Rationale and 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 alpha₇ nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.

Method  

This paper will review several lines of evidence implicating the nicotinic-cholinergic, and specifically, the alpha₇ nicotinic receptor system in the pathology of schizophrenia and the evidence that alpha₇ nicotinic receptor agonists may ameliorate some of these deficits.

Results  

Impaired auditory sensory gating has been linked to the alpha₇ 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 alpha₇ nicotinic receptor mechanism, in both humans and animal models with repeated dosing. The alpha₇ 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.

Conclusion  

Alpha-7 nicotinic receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.