Baseline dependency of nicotine’s sensory gating actions: similarities and differences in low, medium and high P50 suppressors

Abstract

Reduced suppression of the P50 auditory event-related potential in schizophrenia patients relative to normal controls is indicative of a sensory gating deficit and is one of the most robust findings reported for functional brain abnormalities in this disorder. However, there is considerable gating variability in patients and controls and there is little understanding as to how inter-individual differences moderate gating responses to drugs and nicotinic agonists in particular, which have shown potential to reverse gating deficits. In this study the effects of acutely administered nicotine (gum, 6 mg) on sensory gating in a paired (S₁-S₂) auditory stimulus paradigm were investigated in 57 healthy, non-smoking volunteers stratified as low (n = 19), medium (n = 19) and high (n = 19) P50 suppressors on the basis of three separate baseline derived gating indices, P50 ratios, P50 difference scores, and gating difference waveforms. Relative to placebo, nicotine consistently improved gating in low suppressors as stratified with all three gating indices, exerted no effects in medium suppressors and reduced gating in high suppressors. Analysis of individual stimulus (S₂, S₂) amplitudes showed distinctly different mechanisms of action underlying nicotine effects in individuals with low and high baseline suppression. The results parallel similar findings of baseline-dependency in the gating effects of several antipsychotic drugs in healthy volunteers and support the use of group segmentation as a translational model in novel cognitive drug development for schizophrenia.

An acute dose, randomized trial of the effects of CDP-Choline on Mismatch Negativity (MMN) in healthy volunteers stratified by deviance detection level

“…The remaining 8 participants were designated as the "medium" group. This same stratification procedure has been used in our previous work on nicotine and sensory gating (Knott et al 2013). The ANOVAs also included an examination of order effects, but these were not evident with any of the study findings.…”

“…Frequently shown in animal models and in human studies, baseline-dependent differences have influenced behavioural, cognitive, and subjective mood responses to nicotine (Perkins 1999). More recently, baseline-dependent neural responses to nicotine have been evidenced with two widely used biomarkers of SZ, namely, P50-indexed auditory sensory gating (Knott et al , 2013 and MMN-indexed auditory sensory discrimination (Knott et al 2014), with both biomarkers being enhanced by acute nicotine, but only in individuals with relatively diminished, SZ-like P50 gating and MMN baseline responses. In individuals with high baseline gating and discriminability, P50 suppression and MMN amplitude were either not affected, or were attenuated by single dose nicotine treatment.…”

Neurocognitive endophenotypes in schizophrenia: Modulation by nicotinic receptor systems

“…Moreover, it is important to consider the heterogeneity in schizophrenia, especially in terms of smoking status and cognitive endophenotypes, as differential responses to nicotine administration may reflect underlying neurobiological differences within the overarching disorder of schizophrenia. For example, there is considerable inter-individual variability in P50 gating dysfunction in schizophrenia patients (Patterson et al, 2008), and in healthy controls acute nicotine administration appears to benefit only those with marked gating dysfucntion, and can even impair gating in good P50 suppressors (Knott, Fisher, & Miller, 2010; Knott et al, 2013; de la Salle et al, 2013). Accordingly, P50 gating may be one method to select more homogeneous patient groups in future clinical trials.…”

Going up in Smoke? A Review of nAChRs-based Treatment Strategies for Improving Cognition in Schizophrenia

“…Possible reasons for conflicting results are small sample sizes, variability in P50 technique and analysis, timing of recording in relation to last cigarette smoked and differences in smoking chronicity. In a recent study of healthy non-smokers stratified by baseline P50 gating efficiency, nicotine (6 mg gum) enhanced gating in baseline low P50 suppressors, did not affect gating in baseline medium suppressors, and reduced gating in those with high baseline efficiency [145]. Knott et al ., [145] suggest that the effect of a drug on gating may differ as a function of this baseline gating efficiency in a manner similar to inverted-U dose-response relationships that have been used to characterize individual variability for other measures, such as nicotine’s effect on cognitive performance.…”

“…In a recent study of healthy non-smokers stratified by baseline P50 gating efficiency, nicotine (6 mg gum) enhanced gating in baseline low P50 suppressors, did not affect gating in baseline medium suppressors, and reduced gating in those with high baseline efficiency [145]. Knott et al ., [145] suggest that the effect of a drug on gating may differ as a function of this baseline gating efficiency in a manner similar to inverted-U dose-response relationships that have been used to characterize individual variability for other measures, such as nicotine’s effect on cognitive performance. Preclinical and clinical evidence implicate the α7 nAChR in auditory gating [146, 147] and furthermore, some α7 nAChR agonists other than nicotine have been shown to enhance sensory gating in schizophrenia (covered in following sections) [38, 148].…”