Metabotropic and ionotropic glutamate receptors as potential targets for the treatment of alcohol use disorder

Goodwani, Sunil; Saternos, Hannah; Alasmari, Fawaz; Sari, Youssef

doi:10.1016/j.neubiorev.2017.02.024

Cited by 70 publications

(67 citation statements)

References 232 publications

(225 reference statements)

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“…It has been suggested that the interaction between depression and SUD could lead to glial dysfunction and a consequent alteration in glutamatergic neurotransmission [57, 58], so the pharmacological modulation of this circuit may play a key role in the treatment of SUD in comorbidity with other mental disorders. Ketamine, a glutamate-modulating agent, has been shown to reduce suicide in high-risk populations [58-60], so the inclusion of this medication in the treatment of subjects with SUD with suicidal tendencies is an option that would be worth exploring.…”

Section: Discussionmentioning

confidence: 99%

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Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder

et al. 2018

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Background/Aim: Although individuals with substance use disorder (SUD) are at high risk of committing suicide, most studies of postmortem gene expression exclude subjects with SUD due to the potential confounding effect of drugs in the transcriptome. Thus, little is known about the gene expression profile in suicides with SUD. The identification of altered biological processes in suicides with SUD is crucial in the comprehension of the interaction between both pathologies. Methods: We evaluated the gene expression profile in the dorsolateral prefrontal area of suicides and nonsuicides with and without SUD by microarrays. Results: We identified 222 differentially expressed genes, predominately enriched in cell proliferation in the comparison between suicides with and without SUD. When comparing the transcriptome of suicides with SUD to nonsuicides with SUD, we identified 550 differentially expressed genes, mainly enriched in oxidative phosphorylation. Differentially expressed genes (1,417) between suicides and nonsuicides without SUD were detected. Most of them were related to mitochondrial function. Conclusion: Interaction between suicide and SUD seems to influence the expression of genes involved in glial proliferation and glutamatergic neurotransmission. These results highlight, for the first time, that suicides with SUD have a gene expression profile distinct from that of subjects with only one of these disorders.

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Section: Discussionmentioning

confidence: 99%

“…Ketamine, a glutamate-modulating agent, has been shown to reduce suicide in high-risk populations [58-60], so the inclusion of this medication in the treatment of subjects with SUD with suicidal tendencies is an option that would be worth exploring.…”

Section: Discussionmentioning

confidence: 99%

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder

et al. 2018

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“…A prior study from our group reported that upregulating GLT-1 in the NAc and the PFC by ceftriaxone treatment led to an attenuation of EtOH and/or NIC drinking behavior in female P rats (Sari et al, 2016). This indicates that astroglial glutamate transporters, mainly GLT-1, plays a critical role in regulating EtOH or NIC seeking [For review see (Alasmari et al, 2016a, Goodwani et al, 2017]. In the present work, for the first time, we found that peri-adolescent binge-like scheduled access to SUC-NIC downregulated GLT-1 in the NAc compared to water and SUC control groups, while peri-adolescent EtOH-NIC binge-like drinking reduced GLT-1 expression in the NAc compared to the water control and EtOH groups.…”

Section: Accepted Manuscript 17mentioning

confidence: 99%

“…Regarding Group I metabotropic glutamate receptors (mGluRs), mGluR1 is upregulated in animals exposed to EtOH or NIC (Kane et al, 2005. Moreover, it has been shown that mGluR1 antagonists significantly attenuate both EtOH-and NIC-seeking behavior in animals (Dravolina et al, 2007, Besheer et al, 2008, Goodwani et al, 2017 suggesting a potential role for mGluR1 in regulating the reinforcing effects of EtOH and NIC.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Peri-adolescent drinking of ethanol and/or nicotine modulates astroglial glutamate transporters and metabotropic glutamate receptor-1 in female alcohol-preferring rats

Alasmari

Bell

Rao

et al. 2018

Pharmacology Biochemistry and Behavior

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Impairment in glutamate neurotransmission mediates the development of dependence upon nicotine (NIC) and ethanol (EtOH). Previous work indicates that continuous access to EtOH or phasic exposure to NIC reduces expression of the glutamate transporter-1 (GLT-1) and cystine/glutamate antiporter (xCT) but not the glutamate/aspartate transporter (GLAST). Additionally, metabotropic glutamate receptors (mGluRs) expression was affected following exposure to EtOH or NIC. However, little is known about the effects of EtOH and NIC co-consumption on GLT-1, xCT, GLAST, and mGluR1 expression. In this study, peri-adolescent female alcohol preferring (P) rats were given binge-like access to water, sucrose (SUC), SUC-NIC, EtOH, or EtOH-NIC for four weeks. The present study determined the effects of these reinforcers on GLT-1, xCT, GLAST, and mGluR1 expression in the nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC). GLT-1 and xCT expression were decreased in the NAc following both SUC-NIC and EtOH-NIC. In addition, only xCT expression was downregulated in the HIP in both of these latter groups. Also, glutathione peroxidase (GPx) activity in the HIP was reduced following SUC, SUC-NIC, EtOH, and EtOH-NIC consumption. Similar to previous work, GLAST expression was not altered in any brain region by any of the reinforcers. However, mGluR1 expression was increased in the NAc in the SUC-NIC, EtOH, and EtOH-NIC groups. These results indicate that peri-adolescent binge-like drinking of EtOH or SUC with or without NIC may exert differential effects on astroglial glutamate transporters and receptors. Our data further parallel some of the previous findings observed in adult rats.

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“…In the mammalian central nervous system, NMDARs are primarily comprised of two glutamatesensitive GluN2 subunits, occurring in subtypes GluN2A-D, and two glycine-sensitive GluN1 subunits (Paoletti et al, 2013). Memantine, an NMDAR channel blocker (ie uncompetitive antagonist) with preferential action on GluN2C-or GluN2D-containing NMDARs (Parsons et al, 1999;Kotermanski and Johnson, 2009;Riebe et al, 2016), is clinically used for the treatment of Alzheimer's disease, and has been proposed as a potential treatment option for alcohol use disorders (Goodwani et al, 2017). However, preclinical data indicate that memantine can facilitate aggressive behavior in mice when administered either after acute alcohol intake or during alcohol withdrawal (Newman et al, 2012;Hwa et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression

Newman

Terunuma

Wang

et al. 2017

Neuropsychopharmacol.

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Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.

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Metabotropic and ionotropic glutamate receptors as potential targets for the treatment of alcohol use disorder

Cited by 70 publications

References 232 publications

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder

Peri-adolescent drinking of ethanol and/or nicotine modulates astroglial glutamate transporters and metabotropic glutamate receptor-1 in female alcohol-preferring rats

A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression

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