Schizophrenia and the α7 Nicotinic Acetylcholine Receptor

https://doi.org/10.1016/S0074-7742(06)78008-4Get rights and content

In addition to the devastating symptoms of psychosis, many people with schizophrenia also suffer from cognitive impairment. These cognitive symptoms lead to marked dysfunction and can impact employability, treatment adherence, and social skills. Deficits in P50 auditory gating are associated with attentional impairment and may contribute to cognitive symptoms and perceptual disturbances. This nicotinic cholinergic‐mediated inhibitory process represents a potential new target for therapeutic intervention in schizophrenia. This chapter will review evidence implicating the nicotinic cholinergic, and specifically, the α7 nicotinic receptor system in the pathology of schizophrenia. Impaired auditory sensory gating has been linked to the α7 nicotinic receptor gene on the chromosome 15q14 locus. A majority of persons with schizophrenia are heavy smokers. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. The α7 nicotinic agonist 3‐(2,4 dimethoxy)benzylidene‐anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and a new study in persons with schizophrenia has found that DMXBA enhances both P50 auditory gating and cognition. α7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia.

Introduction

In addition to the more obvious symptoms of hallucinations and delusions, people with schizophrenia frequently suffer from cognitive symptoms such as the inability to focus attention. This results in a “flooding” with extraneous sensory stimuli which overwhelms the person's ability to think coherently (Venables, 1992). Poor cognitive functioning contributes to both poor role‐functioning and high costs of care through its association with activities of daily living, productivity, rate of inpatient hospitalization and outpatient utilization, independence, trainability/education levels, employability, and the lost productivity of family members spent caring for their ill relatives (reviewed in Sevy and Davidson, 1995). Cognitive impairment also contributes to poor medication adherence (Jeste et al., 2003) and limits the efficacy of rehabilitative therapies (reviewed in Sharma and Antonova, 2003). Cognitive deficits improve slightly with current antipsychotic medications, but they are not normalized and therefore remain a target for new treatment efforts (Weickert et al., 2003). Given increasing evidence for a role of the nicotinic cholinergic system's role in the cognitive symptoms of schizophrenia, the α7 nicotinic acetylcholine receptor has been proposed as a candidate for the development of medications specifically targeting cognitive deficits in schizophrenia (Martin et al., 2004). This chapter will review the neurobiological findings that led to the development of this promising new drug treatment for schizophrenia as well as new evidence for the beneficial effect of an α7 nicotinic receptor agonist on cognitive impairment in schizophrenia.

Section snippets

Neurobiological and Neurogenetic Evidence for a Link Between the α7 Nicotinic Acetylcholine Receptor and Schizophrenia

Sensory gating, measured using the P50 auditory‐evoked response, is impaired in persons with schizophrenia (Adler et al., 1985). The P50 auditory‐evoked response occurs 40–75 ms following an auditory stimulus. When a second auditory stimulus is presented in close proximity (500 ms), the P50 auditory‐evoked response to the second stimulus is diminished, which is evidence for the activity of an inhibitory process. This impairment has been replicated in multiple independent laboratories (Boutros 1991

The Prototypic α7 Nicotinic Agonist, Nicotine, and Schizophrenia

The frequency of tobacco smoking is elevated in people with schizophrenia in both inpatient (De 1995, Llerena 2003) and outpatient settings (Diwan 1998, Hughes 1986). They are heavier smokers (De 1995, Kelly 1999, Lasser 2000, Masterson 1984) and they extract more nicotine per cigarette smoked than the general population (Olincy 1997, Strand 2005 but see Bozikas et al., 2005). In addition to the health implications of smoking (Goff et al., 2005), the burden of this heavy use includes spending

The Search for an α7 Nicotinic Acetylcholine Receptor Agonist

Two compounds in current clinical use may have direct effects on α7 nicotinic receptors. The anticholinesterase inhibitor galantamine, which has additional modulatory effects on the α7 nicotinic receptor, has been reported to be beneficial for schizophrenia in a case study (Rosse and Deutsch, 2002). Tropisetron, a 5‐HT3 antagonist marketed outside the United States as an antinausea drug, also has efficacy as an α7 nicotinic receptor agonist (Macor 2001, Papke 2005). Tropisetron increases the

The Phase 1 Study of DMXBA in Schizophrenia

On the basis of the success of preclinical trials of α7 agonists in animal models of learning and memory and the safety of these drugs, DMXBA was initially evaluated in normal subjects with a planned development for the treatment of dementia of the Alzheimer's type. DMXBA was found to significantly improve simple reaction time, correct detection during digit vigilance, both word and picture recognition memory, and both immediate and delayed word recall. Additionally, DMXBA improved subject

References (171)

  • V.P. Bozikas et al.

    No increased levels of the nicotine metabolite cotinine in smokers with schizophrenia

    Prog. Neuro‐Psychopharmacol. Biol. Psychiatry

    (2005)
  • C.A. Briggs et al.

    Human alpha‐7 nicotinic acetylcholine receptor responses to novel ligands

    Neuropharmacology

    (1995)
  • C.A. Briggs et al.

    Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS‐21 in vitro and in vivo

    Pharmacol. Biochem. Behav.

    (1997)
  • B. Chini et al.

    Molecular cloning and chromosomal localization of the human alpha‐7‐nicotinic receptor subunit gene (CHRNA7)

    Genomics

    (1994)
  • K.‐R. Chou et al.

    The effectiveness of nicotine‐patch therapy for smoking cessation in patients with schizophrenia

    Int. J. Nurs. Stud.

    (2004)
  • B.A. Clementz et al.

    P50 suppression among schizophrenia and normal comparison subjects: A methodological analysis

    Biol. Psychiatry

    (1997)
  • D.R. Combs et al.

    Antipsychotic medication and smoking prevalence in acutely hospitalized patients with chronic schizophrenia

    Schizophr. Res.

    (2000)
  • H. Coon et al.

    Use of a neurophysiological trait in linkage analysis of schizophrenia

    Biol. Psychiatry

    (1993)
  • C.L. Crowley‐Weber et al.

    Nicotine increases oxidative stress, activates NF‐kB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: Relevance to colon carcinogenesis

    Chem. Biol. Interact.

    (2003)
  • C.M. Cullum et al.

    Neurophysiological and neuropsychological evidence for attentional dysfunction in schizophrenia

    Schizophr. Res.

    (1993)
  • G.W. Dalack et al.

    Smoking, smoking withdrawal and schizophrenia: Case reports and a review of the literature

    Schizophr. Res.

    (1996)
  • G.W. Dalack et al.

    Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia

    Neuropsychopharmacology

    (1999)
  • J. De Leon et al.

    Does clozapine decrease smoking?

    Prog. Neuro‐Psychopharmacology Biol. Psychiatry

    (2005)
  • P. Decina et al.

    Cigarette smoking and neuroleptic‐induced parkinsonism

    Biol. Psychiatry

    (1990)
  • L. Dépatie et al.

    Nicotine and behavioral markers of risk for schizophrenia: A double‐blind, placebo‐controlled, cross‐over study

    Neuropsychopharmacology

    (2002)
  • A. Diwan et al.

    Differential prevalence of cigarette smoking in patients with schizophrenia vs mood disorders

    Schizophr. Res.

    (1998)
  • R. Freedman et al.

    Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia

    Biol. Psychiatry

    (1995)
  • J. Gault et al.

    Genomic organization and partial duplication of the human alpha‐7 neuronal nicotinic acetylcholine receptor gene (CHRNA7)

    Genomics

    (1998)
  • J.M. Griffith et al.

    Nicotinic receptor desensitization and sensory gating deficits in schizophrenia

    Biol. Psychiatry

    (1998)
  • A. Hakki et al.

    Nicotine modulation of apoptosis in human coronary artery endothelial cells

    Int. Immunopharmacol.

    (2002)
  • K.M. Hershman et al.

    GABA‐B antagonists diminish the inhibitory gating of auditory response in the rat hippocampus

    Neurosci. Lett.

    (1995)
  • B.E. Hunter et al.

    A novel nicotinic agonist facilitates induction of long‐term potentiation in the rat hippocampus

    Neurosci. Lett.

    (1994)
  • L.K. Jacobsen et al.

    Nicotine effects on brain function and functional connectivity in schizophrenia

    Biol. Psychiatry

    (2004)
  • S.D. Jeste et al.

    Cognitive predictors of medication adherence among middle‐aged and older outpatients with schizophrenia

    Schizophr. Res.

    (2003)
  • S. Jones et al.

    Nicotinic receptors in the brain: Correlating physiology with function

    TINS

    (1999)
  • W.R. Kem

    The brain alpha‐7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: Studies with DMXBA (GTS‐21)

    Behav. Brain Res.

    (2000)
  • W.R. Kem et al.

    Isolation and structure of a hoplonemertine toxin

    Toxicon

    (1971)
  • K. Koike et al.

    Tropisetron improves deficits in auditory P50 suppression in schizophrenia

    Schizophr. Res.

    (2005)
  • A.L. Larrison‐Faucher et al.

    Nicotine reduces antisaccade errors in task impaired schizophrenic subjects

    Prog. Neuro‐Psychopharmacol. Biol. Psychiatry

    (2004)
  • E.D. Levin et al.

    Development of nicotinic drug therapy for cognitive disorders

    Eur. J. Pharmacol.

    (2000)
  • E. Levin et al.

    Nicotine‐haloperidol interaction and cognitive performance in schizophrenics

    Neuropsychopharmacology

    (1996)
  • J. Addington et al.

    Readiness to stop smoking in schizophrenia

    Can. J. Psychiatry

    (1997)
  • J. Addington et al.

    Smoking cessation treatment for patients with schizophrenia

    Am. J. Psychiatry

    (1998)
  • L.E. Adler et al.

    Normalization of auditory physiology by cigarette smoking in schizophrenic patients

    Am. J. Psychiatry

    (1993)
  • L.E. Adler et al.

    Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients

    Am. J. Psychiatry

    (2004)
  • L.E. Adler et al.

    Improved P50 auditory gating with ondansetron in medicated schizophrenia patients

    Am. J. Psychiatry

    (2005)
  • M.K. Anfang et al.

    Treatment of neuroleptic‐induced akathesia with nicotine patches

    Psychopharmacology

    (1997)
  • C. Arango et al.

    Olanzapine effects on auditory sensory gating in schizophrenia

    Am. J. Psychiatry

    (2003)
  • M.T. Avila et al.

    Effects of nicotine on leading saccades during smooth pursuit eye movements in smokers and nonsmokers with schizophrenia

    Neuropsychopharmacology

    (2003)
  • N.L. Benowitz

    Summary: Risks and benefits of nicotine

  • Cited by (198)

    • Acetylcholine and metacognition during sleep

      2024, Consciousness and Cognition
    View all citing articles on Scopus
    View full text