Functional Magnetic Resonance Imaging of Effects of a Nicotinic Agonist in Schizophrenia

Abstract

3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at α7 nicotinic acetylcholine receptors and is now in early clinical development for treatment of deficits in neurocognition and sensory gating in schizophrenia. During its initial Phase 2 test, functional magnetic resonance imaging studies were conducted to determine if the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus is found during many tasks, including smooth pursuit eye movements, and may reflect inhibitory dysfunction. Placebo and two doses of drug were administered in a random, double-blind crossover design. Following the morning drug/placebo ingestion, subjects underwent functional magnetic resonance imaging (fMRI) while performing a smooth pursuit eye movement task. Data were analyzed from 16 nonsmoking patients, including seven women and 9 men. The 150 mg dose of DMXB-A, compared to placebo, diminished the activity of the hippocampus during pursuit eye movements. The 75 mg dose was ineffective. The effect at the 150 mg dose was negatively correlated with plasma drug levels. The findings are consistent with the previously established function of α7-nicotinic receptors on inhibitory interneurons in the hippocampus and with genetic evidence for deficits in these receptors in schizophrenia. Imaging of drug response is useful in planning future clinical tests of this compound and other nicotinic agonists for schizophrenia.

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

“…In addition, DMXB-A significantly decreased hippocampal activation during a smooth pursuit eye movement task. These findings are consistent with the previously established function of a 7 -nicotinic receptors on the inhibitory interneurons in the hippocampus (Tregellas et al, 2010(Tregellas et al, , 2011.…”

“…DMXB-A treatment was associated with changes in default mode activity as compared with placebo, with reductions in the posterior cingulate, inferior parietal cortex, and medial frontal gyrus, and an increase in precuneus activity. The most robust difference, specifically, reductions posterior cingulate activity, was influenced by the CHRNA7 genotype (Tregellas et al, 2010(Tregellas et al, , 2011. These results suggest normalization of default mode function, but future studies will need to include control subjects for verification of the normal default mode network.…”

“…While it is tempting to conclude that the loss of efficacy over time was due to the possible tachyphylaxis effects of DMXB-A, the findings in this study, like many others, were confounded by a significant practice effect observed across all groups, especially within the MATRICS tasks. During this phase-II trial, patients were also included in functional magnetic resonance imaging studies to determine whether DMXB-A could normalize changes in default mode network and hippocampal activity, two biomarkers of antipsychotic treatment efficacy (Tregellas et al, 2010(Tregellas et al, , 2011. Changes in default mode network activity were evaluated in the context of a polymorphism in CHRNA7, which was previously found to be associated with schizophrenia.…”

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…A significant association of SNP rs8028396 with smoking, as well as with smoking in schizophrenia, in a non-Hispanic Caucasian population was observed (Stephens et al, 2012;Neri et al, 2012). SNP rs3087454 was first shown to be significantly associated to schizophrenia (Stephens et al, 2009) and also influenced differences in synaptic activity, as detected by functional magnetic resonance imaging, between patients with schizophrenia and control subjects performing an auditory oddball task (Tregellas et al, 2010). A Korean population-based study on the development of either schizophrenia or bipolar disorder (BD) demonstrated that SNPs rs2337506, rs6494223, and rs12916879 exhibited only a marginal association with BD (Joo et al, 2010) and that SNP rs6494223 was associated with a protective effect in BD (Ancin et al, 2010) and impaired attention in patients with euthymic bipolar disorder (Ancin et al, 2011).…”

How Human Electrophysiology Informs Psychopharmacology: from Bottom-up Driven Processing to Top-Down Control

“…It is possible that these prefrontal neurons are involved in P50 suppression through cholinergically mediated signals; there is in vitro evidence that cortical ACh release is inhibited by 5-HT-3 receptor activity, with a mediating role for GABA A receptors (Rámirez et al, 1996). Direct augmentation of nicotine receptor activity also restores P50 suppression in schizophrenic patients (Adler et al, 1993), and recently the partial a-7 nicotine agonist DMBX-A (150 mg, 4-weeks regime) reduced hippocampal activation in patients during smooth pursuit (Tregellas et al, 2009). …”