Funda Akkus

Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography

Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [11C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.

Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls. We determined mGluR5 distribution volume ratio (DVR) in the brain of ten patients with OCD and ten healthy controls by using [11C]ABP688 positron-emission tomography. As a clinical measure of OCD severity, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed. We found no significant global difference in mGluR5 DVR between patients with OCD and healthy controls. We did, however, observe significant positive correlations between the Y-BOCS obsession sub-score and mGluR5 DVR in the cortico-striatal-thalamo-cortical brain circuit, including regions of the amygdala, anterior cingulate cortex, and medial orbitofrontal cortex (Spearmans ρs⩾ = 0.68, p < 0.05). These results suggest that obsessions in particular might have an underlying glutamatergic pathology related to mGluR5. The research indicates that the development of metabotropic glutamate agents would be useful as a new treatment for OCD.

Association of long-term nicotine abstinence with normal metabotropic glutamate receptor-5 binding

BACKGROUND Nicotine addiction is a major public health problem and is associated with primary glutamatergic dysfunction. We recently showed marked global reductions in metabotropic glutamate receptor type 5 (mGluR5) binding in smokers and recent ex-smokers (average abstinence duration of 25 weeks). The goal of this study was to examine the role of mGluR5 downregulation in nicotine addiction by investigating a group of long-term ex-smokers (abstinence >1.5 years), and to explore associations between mGluR5 binding and relapse in recent ex-smokers. METHODS Images of mGluR5 receptor binding were acquired in 14 long-term ex-smokers, using positron emission tomography with radiolabeled [11C]ABP688, which binds to an allosteric site with high specificity. RESULTS Long-term ex-smokers and individuals who had never smoked showed no differences in mGluR5 binding in any of the brain regions examined. Long-term ex-smokers showed significantly higher mGluR5 binding than recent ex-smokers, most prominently in the frontal cortex (42%) and thalamus (57%). CONCLUSIONS Our findings suggest that downregulation of mGluR5 is a pathogenetic mechanism underlying nicotine dependence and the high relapse rate in individuals previously exposed to nicotine. Therefore, mGluR5 receptor binding appears to be an effective biomarker in smoking and a promising target for the discovery of novel medication for nicotine dependence and other substance-related disorders.

The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies

In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches—from basic neurobiological approaches to human studies—might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5s important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoCs arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems.

Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

The metabotropic glutamate receptor 5 (mGluR5) is a promising drug target for the treatment of schizophrenia. In this study, we compared mGluR5 distribution volume ration (DVR) in subjects with schizophrenia and healthy controls. Given our previous findings, we matched samples for gender, age, and smoking status. Binding to mGluR5 was determined using positron emission tomography and [11C]ABP688, which binds to an allosteric site with high selectivity. DVR in the 15 individuals with schizophrenia did not differ from that of the 15 controls. In both groups, smoking was associated with marked global reductions in mGluR5 availability (on average 23.8%). In nonsmoking subjects with schizophrenia, there was a positive correlation between mGluR5 DVR in the medial orbitofrontal cortex and the use of antipsychotic drugs (r=0.9, p=0.019). Because antipsychotic drugs such as clozapine appeared to have indirect effects on mGluR5 signaling, our findings may be clinically relevant. They also provide promising leads for elucidating the high comorbidity between schizophrenia and tobacco addiction. Low mGluR5 DVR in smokers my represent a risk factor for schizophrenia. Alternatively, smoking may counteract the potential upregulation of mGluR5 by antipsychotic drugs.

mGluR5 binding as a specific biomarker for nicotine dependence and relapse in humans

Nicotine addiction is a major public health problem and increases the risk for various psychiatric conditions, including depression and schizophrenia. On a neurophysiological level, it is associated with aberrant glutamate activity. We recently showed marked global reductions in metabotropic glutamate receptor subtype 5 (mGluR5) binding in smokers and short-term ex-smokers. Now, we examined mGluR5 in long-term ex-smokers (abstinence>1.5y). In addition, we investigated the effects of chronic nicotine exposure (35 weeks in two groups using 4 and 8 mg/l nicotine) on mGluR5 binding in rats. In humans mGluR5 receptor binding was measured with the highly selective mGluR5 radioligand [11C]ABP688. In male Dark Agouti rats we used PET with the novel mGluR5 radiotracer [18F]PSS232. Long-term ex-smokers and individuals who had never smoked showed no differences in mGluR5 binding in any of the brain regions examined. Long-term ex-smokers showed significantly higher mGluR5 binding than recent ex-smokers, most prominently in the frontal cortex (42%) and the thalamus (57%). At follow-up we found a tendency for lower mGluR5 binding in relapsed vs. abstinent ex-smokers. In rats, we demonstrated that nicotine consumption reduces mGluR5 binding, although this effect did not follow a linear dose-response-type relationship. In a series of studies we provided evidence for a downregulation of mGluR5 as a pathological mechanism involved in nicotine dependence and the relapse to smoking. Altogether, these findings suggest that mGluR5 binding is a clinically relevant biomarker for the course of nicotine addiction and a promising target for the discovery of novel drugs against nicotine dependence and other substance-related disorders.