Laura F. Martin

Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia

Rationale and objectiveAuditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha7 nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia.MethodThis paper will review several lines of evidence implicating the nicotinic-cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia and the evidence that alpha7 nicotinic receptor agonists may ameliorate some of these deficits.ResultsImpaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha7 nicotinic receptor mechanism, in both humans and animal models with repeated dosing. The alpha7 nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures.ConclusionAlpha-7 nicotinic receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.

Effects of nicotine on cognitive deficits in schizophrenia.

Several lines of evidence suggest a pathophysiological role for nicotinic receptors in schizophrenia. Activation by nicotine alters physiological dysfunctions, such as eye movement and sensory gating abnormalities, but effects on neuropsychological performance are just beginning to be investigated. Nicotine-induced desensitization and the well-known tachyphylaxis of nicotinic receptors may confound such efforts. In all, 20 schizophrenics, 10 smokers, and 10 nonsmokers were assessed following the administration of nicotine gum and placebo gum. The Repeatable Battery for the Assessment of Neuropsychological Status was administered. Nicotine affected only the Attention Index; there were no effects on learning and memory, language, or visuospatial/constructional abilities. Attentional function was increased in nonsmokers, but decreased in nicotine-abstinent smokers after nicotine administration. The effects of nicotine in schizophrenia do not extend to all areas of cognition. Effects on attention may be severely limited by tachyphylaxis, such that decremented performance occurs in smokers, while modest effects may be achieved in nonsmokers.

Schizophrenia and the α7 Nicotinic Acetylcholine Receptor

In addition to the devastating symptoms of psychosis, many people with schizophrenia also suffer from cognitive impairment. These cognitive symptoms lead to marked dysfunction and can impact employability, treatment adherence, and social skills. Deficits in P50 auditory gating are associated with attentional impairment and may contribute to cognitive symptoms and perceptual disturbances. This nicotinic cholinergic-mediated inhibitory process represents a potential new target for therapeutic intervention in schizophrenia. This chapter will review evidence implicating the nicotinic cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia. Impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. A majority of persons with schizophrenia are heavy smokers. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. The alpha7 nicotinic agonist 3-(2,4 dimethoxy)benzylidene-anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and a new study in persons with schizophrenia has found that DMXBA enhances both P50 auditory gating and cognition. alpha7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia.

Effects of an Alpha 7-Nicotinic Agonist on Default Network Activity in Schizophrenia

BACKGROUND 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at α7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia. This study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia. METHODS Placebo and two doses of DMXB-A were administered in a random, double-blind crossover design during a Phase 2 study of DMXB-A. Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task. Independent component analysis was used to identify the default network component. Default network changes were evaluated in the context of a polymorphism in CHRNA7, the α7-nicotinic acetylcholine receptor subunit gene, which was previously found to be associated with schizophrenia. RESULTS Compared with placebo, both 150 and 75 mg twice daily DMXB-A altered default network activity, including a reduction in posterior cingulate, inferior parietal cortex, and medial frontal gyrus activity and an increase in precuneus activity. The most robust difference, posterior cingulate activity reduction, was affected by CHRNA7 genotype. CONCLUSIONS The observed DMXB-A-related changes are consistent with improved default network function in schizophrenia. Pharmacogenetic analysis indicates mediation of the effect through the α7-nicotinic receptor. These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents.

Gray matter volume differences and the effects of smoking on gray matter in schizophrenia

OBJECTIVE Many studies have evaluated differences in gray matter volume in schizophrenia, but have not considered the possible effects of smoking, which is extraordinarily common in people with the illness. The present study used voxel-based morphometry (VBM) to examine differences in gray matter in subjects with schizophrenia and evaluate the effects of smoking on this measure. METHODS Thirty-two subjects with schizophrenia (14 smokers, 18 non-smokers) and 32 healthy comparison subjects participated in the study. Whole brain, voxel-wise analyses of regional gray matter volume were conducted using voxel-based morphometry (VBM). RESULTS Reduced gray matter was observed in the schizophrenia group in the orbitofrontal cortex, bilateral insula and superior temporal gyri (STG), bilateral dorsolateral prefrontal cortices (DLPFC), medial frontal gyrus, and cingulate gyrus. Within this group, smoking subjects had greater lateral prefrontal and STG gray matter volumes relative to non-smoking subjects. CONCLUSIONS The finding of reduced gray matter volume in prefrontal and temporal regions in schizophrenia is consistent with prior anatomical tracing and whole-brain voxel-based studies. Greater gray matter volumes in smoking relative to non-smoking subjects with schizophrenia highlight a potential experimental confound in volumetric studies and suggests that smoking may be associated with a relative preservation of lateral prefrontal and temporal gray matter in schizophrenia.

