Association of Promoter Variants in the α7 Nicotinic Acetylcholine Receptor Subunit Gene With an Inhibitory Deficit Found in Schizophrenia

Leonard, Sherry; Gault, Judith; Hopkins, Jan; Logel, Judith; Vianzon, Ruby; Short, Margaret N.; Drebing, Carla; Berger, Ralph; Venn, Diana; Sirota, Pinkhas; Zerbe, Gary O.; Olincy, Ann; Ross, Randal G.; Adler, Lawrence E.; Freedman, Robert

doi:10.1001/archpsyc.59.12.1085

Cited by 423 publications

(352 citation statements)

References 61 publications

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“…A finding of genetic linkage of P50 phenotype at 15q14 (near the location of a 7 nicotinic receptor gene (Freedman et al, 1997;Leonard et al, 2002). PPI Sensory gating of the startle response to loud sound (pulse) by a muted auditory prepulse.…”

Section: Yes-n40mentioning

confidence: 99%

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

Carpenter

Koenig

2007

Neuropsychopharmacol

183

128

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Section: Yes-n40mentioning

confidence: 99%

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

Carpenter

Koenig

2007

Neuropsychopharmacol

183

128

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“…Postmortem studies have revealed a reduction in lowaffinity nAChRs in the hippocampus, and reduced smokingrelated upregulation of high-affinity nAChRs in the cortex, hippocampus, and caudate at all levels of smoking compared with controls Breese et al, 2000). Deficient P50 auditory sensory gating has been linked to polymorphisms at the site of the a7nAChR gene on chromosome 15q14 and is transiently reversed by nicotine administration in smokers with schizophrenia and in nonsmoking first-degree relatives of patients with schizophrenia (Adler et al, 1992(Adler et al, , 1993Freedman et al, 1997;Leonard et al, 2002). Nicotine also improves diseaseassociated deficits in prepulse inhibition (PPI) of the acoustic startle response (Kumari et al, 2001) and oculomotor function, with improvements reported in smooth pursuit eye movement (SPEM) and antisaccade error rates (Olincy et al, 1998(Olincy et al, , 2003Depatie et al, 2002;Sherr et al, 2002;Avila et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Transdermal Nicotine on Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls

Barr

Culhane

Jubelt

et al. 2007

Neuropsychopharmacol

214

151

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Abundant evidence indicates that the neuronal nicotinic acetylcholine receptor (nAChR) system is integral to regulation of attentional processes and is dysregulated in schizophrenia. Nicotinic agonists may have potential for the treatment of cognitive impairment in this disease. This study investigated the effects of transdermal nicotine on attention in individuals with schizophrenia (n ¼ 28) and healthy controls (n ¼ 32). All participants were nonsmokers in order to eliminate confounding effects of nicotine withdrawal and reinstatement that may occur in the study of smokers. Subjects received 14 mg transdermal nicotine and identical placebo in a randomized, placebocontrolled, crossover design. A cognitive battery was conducted before and 3 h after each patch application. The primary outcome measure was performance on the Continuous Performance Test Identical Pairs (CPT-IP) Version. Nicotine significantly improved the performance on the CPT-IP as measured by hit reaction time, hit reaction time standard deviation and random errors in both groups. In addition, nicotine reduced commission errors on the CPT-IP and improved the performance on a Card Stroop task to a greater extent in those with schizophrenia vs controls. In summary, nicotine improved attentional performance in both groups and was associated with greater improvements in inhibition of impulsive responses in subjects with schizophrenia. These results confirm previous findings that a single dose of nicotine improves attention and suggest that nicotine may specifically improve response inhibition in nonsmokers with schizophrenia.

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“…Linkage of this region to schizophrenia was further replicated in families from the NIMH Schizophrenia Genetics Initiative [40] and in other studies [41,42,43,44], but there have also been some negative studies in this region [45,46]. Multiple single nucleotide polymorphisms (SNP)have been identified in the 15q14 gene promoter region that are more frequently present in people with schizophrenia and their family members than normal controls [47,48]. Furthermore, the presence of a SNP in the 15q14 gene CHRNA7 5′ core promoter is significantly associated with P50 suppression deficits [47].…”

mentioning

confidence: 95%

“…Multiple single nucleotide polymorphisms (SNP)have been identified in the 15q14 gene promoter region that are more frequently present in people with schizophrenia and their family members than normal controls [47,48]. Furthermore, the presence of a SNP in the 15q14 gene CHRNA7 5′ core promoter is significantly associated with P50 suppression deficits [47]. Association of CHRNA7 polymorphisms with P50 gating has been replicated, but the specific allelic associations differ, which suggests that responsible mutations have not yet been unambiguously identified [47,48].…”

mentioning

confidence: 99%

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Olincy

Stevens

2007

Biochemical Pharmacology

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125

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Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinic in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal α7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for α7 subtype of the nicotinic cholinergic receptors in these processes. Rodent studies also demonstrated the efficacy of a selective partial α7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for α7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. KeywordsSchizophrenia; nicotinic receptors; DMXBA; P50 auditory evoked potential; cognitive deficits; nicotine Although the positive symptoms such as hallucinations and delusions of schizophrenia are partially treated with the available antipsychotic medications, social and occupational dysfunction remains a major issue in treating this disorder. Cognitive deficits have been identified as more closely related to ability to adequately function [1]. In the search for new and more effective therapeutic agents for schizophrenia, recent attention has turned the nicotinic cholinergic receptors system. α7 and P50 Auditory GatingPeople with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed

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Association of Promoter Variants in the α7 Nicotinic Acetylcholine Receptor Subunit Gene With an Inhibitory Deficit Found in Schizophrenia

Abstract: Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia.

Cited by 423 publications

References 61 publications

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

The Effects of Transdermal Nicotine on Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

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