Schizophrenia and Nicotinic Receptors

Abstract

Patients with schizophrenia often cannot respond to important features of their environment and filter out irrelevant stimuli. This dysfunction could be related to an underlying defect in inhibition--i.e., the brain's ability to alter its sensitivity to repeated stimuli. One of the neuronal mechanisms responsible for such inhibitory gating involves the activation of cholinergic nicotinic receptors in the hippocampus. These receptors are diminished in many specimens of hippocampal brain tissue obtained postmortem from schizophrenic patients. In living schizophrenic patients, stimulation of cholinergic receptors by nicotine transiently restores inhibitory gating of evoked responses to sensory stimuli. Many people with schizophrenia are heavy smokers, but the properties of the nicotinic receptor favor only short-term activation, which may explain why cigarette smoking is only a transient symptomatic remedy. This paper reviews the clinical phenomenology of inhibitory gating deficits in people with schizophrenia, the neurobiology of such gating mechanisms, and the evidence that some individuals with the disorder may have a heritable deficit in the nicotinic cholinergic receptors involved in this neurobiological function. Inhibitory gating deficits are only partly normalized by neuroleptic drugs and are thus a target for new therapeutic strategies for 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.…”

Nicotine use in patients with schizophrenia evaluated by the Fagerström Tolerance Questionnaire: a descriptive analysis from a Brazilian sample

“…4 Freedman et al suggested that vulnerability to schizophrenia was associated with smoking. 10 Patients with schizophrenia would have more difficulty in discriminating stimuli, a deficit also found in family members. Nicotine use would normalize these deficits through stimulation of specific receptors with low affinity to nicotine, therefore family members who are not affected by schizophrenia would smoke more than the non-affected general population.…”

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].…”