Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia.
OBJECTIVE
Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha(7) nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.


METHODS
This paper will review several lines of evidence implicating the nicotinic-cholinergic, and specifically, the alpha(7) nicotinic receptor system in the pathology of schizophrenia and the evidence that alpha(7) nicotinic receptor agonists may ameliorate some of these deficits.


RESULTS
Impaired auditory sensory gating has been linked to the alpha(7) nicotinic receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. 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. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha(7) nicotinic receptor mechanism, in both humans and animal models with repeated dosing. The alpha(7) nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures.


CONCLUSIONS
Alpha-7 nicotinic receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.
Martin
Laura F
LF
Department of Psychiatry, Department of Veterans Affairs and University of Colorado Health Sciences Center, 4200 East Ninth Avenue, C268-71, Denver, CO 80262, USA. Laura.martin@uchsc.edu
Kem
William R
WR
Freedman
Robert
R
D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000209:etiology; D001597:Benzylidene Compounds / Q000627:therapeutic use; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003024:Clozapine / Q000627:therapeutic use; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006801:Humans; D009433:Neural Inhibition / Q000187:drug effects; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011725:Pyridines / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy*; D012678:Sensation Disorders / Q000188:drug therapy / Q000209:etiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D014150:Antipsychotic Agents; D001597:Benzylidene Compounds; C579167:Chrna7 protein, human; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D003024:Clozapine