. [PubMed]
  • George TP, Termine A, Sacco KA, Allen TM, Reutenauer E, Vessicchio JC, Duncan EJ. A preliminary study of the effects of cigarette smoking on prepulse inhibition in schizophrenia: Involvement of nicotinic receptor mechanisms. Schizophrenia Research. 2006;87:307–315. [PubMed]
  • George TP, Vessicchio JC, Termine A, Sahady DM, Head CA, Pepper WT, Kosten TR, Wexler BE. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology. 2002;26:75–85. [PubMed]
  • Glynn SM, Sussman S. Why Patients Smoke. Hospital and Community Psychiatry. 1990;41:1027–1028. [PubMed]
  • Gotti C, Zoli M, Clementi F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends in Pharmacological Sciences. 2006;27:482–491. [PubMed]
  • Grady SR, Marks MJ, Collins AC. Desensitization of nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes. Journal of Neurochemistry. 1994;62:1390–1398. [PubMed]
  • Graham FK. More Or Less Startling Effects of Weak Pre-Stimulation. Psychophysiology. 1975;12:238–248. [PubMed]
  • Griffith JM, O’Neill JE, Petty F, Garver D, Young D, Freedman R. Nicotinic receptor desensitization and sensory gating deficits in schizophrenia. Biological Psychiatry. 1998;44:98–106. [PubMed]
  • Guan ZZ, Zhang X, Blennow K, Nordberg A. Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. Neuroreport. 1999;10:1779–1782. [PubMed]
  • Guo JZ, Tredway TL, Chiappinelli VA. Glutamate and GABA release are enhanced by different subtypes of presynaptic nicotinic receptors in the lateral geniculate nucleus. Journal of Neuroscience. 1998;18:1963–1969. [PubMed]
  • Hakko H, Lintunen J, Lappalainen J, Makikyro T, Rasanen P, Timonen M. Nicotine use and dependence and their association to psychiatric disorders in a large sample of adolescent psychiatric inpatients. Addictive Behaviors. 2006;31:1873–1880. [PubMed]
  • Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Molecular Psychiatry. 2005;10:40–68. [PubMed]
  • Heath AC, Martin NG. Genetic models for the natural history of smoking: Evidence for a genetic influence on smoking persistence. Addict Behav. 1993;18:19–34. [PubMed]
  • Holzman PS, Proctor LR, Hughes DW. Eye-tracking patterns in schizophrenia. Science. 1973;181:179–181. [PubMed]
  • Holzman PS, Solomon CM, Levin S, Waternaux CS. Pursuit eye movement dysfunctions in schizophrenia. Family evidence for specificity. Archives of General Psychiatry. 1984;41:136–139. [PubMed]
  • Hunter BE, de FC, Papke RL, Kem WR, Meyer EM. A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus. Neuroscience Letters. 1994;168:130–134. [PubMed]
  • Iacono WG, Moreau M, Beiser M, Fleming JAE, Lin T-Y. Smooth-pursuit eye tracking in first-episode psychotic patients and their relatives. J Abnorm Psych. 1992;101:104–116. [PubMed]
  • Jacobsen LK, D’Souza DC, Mencl WE, Pugh KR, Skudlarski P, Krystal JH. Nicotine effects on brain function and functional connectivity in schizophrenia. Biological Psychiatry. 2004;55:850–858. [PubMed]
  • Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD, Meyer J, Zambuto CT, Schmitt K, Matise TC, Harkavy-Friedman JM, Hampe C, Lee H, Shore D, Wynne D, Faraone SV, Tsuang MT, Cloninger CR. NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet. 1998;81:282–289. [PubMed]
  • Kem WR. The brain alpha 7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer’s disease: studies with DMXBA (GTS-21) Behavioural Brain Research. 2000;113:169–181. [PubMed]
  • Klein C, Andresen B. On the influence of smoking upon smooth pursuit eye movements of schizophrenics and normal controls. J Psychophysiol. 1991;5:361–369.
  • Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, Nakazato M, Okamura N, Stevens KE, Freedman R, Iyo M. Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophrenia Research. 2005;76:67–72. [PubMed]
  • Kumari V, Crawford T, Soni W, Chitnis X, Piper K, Sharma T. Prepulse inhibition effects do not correlate with anti-saccadic abnormalities in schizophrenia. Schizophrenia Research. 2000;41:146–147.
