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Lighting Up Nicotinic Receptors

15 December 2011. Two new papers, by teams at Yale School of Medicine* and at the University of Maryland School of Medicine, join a growing body of research on the role of nicotinic acetylcholine receptors (nAChRs) in schizophrenia. In an imaging study of cigarette smokers with schizophrenia published online in the American Journal of Psychiatry, the Yale team, headed by the late Julie Staley, reports that the availability of nAChRs in several brain regions was markedly lower in patients than in smokers without mental illness, as well as a significant negative correlation in the patient group between nAChR availability and negative symptoms. In a controlled trial of the nAChR agonist varenicline published in the December issue of the Archives of General Psychiatry, the Maryland group led by L. Elliot Hong found that a moderate dose of the drug significantly improved measures on three well-validated schizophrenia biomarkers.

Some studies of nAChRs by schizophrenia researchers are aimed at finding treatments for the severe and damaging nicotine addiction seen in numerous patients (see SRF related news story; Wing et al., 2011), while others see patients’ conspicuous consumption of tobacco as reflecting important aspects of schizophrenia pathophysiology that could lead to novel, nAChR-based treatments for the disease itself. The newly published papers take this latter perspective.

Nicotine and negative symptoms
Chronic exposure to acetylcholine or nicotine causes a desensitization of nAChRs that is offset in smokers by receptor upregulation, which increases the availability of nicotinic binding sites (Marks et al., 2011). However, a postmortem study of smokers with schizophrenia (Breese et al., 2000) noted a deficit in nAChR upregulation, which added to suspicions that nAChR dysfunction may contribute to the pathophysiology of the illness. This view has been bolstered by genetic studies of schizophrenia that implicate the nAChR-related genes CHRNA7 (Freedman et al., 1997), CHRNA4, and CHRNB2 (De Luca et al., 2006).

First author Deepak Cyril D’Souza and colleagues at Yale focused on so-called β2* receptors, a subcategory of the nAChR superfamily that includes any such receptors containing β2 subunits. These receptors, particularly the α4β2 subtype, are widely expressed in the brain, and play a major role in tobacco addiction by modulating dopamine release in midbrain reward regions (McGranahan et al., 2011).

Based on SPECT (single-photon emission computed tomography) assessments of β2* availability in 11 smokers with schizophrenia and in age- and gender-matched comparison smokers, the team reported that the subjects with schizophrenia had 21 to 26 percent fewer binding sites than the comparison smokers in the frontal and parietal cortices and in the thalamus (no significant differences were seen in the hippocampus or striatum).

Moreover, among the smokers with schizophrenia, there was a “specific and robust” negative correlation between β2* availability and negative symptoms scores, as measured by both the SANS and PANSS scales, a pattern that held for all brain regions examined. This means that individuals with less β2* availability had more severe negative symptoms than individuals with greater β2* availability.

These findings are not likely to be due to differences in antipsychotic treatment, say the authors, but would be strengthened by expanded studies that include nonsmoking individuals with schizophrenia as comparison subjects, to determine whether reduced upregulation of nAChRs is a general characteristic of schizophrenia. Nonetheless, they write, given the paucity of effective medications for negative symptoms, the data argue for further testing of drugs targeting nAChRs, a strategy that has been given priority by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project (Buchanan et al., 2007).

Boosting biomarkers
One such compound, varenicline, is an nAChR partial agonist with high affinity for the α4β2 subtype that has been used successfully in smoking cessation programs under the trade names Chantix and Champix. In the new study from the University of Maryland, first author Elliot Hong and colleagues measured the effects of a moderate, long-term dose of varenicline on several sensory and cognitive biomarkers associated with schizophrenia that have also been used in previous studies testing effects of smoking or nicotine.

A range of biomarkers was chosen because, in addition to modulating dopaminergic systems, nAChRs also regulate GABAergic and glutamatergic circuits in the striatum, prefrontal cortex, and hippocampus, and hence affect many sensory and cognitive functions. Previous trials of varenicline in smokers with schizophrenia have been unblinded (Smith et al., 2009) or non-randomized (Liu et al., 2011), but the Maryland group chose a double-blind, randomized, placebo-controlled study design in which both smokers and nonsmokers with schizophrenia or schizoaffective disorder (N = 69) were given placebo or varenicline on four parallel tracks.

No significant treatment effects were seen after two weeks on varenicline, but at eight weeks the treatment groups (N = 32) showed significant improvements in startle reactivity; P50 sensory gating; and antisaccade performance, a measure of executive function. No improvements were seen in prepulse inhibition; spatial working memory; maintenance or predictive smooth-pursuit eye movement; cognitive processing speed; sustained attention; or scores on the MATRICS Consensus Cognitive Battery (MCCB; August et al., 2011).

Improvements in cognitive measures have been seen in previous studies employing nicotine or varenicline, but the Maryland group attributes these discrepancies to the limitations of short-term challenge studies, open-label study designs, and crucial pharmacological differences between nicotine and varenicline. Nicotine, a full agonist at nAChRs, robustly stimulates midbrain dopamine release, while varenicline is “a 30 percent to 60 percent partial agonist (of the nicotinic effect on dopamine turnover) and also a partial antagonist [via competitive binding] of α4β2” receptors. “[O]ur study suggests that the α4β2 partial agonist-antagonist is modest…. Instead, it reduces selected biomarker deficits, particularly P50 gating and antisaccadic deficits.”—Pete Farley.* *Contributor Pete Farley is an employee of Yale University, where he serves as managing editor of Medicine@Yale.

D'Souza DC, Esterlis I, Carbuto M, Krasenics M, Seibyl J, Bois F, Pittman B, Ranganathan M, Cosgrove K, Staley J. Lower β2*-nicotinic acetylcholine receptor availability in smokers with schizophrenia. Am J Psychiatry. Abstract

Hong LE, Thaker GK, McMahon RP, Summerfelt A, Rachbeisel J, Fuller RL, Wonodi I, Buchanan RW, Myers C, Heishman SJ, Yang J, Nye A. Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 2011 Dec;68(12):1195-206. Abstract

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