mGluR1/5 receptor densities in the brains of alcoholic subjects: A whole-hemisphere autoradiography study
Introduction
Glutamate is major excitatory neurotransmitter in brain. It has been estimated that approximately 60% of all neurons in brain utilize glutamate as their main neurotransmitter (Nieuwenhuys, 1994). Glutamate also plays a pivotal role in drug addiction, drug self-administration, reward-related processes and relapse (Tzschentke and Schmidt, 2003, Kalivas and Volkow, 2005, Gass and Olive, 2008). Increased glutamatergic neurotransmission and hyper-excitability during withdrawal and abstinence are associated with an increased risk for relapse (Tsai and Coyle, 1998), in addition to changes in the glutamatergic system after chronic alcohol intake (Nagy et al., 2005, Krupitsky et al., 2007).
Ionotropic glutamate receptors (including NMDA-, AMPA- and Kainate-receptors) mediate fast excitatory neurotransmission, while mGluRs are members of the large family of G-protein-coupled receptors, which mediate a slower modulatory response. Activated G-proteins modulate the function of various intracellular effector molecules that include ion channels. Further, second messenger cascades provide a mechanism to modulate cell excitability and synaptic transmission. mGluRs consist of eight subtypes (mGluR1-8) (for review, see Olive, 2009) subdivided into three functional groups (mGluR I–III). Group I contains mGluR1 and mGluR5 (Niswender and Conn, 2010).
Group I mGluRs, which are the mGluR1 and mGlur5, are postsynaptic receptors that are coupled to Gq/G11 protein. They activate phospholipase C in the hydrolysis of phosphotinositides in the production of inositol triphosphate (IP) and diacetylglycerol (DAG), thus leading to calcium mobilization and activation of protein kinase C (for review, see Niswender and Conn, 2010). In addition, the postsynaptic terminal mGluR5s are physically linked to the NR2B subunit of NMDA-receptor by a chain of interacting proteins that include the PSD-95, Shank and Homer—proteins (Tu et al., 1999). mGluR1 receptors are extensively expressed in Purkinje cells of cerebellum and olfactory bulb. High expression is also found in the pars compacta of substantia nigra, lateral septum, globus pallidum, and the thalamic relay nuclei (Martin et al., 1992, Shigemoto et al., 1992, Baude et al., 1993). mGluR5 receptors are also highly expressed in the septum, basal ganglia, amygdala, nucleus accumbens and in hippocampus (Palucha and Pilc, 2007), in addition to hippocampal pyramidal cells, where mGluR1 was not detectable (Romano et al., 1995). The cells in CA1 of hippocampus, however, do express mRNA for mGluR1 (Shigemoto et al., 1992, Berthele et al., 1998). mGlur5 receptors are highly expressed at least in CA1 and CA3 regions of the hippocampus, whereas mGluR1 is restricted to the CA3 region (Shigemoto et al., 1992, Shigemoto et al., 1993, Romano et al., 1995, Lavreysen et al., 2004).
Emerging evidence suggests that metabotropic glutamate receptors (mGluR) play a role in alcoholism. Several mGluR receptors (i.e., mGluR1, mGluR5, and mGluR2/3) have been shown to regulate alcohol self-administration and relapse-like behavior (Backstrom et al., 2004, Schroeder et al., 2005, Schroeder et al., 2008, Backstrom and Hyytia, 2006, Hodge et al., 2006, Besheer et al., 2008b, Besheer et al., 2008a). In particular, mGluR5 is especially abundant in brain regions known to be involved in drug reinforcement (Shigemoto et al., 1993, Romano et al., 1995, Lu et al., 1999, Volkow et al., 2003). However, there is little information regarding the role of mGluRs in the human alcoholic brain.
In several rodent studies, the mGluR5 antagonist MPEP reduced ethanol consumption by decreasing operant ethanol self-administration, which suggests that mGluR5 receptors may moderate both the maintenance of ethanol self-administration and abstinence-induced increases in ethanol intake (Schroeder et al., 2005, Hodge et al., 2006). In animal models, MPEP appears to have prevented the development of ethanol dependence (Blednov and Harris, 2008) whereas antagonists of either mGluR1 or mGlur2/3 have failed to do so. It has been suggested that the effects of mGluR5 antagonism may involve an attenuation of the neurochemical signals that mediate ethanol reward, whereas those of mGlur1 antagonism may increase sensitivity to the inhibitory effects of ethanol (Lominac et al., 2006). It has also been suggested that the effect of mGlur5 antagonism on ethanol consumption is not due to motor impairment, whereas the effect on mGlur1 antagonism may be related to it (Besheer et al., 2008b, Besheer et al., 2008a).
