Nicotinic Receptor Function in Schizophrenia

Abstract

Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal nicotinic receptors, the alpha 7 nicotinic receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 nicotinic receptor block normal gating of the second of paired auditory stimuli. Regional localization of receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 nicotinic receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.

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

“…These findings are analogous to improvements following nicotine administration demonstrated using a number of experimental paradigms that reflect inhibitory functioning such as auditory p50 gating, PPI and eye movement tasks (Adler et al, 1993;Kumari et al, 2001;Depatie et al, 2002;Olincy et al, 2003;Postma et al, 2006). The effects of nicotine on auditory P50 gating appears to be due to activation of the a7nAChR, which may facilitate inhibition in the hippocampus via activation of GABAergic interneurons (Freedman et al, 1994;Hershman et al, 1995;Leonard et al, 1996). Nicotine effects on response inhibition in this study could also be mediated by enhancement of dopaminergic functioning.…”

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

“…Therefore, it could be argued that these effects do not constitute an alteration in gating per se but rather a change in the animal's reactivity to the initial stimulus. While considerable effort continues to be directed toward understanding the physiological basis of auditory gating (for a review, see Leonard et al, 1996), a growing body of evidence suggests that a diminished response to conditioning stimuli may have functional and clinical importance. For example, significant reductions in conditioning response amplitude have been observed following blockade of a7nAChRs (Luntz-Leybman et al, 1992).…”

α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

“…Moreover, an association has been demonstrated between the homozygous 113 bp allele on the D15S1360 polymorphism of the CNRNA7 gene and smoking risk in schizophrenia [63]. Taken together, these results suggest that the CHRNA7 gene is likely susceptible to the deficits of P50 sensory gating in schizophrenia [10, 23, 44, 49, 50, 53, 58, 63-67]. Interestingly, a 2 bp deletion in exon 6 of CHRFAM7A, which disrupts the hybrid gene for the CHRNA7 gene, was associated with episodic memory performance in schizophrenia, suggesting that the CHRFAM7A/CHRNA7 locus plays a role in modulating episodic memory function [68].…”