  • Kumari V, Postma P. Nicotine use in schizophrenia: The self medication hypotheses. Neuroscience and Biobehavioral Reviews. 2005;29:1021–1034. [PubMed]
  • Kumari V, Soni W, Sharma T. Influence of cigarette smoking on prepulse inhibition of the acoustic startle response in schizophrenia. Human Psychopharmacology-Clinical and Experimental. 2001;16:321–326. [PubMed]
  • Larrison-Faucher AL, Matorin AA, Sereno AB. Nicotine reduces antisaccade errors in task impaired schizophrenic subjects. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2004;28:505–516. [PubMed]
  • Leger C, Stip E, Lussier I. Attention and memory impairment in schizophrenia: a longitudinal study of drug naive patients. Annales Medico-Psychologiques. 2000;158:750–767.
  • Leonard S. Consequences of low levels of nicotinic acetylcholine receptors in schizophrenia for drug development. Drug Development Research. 2003;60:127–136.
  • Leonard S, Adler LE, Benhammou K, Berger R, Breese CR, Drebing C, Gault J, Lee MJ, Logel J, Olincy A, Ross RG, Stevens K, Sullivan B, Vianzon R, Vernich DE, Waldo M, Walton K, Freedman R. Smoking and mental illness. Pharmacol Biochem Behav. 2001;70:561–570. [PubMed]
  • Leonard S, Bertrand D. Neuronal nicotinic receptors: from structure to function. Nicotine & Tobacco Research. 2001;3:203–223. [PubMed]
  • Leonard S, Breese C, Adams C, Benhammou K, Gault J, Stevens K, Lee M, Adler L, Olincy A, Ross R, Freedman R. Smoking and schizophrenia: abnormal nicotinic receptor expression. European Journal of Pharmacology. 2000;393:237–242. [PubMed]
  • Leonard S, Gault J, Moore T, Hopkins J, Robinson M, Olincy A, Adler LE, Cloninger CR, Kaufmann CA, Tsuang MT, Faraone SV, Malaspina D, Svrakic DM, Freedman R. Further investigation of a chromosome 15 locus in schizophrenia: analysis of affected sibpairs from the NIMH Genetics Initiative. Am J Med Genet. 1998;81:308–312. [PubMed]
  • Levin ED, McClernon FJ, Rezvani AH. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology. 2006;184:523–539. [PubMed]
  • Levin ED, Simon BB. Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology. 1998;138:217–230. [PubMed]
  • Levy RB, Aoki C. alpha 7 nicotinic acetylcholine receptors occur at postsynaptic densities of AMPA receptor-positive and -negative excitatory synapses in rat sensory cortex. Journal of Neuroscience. 2002;22:5001–5015. [PMC free article] [PubMed]
  • Lewis CM, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. American Journal of Human Genetics. 2003;73:34–48. [PubMed]
  • Liu CM, Hwu HG, Lin MW, Ou-Yang WC, Lee SFC, Fann CSJ, Wong SH, Hsieh SH. Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13–14 in Taiwanese families. American Journal of Medical Genetics. 2001;105:658–661. [PubMed]
  • Lohr JB, Flynn K. Smoking and schizophrenia. Schizo Res. 1992;8:93–102. [PubMed]
  • Luntz-Leybman V, Bickford PC, Freedman R. Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res. 1992;587:130–136. [PubMed]
  • Mansvelder HD, McGehee DS. Cellular and synaptic mechanisms of nicotine addiction. Journal of Neurobiology. 2002;53:606–617. [PubMed]
  • Mansvelder HD, van Aerde KI, Couey JJ, Brussaard AB. Nicotinic modulation of neuronal networks: from receptors to cognition. Psychopharmacology. 2006;184:292–305. [PubMed]
  • Marks MJ, Grady SR, Yang J-M, Lippiello PM, Collins AC. Desensitization of nicotine-stimulated 86Rb+ efflux from mouse brain synaptosomes. 1994 submitted. [PubMed]
  • Martin LF, Kem WR, Freedman R. Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology. 2004;174:54–64. [PubMed]
  • Marutle A, Zhang X, Court J, Piggott M, Johnson M, Perry R, Perry E, Nordberg A. Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia. Journal of Chemical Neuroanatomy. 2001;22:115–126. [PubMed]
  • McEvoy J, Freudenreich O, McGee M, Vanderzwaag C, Levin, Rose J. Clozapine decreases smoking in patients with chronic schizophrenia. Biological Psychiatry. 1995;37:550–552. [PubMed]
  • McGehee DS, Role LW. Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Ann Rev Physiol. 1995;57:521–546. [PubMed]
  • McGehee DS, Role LW. Presynaptic ionotropic receptors. [Review] [96 refs] Current Opinion in Neurobiology. 1996;6:342–349. [PubMed]
  • Meincke U, Heekeren K, Gouzoulis-Mayfrank E. PPI, habituation and sensitization of startle reflexes in schizophrenia. European Neuropsychopharmacology. 2004;14:S142.
