Glial abnormalities in substance use disorders and depression: Does shared glutamatergic dysfunction contribute to comorbidity?

Niciu, Mark J.; Henter, Ioline D.; Sanacora, Gerard

doi:10.3109/15622975.2013.829585

Cited by 27 publications

(23 citation statements)

References 183 publications

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“…Further, reductions in expression of GFAP have been reported in both preclinical animal models of depression, as well as in human postmortem studies of psychiatric disease, most notably depression but also schizophrenia (for review, see (40–42)). Indeed, considerable evidence from the human literature indicates that glial dysfunction and more specifically decreased astrocyte density and astrocyte-mediated glutamate uptake may reflect a cellular feature of the high degree of comorbidity observed between substance use disorders and depression (43). …”

Section: Discussionmentioning

confidence: 99%

Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core

Scofield

Siemsen

et al. 2016

Biological Psychiatry

140

148

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Background As a more detailed picture of nervous system function emerges, diversity of astrocyte function becomes more widely appreciated. While it has been shown that cocaine experience impairs astroglial glutamate uptake and release in the nucleus accumbens (NAc), few studies have explored effects of self-administration on the structure and physiology of astrocytes. We investigated the effects of extinction from daily cocaine self-administration on astrocyte characteristics including GFAP expression, surface area, volume, and colocalization with a synaptic marker. Methods Cocaine or saline self-administration and extinction were paired with GFAP Westerns, immunohistochemistry, and fluorescent imaging of NAc core astrocytes (30 saline-administering and 36 cocaine-administering male Sprague Dawley rats were employed). Imaging was performed using a membrane-tagged Lck-GFP driven by the GFAP promoter, coupled with synapsin I immunohistochemistry. Results GFAP expression was significantly reduced in the NAc core following cocaine self-administration and extinction. Similarly, we observed an overall smaller surface area and volume of astrocytes, as well as reduced colocalization with synapsin I, in cocaine-administering animals. Cocaine-mediated reductions in synaptic contact were reversed by the β-lactam antibiotic ceftriaxone. Conclusions Multiple lines of investigation indicate that NAc core astrocytes exist in a hypo-reactive state following cocaine self-administration and extinction. Decreased association with synaptic elements may be particularly meaningful, as cessation of chronic cocaine use is associated with changes in synaptic strength and resistance to the induction of synaptic plasticity. We hypothesize that the reduced synaptic colocalization of astrocytes represents an important maladaptive cellular response to cocaine and the mechanisms underlying relapse vulnerability.

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Section: Discussionmentioning

confidence: 99%

Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core

Scofield

Siemsen

et al. 2016

Biological Psychiatry

140

148

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“…Thus, 1 H-MRS measurement of glutamine may provide an index of astrocytic functioning relating to this particular cycle; the ratio of glutamine-to-glutamate may be particularly salient. Notably, alterations in glutamine (2) and astrocyte functionality (36) have been associated with a number of psychiatric conditions.…”

Section: Discussionmentioning

confidence: 99%

Reliability of 7T¹H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation

Lally

Liu

Banerjee

et al. 2015

J. Magn. Reson. Imaging

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Purpose Evidence suggests that aberrant glutamatergic-signalling plays a role in numerous psychopathologies. To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy (1H-MRS) can non-invasively measure glutamatergic function. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. Materials and Methods At 7 T MR, we acquired 1H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (N = 26) twice on two separate days. An adapted echo time optimised point resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 parts per million, was used to excite and acquire the spectra. In house software was used to model glutamate, glutamine, and glutathione, amongst other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. Results Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs ≥ 0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC > 0.62). A negative correlation was observed between glutathione concentration and age (r(24) = −0.37; P < .05), and a gender effect was noted on glutamine and glutathione. Conclusion The adapted sequence provides good reliability to measure glutamate, glutamine and glutathione signals.

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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%

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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Glial abnormalities in substance use disorders and depression: Does shared glutamatergic dysfunction contribute to comorbidity?

Cited by 27 publications

References 183 publications

Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core

Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core

Reliability of 7T¹H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation

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

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Glial abnormalities in substance use disorders and depression: Does shared glutamatergic dysfunction contribute to comorbidity?

Cited by 27 publications

References 183 publications

Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core

Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core

Reliability of 7T1H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation

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

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Reliability of 7T¹H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation