Elsevier

Biochemical Pharmacology

Volume 74, Issue 8, 15 October 2007, Pages 1192-1201
Biochemical Pharmacology

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

https://doi.org/10.1016/j.bcp.2007.07.015Get rights and content

Abstract

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 nicotinie 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 the α7 subtype of the nicotinic cholinergic receptor 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.

Section snippets

α7 and P50 auditory gating

People 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 by extraneous sensory stimuli [2] which impairs the person's ability to think coherently. This “flooding” has been modeled in the laboratory physiologically by measuring the amplitude of the evoked responses to identical paired auditory stimuli separated by 500 ms [3]. The P50 auditory evoked response occurs 40–75 ms

α7 in learning and memory

Although nicotine seems to improve cognition, the involvement of high or low affinity nicotinic cholinergic receptors is unclear. Withdrawal from nicotine in normal smokers has been shown to cause attention impairments [59]. Nicotine administration may just be relieving withdrawal and correcting those deficits. However, if low-dose nicotine is administered to normal non-smokers, thereby avoiding the confound of withdrawal, there is enhanced performance on the continuous performance test with

DMXBA as a prototype drug

Nicotine has several limitations as a therapeutic agent for schizophrenia. Nicotine induces tachyphylaxis and thus does not maintain sustained benefit. Additionally, the long-term health risks of chronic nicotine use are unknown. Nicotine is also addictive and without sustained use, people can experience symptoms of withdrawal [79]. Thus, alternative nicotinic agonists that are less potentially toxic would be helpful in the treatment of schizophrenia.

One of the few agents that has reached

Other potential nicotinic targets

A series of other putative cholinergic receptor agonists have been developed as potential candidates for the treatment of schizophrenia and Alzheimer's disease. Drugs currently in development include a 1,4-diaza-bicyclo[3.2.2]nonane-4-carboxylic acid 4-pyridin-2yl-phenyl ester at Pfizer Inc., and a N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14 PHA-543,613) also at Pfizer, Inc. The second compound demonstrates reversal of amphetamine-induced N40 gating deficit in

Discussion

The α7 nicotinic cholinergic receptor role in schizophrenia has been established through multiple independent pathways. An initial clinical observation of increased frequency of smoking in schizophrenia lead to the observation that these patients extract more nicotine from the cigarettes they smoke than do other smokers [15], [10]. Examination of the symptom of being overwhelmed by extraneous sensory stimuli lead to finding a physiological deficit, the P50 auditory evoked potential, which

Acknowledgements

This work was supported by an NIMH grant (MH065588) to AO, an NIMH grant (MH073725) to KES and the NARSAD Toulmin Independent Investigator Award to KES.

References (129)

  • G.G. Nomikos et al.

    Role of alpha-7 nicotinic receptors in nicotine dependence and implications for psychiatric illness

    Behav Brain Res

    (2000)
  • J.M. Griffith et al.

    Nicotinic receptor desensitization and sensory gating deficits in schizophrenia

    Biol Psychiatry

    (1998)
  • M.C. Waldo et al.

    Codistribution of a sensory gating deficit and schizophrenia in multi-affected families

    Psychiatry Res

    (1991)
  • S. Shirazi-Southall et al.

    Effects of typical and atypical antipsychotics and receptor selective compounds on acetylcholine efflux in the hippocampus of the rat

    Neuropsychopharmacology

    (2002)
  • J.P. McEvoy et al.

    Smoking and therapeutic response to clozapine in patients with schizophrenia

    Biol Psychiatry

    (1999)
  • J. Becker et al.

    Clozapine, but not typical antipsychotics, correct P50 suppression deficit in patients with schizophrenia

    Clin Neurophysiol

    (2004)
  • L.E. Adler et al.

    Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics

    Biol Psychiatry

    (1992)
  • R. Freedman et al.

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

    Biol Psychiatry

    (1995)
  • A. Marutle et al.

    Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia

    J Chem Neuroanat

    (2001)
  • K.E. Stevens et al.

    Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains

    Neuropsychopharmacology

    (1996)
  • K.E. Stevens et al.

    Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal auditory gating in two animal models

    Pharmacol Biochem Behav

    (1997)
  • E.X. Albuquerque et al.

    Contribution of nicotinic receptors to the function of synapses in the central nervous system: the action of choline as a selective agonist of alpha-7 receptors

    J Physiol (Paris)

    (1998)
  • K.M. Hershman et al.

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

    Neurosci Lett

    (1995)
  • S. Mexal et al.

    Alpha 7 nicotinic receptor gene promoter polymorphisms in inbred mice affect expression in a cell type-specific fashion

    J Biol Chem

    (2007)
  • D. Hatsukami et al.

    The effects of varying cigarette deprivation duration on cognitive and performance tasks

    J Sub Abuse

    (1989)
  • A.L. Wilson et al.

    Nicotine patches in Alzheimer's disease: pilot study on learning, memory, and safety

    Pharmacol Biochem Behav

    (1995)
  • 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)
  • L.K. Jacobsen et al.

    Nicotine effects on brain function and functional connectivity in schizophrenia

    Biol Psychiatry

    (2004)
  • L. Dépatie et al.

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

    Neuropsychopharmacology

    (2002)
  • R.C. Smith et al.

    Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia

    Neuropsychopharmacology

    (2002)
  • J.D. Sherr et al.

    The effects of nicotine on specific eye tracking measures in schizophrenia

    Biol Psychiatry

    (2002)
  • W.R. Kem et al.

    Isolation and structure of a hoplonemertine toxin

    Toxicon

    (1971)
  • C.A. Briggs et al.

    Human alpha-7 nicotinic acetylcholine receptor responses to novel ligands

    Neuropharmacology

    (1995)
  • R.L. Papke et al.

    Alpha-7 Receptor-selective agonists and modes of alpha-7 receptor activation

    Eur J Pharmacol

    (2000)
  • V. Luntz-Leybman et al.

    Cholinergic gating of response to auditory stimuli in rat hippocampus

    Brain Res

    (1992)
  • K.E. Stevens et al.

    Selective alpha 7 nicotinic receptor stimulation normalizes chronic cocaine-induced loss of hippocampal sensory inhibition in C3H mice

    Biol Psychiatry

    (1999)
  • J.K. Simosky et al.

    Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice

    Biol Psychiatry

    (2001)
  • T.P. George et al.

    A preliminary study of the effects of cigarette smoking on prepulse inhibition in schizophrenia: involvement of nicotinic receptor mechanisms

    Schizophrenia Res

    (2006)
  • C.R. Bowie et al.

    Cognition in schizophrenia: impairments, determinants, and functional importance

    Psychiatry Clin North Am

    (2005)
  • M.F. Green et al.

    Neurocognitive deficits and functional outcome in schiophrenia: are we measuring the “right stuff”?

    Schizophr Bull

    (2000)
  • P.H. Venables

    Hippocampal function and schizophrenia: experimental psychological evidence

    Ann NY Acad Sci

    (1992)
  • N.N. Boutros et al.

    Replication and extension of P50 findings in schizophrenia

    Clin Electroencephalogr

    (1991)
  • L. Judd et al.

    Sensory gating deficits in schizophrenia: new results

    Am J Psychiatry

    (1992)
  • E. Masterson et al.

    Smoking and malignancy in schizophrenia

    Br J Psychiatry

    (1984)
  • J.R. Hughes et al.

    Prevalence of smoking among psychiatric outpatients

    Am J Psychiatry

    (1986)
  • D.C. Goff et al.

    Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects

    Am J Psychiatry

    (1992)
  • C. Kelly et al.

    Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland

    Am J Psychiatry

    (1999)
  • K. Lasser et al.

    Smoking and mental illness: a population-based prevalence study

    JAMA

    (2000)
  • J. De Leon et al.

    Schizophrenia and smoking: an epidemiological survey in a state hospital

    Am J Psychiatry

    (1995)
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