  • Mexal S, Frank M, Berger R, Adams CE, Ross RG, Freedman R, Leonard S. Differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic and control smokers. Molecular Brain Research. 2005;139:317–332. [PubMed]
  • Myers CS, Robles O, Kakoyannis AN, Sherr JD, Avila MT, Blaxton TA, Thaker GK. Nicotine improves delayed recognition in schizophrenic patients. Psychopharmacology. 2004;174:334–340. [PubMed]
  • Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R. Gating of auditory P50 in schizophrenics: Unique effects of clozapine. Biological Psychiatry. 1996;40:181–188. [PubMed]
  • O’Neill HC, Rieger K, Kem WR, Stevens KE. DMXB, an alpha(7) nicotinic agonist, normalizes auditory gating in isolation-reared rats. Psychopharmacology. 2003;169:332–339. [PubMed]
  • Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R. Proof-of-concept trial of an alpha 7 nicotinic agonist in schizophrenia. Archives of General Psychiatry. 2006;63:630–638. [PubMed]
  • Olincy A, Johnson LL, Ross RG. Differential effects of cigarette smoking on performance of a smooth pursuit and a saccadic eye movement task in schizophrenia. Psychiatry Research. 2003;117:223–236. [PubMed]
  • Olincy A, Ross RG, Young DA, Roath M, Freedman R. Improvement in smooth pursuit eye movements after cigarette smoking in schizophrenic patients. Neuropsychopharm. 1998;18:175–185. [PubMed]
  • Olincy A, Young DA, Freedman R. Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biological Psychiatry. 1997;42:1–5. [PubMed]
  • Owen MJ, Williams NM, O’Donovan MC. The molecular genetics of schizophrenia: findings promise new insights. Molecular Psychiatry. 2004;9:14–27. [PubMed]
  • Peng X, Katz M, Gerzanich V, Anand R, Lindstrom J. Human α7 acetylcholine receptor: Cloning of the α7 subunit from the SHSY-5Y cell line and determination of pharmacological properties of native receptors and functional α7 homomers expressed in Xenopus oocytes. Mol Pharm. 1994;45:546–554. [PubMed]
  • Perl O, Strous RD, Dranikov A, Chen R, Fuchs S. Low levels of alpha 7-nicotinic acetylcholine receptor mRNA on peripheral blood lymphocytes in schizophrenia and its association with illness severity. Neuropsychobiology. 2006;53:88–93. [PubMed]
  • Psychiatric News. Molecular Targets Ranked. Psychiatr News. 2006;41:16–1a.
  • Quick MW, Lester RAJ. Desensitization of neuronal nicotinic receptors. Journal of Neurobiology. 2002;53:457–478. [PubMed]
  • Radek RJ, Miner HM, Bratcher NA, Decker MW, Gopalakrishnan M, Bitner RS. alpha(4)beta(2) nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating. Psychopharmacology. 2006;187:47–55. [PubMed]
  • Raux G, Bonnet-Brilhault F, Louchart S, Houy E, Gantier R, Levillain D, Allio G, Haouzir S, Petit M, Martinez M, Frebourg T, Thibaut F, Campion D. The-2 bp deletion in exon 6 of the ‘alpha 7-like’ nicotinic receptor subunit gene is a risk factor for the P50 sensory gating deficit. Molecular Psychiatry. 2002;7:1006–1011. [PubMed]
  • Riley BP, Makoff AM, Magudi-Carter M, Jenkins TJ, Williamson R, Collier DA, Murray RM. Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families. Am J Med Gen. 2000;96:196–201. [PubMed]
  • Ross RG, Olincy A, Harris JG, Radant A, Adler LE, Freedman R. Anticipatory saccades during smooth pursuit eye movements and familial transmission of schizophrenia. Biol Psych. 1998;44:690–697. [PubMed]
  • Rousseau SJ, Jones IW, Pullar IA, Wonnacott S. Presynaptic alpha 7 and non-alpha 7 nicotinic acetylcholine receptors modulate [H-3]D-aspartate release from rat frontal cortex in vitro. Neuropharmacology. 2005;49:59–72. [PubMed]
  • Sacco KA, Bannon KL, George TP. Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders. Journal of Psychopharmacology. 2004;18:457–474. [PMC free article] [PubMed]
  • Sacco KA, Termine A, Seyal A, Dudas MM, Vessicchio JC, Krishnan-Sarin S, Jatlow PI, Wexler BE, George TP. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia - Involvement of nicotinic receptor mechanisms. Archives of General Psychiatry. 2005;62:649–659. [PubMed]
  • Saccone SF, et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet. 2007;16:36–49. [PMC free article] [PubMed]
