Judit Sovago

Reduced Metabotropic Glutamate Receptor 5 Density in Major Depression Determined by [11C]ABP688 PET and Postmortem Study

OBJECTIVE Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects. METHOD Images of mGluR5 receptor binding were acquired using PET with [(11)C]ABP688, which binds to an allosteric site with high specificity, in 11 unmedicated individuals with major depression and 11 matched healthy comparison subjects. The amount of mGluR5 protein was investigated using Western blot in postmortem brain samples of 15 depressed individuals and 15 matched comparison subjects. RESULTS The PET study revealed lower levels of regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus, and the hippocampus in the depression group relative to the comparison group. Severity of depression was negatively correlated with mGluR5 binding in the hippocampus. The postmortem study showed lower levels of mGluR5 protein expression in the prefrontal cortex (Brodmanns area 10) in the depression group relative to the comparison group, while prefrontal mGluR1 protein expression did not differ between groups. CONCLUSIONS The lower levels of mGluR5 binding observed in the depression group are consonant with the lower levels of protein expression in brain tissue in the postmortem depression group. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression.

Increased Metabotropic Glutamate Receptor Subtype 5 Availability in Human Brain After One Night Without Sleep

BACKGROUND Sleep deprivation (wake therapy) provides rapid clinical relief in many patients with major depressive disorder (MDD). Changes in glutamatergic neurotransmission may contribute to the antidepressant response, yet the exact underlying mechanisms are unknown. Metabotropic glutamate receptors of subtype 5 (mGluR5) are importantly involved in modulating glutamatergic neurotransmission and neuronal plasticity. The density of these receptors is reduced in the brain of patients with MDD, particularly in brain structures involved in regulating wakefulness and sleep. We hypothesized that prolonged wakefulness would increase mGluR5 availability in human brain. METHODS Metabotropic glutamate receptor subtype 5 binding was quantified with positron emission tomography in 22 young healthy men who completed two experimental blocks separated by 1 week. Two positron emission tomography examinations were conducted in randomized, crossover fashion with the highly selective radioligand, ¹¹C-ABP688, once after 9 hours (sleep control) and once after 33 hours (sleep deprivation) of controlled wakefulness. ¹¹C-ABP688 uptake was quantified in 13 volumes of interest with high mGluR5 expression and presumed involvement in sleep-wake regulation. RESULTS Sleep deprivation induced a global increase in mGluR5 binding when compared with sleep control (p<.006). In anterior cingulate cortex, insula, medial temporal lobe, parahippocampal gyrus, striatum, and amygdala, this increase correlated significantly with the sleep deprivation-induced increase in subjective sleepiness. CONCLUSIONS This molecular imaging study demonstrates that cerebral functional mGluR5 availability is increased after a single night without sleep. Given that mGluR5 density is reduced in MDD, further research is warranted to examine whether this mechanism is involved in the potent antidepressant effect of wake therapy.

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.

A Placebo-Controlled Trial of AQW051 in Patients With Moderate to Severe Levodopa-Induced Dyskinesia.

This phase 2 randomized, double‐blind, placebo‐controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinsons disease and levodopa‐induced dyskinesia.