Cloninger has suggested a dual typology of alcoholics, with anxiety-prone type 1 alcoholics and socially hostile type 2 alcoholics (Cloninger et al., 1988b, Cloninger, 1995). We previously reported many type-specific alterations in receptor and transporter densities among Cloninger type 1 and type 2 alcoholics (Mantere et al., 2002, Tupala and Tiihonen, 2004, Storvik et al., 2008, Storvik et al., 2009b, Lehtonen et al., 2010, Laukkanen et al.,), while suggesting that the neurochemistry may be differentially affected between these two alcoholic subgroups. However, despite the critical role of the glutamate system in alcohol dependence, the differences in mGluR1/5 densities among alcoholic subtypes have not been reported to date. To our knowledge, this is the first study to study mGluR1/5 receptor density in alcoholism.
Section snippets
Materials and methods
The methodologies for this study have been described earlier by our group (Storvik et al., 2008, Tupala et al., 2000, Tupala et al., 2001a, Tupala et al., 2001b, Tupala et al., 2008). In brief, post-mortem brain left hemispheres (17 alcoholics and 8 controls) were obtained during clinical autopsy from the Department of Forensic Medicine, University of Oulu, Finland, and two of the non-alcoholic control brains were obtained from the Department of Forensic Medicine, University of Eastern Finland,
Results
[3H] Quisqualic acid bound to the striatum and hippocampus, indicating the presence of mGluR1/5 in these structures (Fig. 1, Fig. 2). [3H] Quisqualic acid did not bind or accumulate in the white matter. The results of selective [3H]Quisqualic acid binding to mGluR1/5 are presented in Table 1. A significant difference between the three subject groups was observed in the CA2 layer of the hippocampus (p=0.026, age adjusted). mGluR1/5 density was observed to be increased in the CA2 layer of the
Discussion
The main limitation in the study is that Quisqualic acid, which was used as a radioactive ligand, binds to both mGluR1 and mGluR5. However, the literature suggests that only mGluR5 is highly expressed in the hippocampus, and it has been identified in CA1 pyramidal cells, where mGluR1 was not detectable (Shigemoto et al., 1992, Baude et al., 1993, Romano et al., 1995, Berthele et al., 1998, Palucha and Pilc, 2007). On the contrary, the mGluR1 subunit is enriched in a subregion of the dentate
Acknowledgments
We wish to thank Pirkko Räsänen, MD, PhD for her help with the diagnostics. We also thank Terttu Särkioja, MD, PhD and Kari Karkola, MD, PhD for providing the post-mortem brains for this study.
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2021, Alcohol: Neurobiology of AddictionIncreased [³H]quisqualic acid binding density in the dorsal striatum and anterior insula of alcoholics: A post-mortem whole-hemisphere autoradiography study
2019, Psychiatry Research - NeuroimagingCitation Excerpt :Our findings of altered mGluR1/5 binding in the hippocampus of Cloninger type 2 alcoholics is in line with these studies, suggesting altered group I mGluR function of this area in alcoholism. In our previous study about [³H]quisqualic acid binding density on the level of ventral striatum, we found increased mGluR1/5 binding density in the CA2 area of hippocampus in Cloninger type 1 alcoholics, and no further differences between the groups were detected (Kupila et al., 2013). In that study, one area of the ventral striatum was defined as nucleus accumbens, beginning at the level where the caudate nucleus and putamen unite.
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2018, Progress in NeurobiologyCitation Excerpt :This study concluded that NMDAR is implicated significantly in the development of alcohol addiction. Like preclinical studies, increase in mGluR1/5 expression has been documented in hippocampus of type 1 alcoholics (non-genetic) as compared to either type 2 alcoholics (genetic) or healthy subjects (Kupila et al., 2013). Interestingly, postmortem analysis of ACC from alcoholics also revealed a reduction in mGluR2 transcript levels (aminMeinhardt et al., 2013), and this decrease in mGluR2-mediated neurotransmission is thought to be critical in relapse to alcohol.
Genetic studies of alcohol dependence in the context of the addiction cycle
2017, NeuropharmacologyCitation Excerpt :A modest association (p < 10–6) was found in a SNP (rs6483362) in GRM5 which encodes the glutamate metabotropic-5 G-protein coupled receptor (mGlu5) (Fig. 1 and Table 3). mGlu1/5 receptor binding is increased in the hippocampus of type 1 alcoholics (Kupila et al., 2013). mGlu5 receptor antagonists reduce alcohol-withdrawal induced anxiety in rats (Kumar et al., 2013).
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