  • Sharma T, Antonova L. Cognitive function in schizophrenia - Deficits, functional consequences, and future treatment. Psychiatric Clinics of North America. 2003;26:25. [PubMed]
  • Shirazi-Southall S, Rodriguez DE, Nomikos GG. Effects of typical and atypical antipsychotics and receptor selective compounds on acetylcholine efflux in the hippocampus of the rat. Neuropsychopharmacology. 2002;26:583–594. [PubMed]
  • Shoop RD, Martone ME, Yamada N, Ellisman MH, Berg DK. Neuronal acetylcholine receptors with alpha 7 subunits are concentrated on somatic spines for synaptic signaling in embryonic chick ciliary ganglia. Journal of Neuroscience. 1999;19:692–704. [PubMed]
  • Simosky JK, Stevens KE, Kern WR, Freedman R. Intragastric DMXB-A, an alpha 7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice. Biological Psychiatry. 2001;50:493–500. [PubMed]
  • Smith RC, Singh A, Infante M, Khandat A, Kloos A. Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology. 2002;27:479–497. [PubMed]
  • Stevens KE, Freedman R, Collins AC, Hall M, Leonard S, Marks JM, Rose GM. Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains. Neuropsychopharmacology. 1996;15:152–162. [PubMed]
  • Stevens KE, Kem WR, Mahnir VM, Freedman R. Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharm. 1998;136:320–327. [PubMed]
  • Stober G, Saar K, Ruschendorf F, Meyer J, Nurnberg G, Jatzke S, Franzek E, Reis A, Lesch KP, Wienker TF, Beckmann H. Splitting schizophrenia: Periodic catatonia-susceptibility locus on chromosome 15q15. American Journal of Human Genetics. 2000;67:1201–1207. [PubMed]
  • Strand JE, Nyback H. Tobacco use in schizophrenia: a study of cotinine concentrations in the saliva of patients and controls. European Psychiatry. 2005;20:50–54. [PubMed]
  • Tanabe J, Tregellas JR, Martin LF, Freedman R. Effects of nicotine on hippocampal and cingulate activity during smooth pursuit eye movement in schizophrenia. Biological Psychiatry. 2006;59:754–761. [PubMed]
  • Tsuang DW, Skol AD, Faraone SV, Bingham S, Young KA, Prabhudesai S, Haverstock SL, Mena F, Menon AS, Bisset D, Pepple J, Sauter F, Baldwin C, Weiss D, Collins J, Boehnke M, Schellenberg GD, Tsuang MT. Examination of genetic linkage of chromosome 15 to schizophrenia in a large veterans affairs cooperative study sample. American Journal of Medical Genetics. 2001;105:662–668. [PubMed]
  • Tsuang MT, Faraone SV. The genetic epidemiology of schizophrenia. Comp Ther. 1994;20:130–135. [PubMed]
  • Vijayaraghavan S, Pugh PC, Zhang Z-W, Rathouz MM, Berg DK. Nicotinic receptors that bind α-bungarotoxin on neurons raise intracellular free Ca++ Neuron. 1992;8:353–362. [PubMed]
  • Villiger Y, Szanto I, Jaconi S, Blanchet C, Buisson B, Krause KH, Bertrand D, Romand JA. Expression of an alpha 7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes. Journal of Neuroimmunology. 2002;126:86–98. [PubMed]
  • Waldo MC, Adler LE, Leonard S, Olincy A, Ross RG, Harris JG, Freedman R. Familial transmission of risk factors in the first-degree relatives of schizophrenic people. Biological Psychiatry. 2000;47:231–239. [PubMed]
  • Weiser M, Reichenberg A, Grotto IYR, Knobler HY, Lubin G, Nahon D, Davidson M. Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: A historical-prospective cohort study. Schizophrenia Research. 2003;60:55. [PubMed]
  • Wonnacott S. Presynaptic nicotinic ACh receptors. [Review] [76 refs] Trends in Neurosciences. 1997;20:92–98. [PubMed]
  • Xu JZ, Pato MT, Dalla Torre C, Medeiros H, Carvalho C, Basile VS, Bauer A, Dourado A, Valente J, Soares MJ, Macedo AA, Coelho I, Ferreira CP, Azevedo MH, Macciardi F, Kennedy JL, Pato CN. Evidence for linkage disequilibrium between the alpha 7- nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families. American Journal of Medical Genetics. 2001;105:669–674. [PubMed]
  • Zhu PJ, Chiappinelli VA. Nicotinic receptors mediate increased GABA release in brain through a tetrodotoxin-insensitive mechanism during prolonged exposure to nicotine. Neuroscience. 2002;115:137–144. [PubMed]
  • Ziedonis DM, Kosten TR, Glazer WM, Frances RJ. Nicotine dependence and schizophrenia. [Review] [12 refs] Hospital & Community Psychiatry. 1994;45:204–206. [PubMed]