Effects of Nicotine on Hippocampal and Cingulate Activity During Smooth Pursuit Eye Movement in Schizophrenia

BACKGROUND Abnormal smooth pursuit eye movement (SPEM) in schizophrenic patients is a well known phenomenon, but the neurophysiological mechanisms underlying the deficit are unknown. Nicotine temporarily improves SPEM and has been associated with reduced hippocampal hemodynamic activity in schizophrenics. Nicotines effect on brain activity in control subjects performing SPEM has not been studied. The purpose of this work was to determine if nicotine differentially affects brain activity in schizophrenic and control subjects during pursuit eye tracking. METHODS 16 subjects with schizophrenia and 16 control subjects underwent functional MR imaging during SPEM after receiving placebo or nicotine gum. Four brain regions were analyzed for main effects of group, drug, and interactions: hippocampus, cingulate gyrus, frontal eye fields, and area MT. RESULTS Nicotine reduced hippocampal activity in both groups, but the effect was greater in control subjects. A group by drug interaction was observed in the anterior cingulate gyrus, where nicotine decreased activity in control subjects and increased activity in schizophrenic subjects. There were no significant effects of group, drug, or interactions in frontal eye fields or area MT. CONCLUSIONS Nicotine may improve SPEM performance in people with schizophrenia through cholinergic stimulation of the hippocampus and cingulate gyrus. Potential mechanisms include improved inhibitory function and attention.

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

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 (fMRI) studies were conducted to determine whether the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus in schizophrenia 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. After the morning drug/placebo ingestion, subjects underwent fMRI while performing a smooth pursuit eye movement task. Data were analyzed from 16 nonsmoking patients, including 7 women and 9 men. The 150-mg dose of DMXB-A, compared with placebo, diminished the activity of the hippocampus during pursuit eye movements, but 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.

Nicotine increases brain functional network efficiency

Despite the use of cholinergic therapies in Alzheimers disease and the development of cholinergic strategies for schizophrenia, relatively little is known about how the system modulates the connectivity and structure of large-scale brain networks. To better understand how nicotinic cholinergic systems alter these networks, this study examined the effects of nicotine on measures of whole-brain network communication efficiency. Resting state fMRI was acquired from fifteen healthy subjects before and after the application of nicotine or placebo transdermal patches in a single blind, crossover design. Data, which were previously examined for default network activity, were analyzed with network topology techniques to measure changes in the communication efficiency of whole-brain networks. Nicotine significantly increased local efficiency, a parameter that estimates the networks tolerance to local errors in communication. Nicotine also significantly enhanced the regional efficiency of limbic and paralimbic areas of the brain, areas which are especially altered in diseases such as Alzheimers disease and schizophrenia. These changes in network topology may be one mechanism by which cholinergic therapies improve brain function.

Cerebellar hyperactivity during smooth pursuit eye movements in bipolar disorder

INTRODUCTION Smooth pursuit eye movements (SPEM) are abnormal in individuals with schizophrenia and individuals with bipolar disorder. Functional imaging methods have revealed greater hippocampal activity and less frontotemporal, visual, and posterior cerebellar activity in individuals with schizophrenia when performing a SPEM task. The underlying neurobiology of SPEM deficits in bipolar disorder is unknown. METHODS Functional magnetic resonance imaging at 3T was performed on fourteen subjects with bipolar disorder and 14 subjects without psychiatric illness during a block design SPEM task. Clinical measures were assessed on the day of testing and related to imaging measures. RESULTS Subjects with bipolar disorder had greater hemodynamic response than control subjects in cerebellar vermis. Responses were associated with levels of depressive symptoms on the day of study. DISCUSSION Increased cerebellar vermis activity during the smooth pursuit eye movement task in individuals with bipolar disorder further implicates cerebellar involvement in bipolar disorder. Increased hemodynamic response within the hippocampus was not seen in these individuals and may be a finding specific to schizophrenia.

Nicotine Increases Cerebellar Activity during Finger Tapping

Nicotine improves performance on several cognitive and sensorimotor tasks. The neuronal mechanisms associated with these changes in performance are, however, largely unknown. Functional magnetic resonance imaging (fMRI) was used to examine the effect of nicotine on neuronal response in nineteen healthy subjects while they performed an auditory-paced finger tapping task. Subjects performed the task, after receiving either a nicotine patch or placebo treatment, in a single blind, crossover design. Compared to placebo, nicotine treatment increased response in the cerebellar vermis. Increased vermal activity, in the absence of changes in other task-related regions suggests specificity in nicotine’s effects.