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 [11C]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 (Brodmann's 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.
334 Objectives The metabotropic glutamate receptor 5 (mGluR5) has been implicated in addiction. Specifically, the mGluR5 has been suggested to be particularly involved in nicotine addiction. In order to verify whether smoking was associated with changes in the availability of mGluR5, we performed PET studies with 11C-ABP688 in smokers and non-smokers. Methods Fourteen smokers (8 women, mean age 33.5 years; 6 men, mean age 37.8 years; average nicotine consumption: 17 cigarettes per day) and fourteen healthy controls (8 women, mean age 34.6 years; 6 men, mean age 39 years) were recruited for the study. Clinical measures included nicotine addiction as assessed by the Fragestrom Test for Nicotine Dependence (FTND). PET images of mGluR5 distribution were acquired after a bolus injection of 780-800 MBq of 11C-ABP688. Total volume of distribution normalized to the cerebellum was used as a measure of receptor density. Differences between smokers and non-smokers in the binding of 11C-ABP688 were assessed in pre-defined regions-of-interest. Results A marked global reduction of 22.8±4.3% in mGluR5 density in smokers relative to non-smokers was found. The most prominent reductions were found in the left orbitofrontal cortex (33.7%, p Conclusions These results suggest an important role of mGluR5 in the pathophysiology of nicotine dependence in humans. The reductions in mGluR5 may represent compensatory and/or pathogenetic changes associated with nicotine addiction
Agonist stimulated [ 35 S]guanosine 5¢-c-thiotriphosphate ([ 35 S]GTPcS) binding autoradiography was established for the examination of dopamine-D2 ⁄ D3 receptors in human brain sections. The distribution of G proteins activated by dopamine-D2 ⁄ D3 receptors was studied in whole hemisphere cryosections. Dopamine stimulated [ 35 S]GTPcS binding in brain regions with high densities of dopamine D2-like receptors, i.e. putamen (23 ± 2%, mean ± SEM,% stimulation over basal binding), caudate (20 ± 0%) and substantia nigra (22 ± 2%), but also in regions with lower receptor densities such as amygdala (17 ± 8%), hippocampus (16 ± 6%), anterior cingulate (13 ± 3%), and thalamus (12 ± 2%). Dopamine stimulated [ 35 S]GTPcS binding to significantly higher levels in the dorsal than in the ventral part of the striatum. Dopamine caused low or very low stimulation in all cortical areas. Raclopride, a selective D2 ⁄ D3 receptor antagonist, potently inhibited dopamine stimulated [ 35 S]GTPcS binding, whereas R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5tetrahydro-1H-3-benzazepine hydrochloride (SCH23390), a selective D1 antagonist, did not block the [ 35 S]GTPcS binding response stimulated by dopamine. Hence, the stimulatory effect of dopamine was primarily mediated by D2 ⁄ D3 receptors. Quinpirole stimulated [ 35 S]GTPcS binding in the same regions as dopamine. The maximal level of stimulation induced by dopamine and quinpirole was not significantly different. The present study demonstrates that agonist stimulated [ 35 S]GTPcS binding autoradiography could be a suitable technique for the examination of dopamine-D2 ⁄ D3 receptors in the human brain. This functional assay could provide useful new information about dopamine receptor ⁄ G protein coupling in the postmortem human brain, and reveal possible disease related alterations of the interaction between D2 ⁄ D3 receptors and G proteins.
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 [(11)C]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.
