Blockade of Astrocytic Glutamate Uptake in the Prefrontal Cortex Induces Anhedonia

John, Catherine S.; Smith, Karen; Veer, Ashlee Van’t; Gompf, Heinrich S.; Carlezon, William A.; Cohen, Bruce M.; Öngür, Döst; Bechtholt-Gompf, Anita J

doi:10.1038/npp.2012.105

Cited by 117 publications

(91 citation statements)

References 61 publications

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“…In the present report, we were able to replicate the anhedonic-like effects that we have previously reported when DHK is infused centrally or into the prefrontal cortex (Bechtholt-Gompf et al, 2010;John et al, 2012) by showing that intra-CEA DHK increases ICSS thresholds (T0) and at the higher doses induced a complete cessation of responding in some rats. This finding is indicative of an anhedonic-like effect and is consistent with previous reports demonstrating that interfering with astrocytic function in specific brain regions can induce signs of depression (Herberg and Rose, 1990;Lee et al, 2007;Banasr and Duman, 2008).…”

Section: Discussionsupporting

confidence: 84%

“…Decreased Max Rates can be the result of decreased hedonic value of stimulation (Do Carmo et al, 2009) or reduced performance ability (Carlezon and Chartoff, 2007). The time-course of these effects are consistent with our previous findings using central (Bechtholt-Gompf et al, 2010) or intra-cortical infusions of DHK (John et al, 2012).…”

Section: Effects Of Dhk On Icsssupporting

confidence: 91%

“…We have previously reported that ICV or intra-PFC DHK is capable of increasing intracranial selfstimulation (ICSS) thresholds and latency to begin drinking sucrose, suggesting that both central and region-specific increases in glutamate can induce anhedonic-like symptoms in rats (Bechtholt-Gompf et al, 2010;John et al, 2012). Here, we used ICSS as a measure of motivation and anhedonia (Carlezon and Chartoff, 2007) to determine whether intra-CEA DHK is sufficient to replicate the anhedonic-like effects we observed previously with ICV infusion.…”

Section: Introductionmentioning

confidence: 80%

“…DHK does not bind to AMPA/kainite or other glutamate receptors with significant affinity (Johnston et al, 1979), indicating selectivity for GLT-1. Doses of DHK were derived from preliminary studies and previously published behavioral data (Lee et al, 2007;Bechtholt-Gompf et al, 2010;John et al, 2012). DHK was dissolved in phosphate-buffered saline (pH 7.4) as previously reported (Lee et al, 2007).…”

Section: Drugsmentioning

confidence: 99%

“…The rats were trained on a fixed-ratio-one schedule of reinforcement to obtain brain stimulation as previously described (Carlezon and Chartoff, 2007;Bechtholt-Gompf et al, 2010;John et al, 2012). Briefly, rats were trained to lever press for a 0.5-s pulse train.…”

Section: Intracranial Self-stimulationmentioning

confidence: 99%

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Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

John

Sypek

Carlezon

et al. 2015

Neuropsychopharmacol

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Depression has been associated with abnormalities in glutamatergic neurotransmission and decreased astrocyte number in limbic areas. We previously demonstrated that global and prefrontal cortical blockade of the astrocytic glutamate transporter (GLT-1) induces anhedonia and c-Fos expression in areas that regulate anxiety, including the central amygdala (CEA). Given the role of the amygdala in anxiety and the high degree of comorbidity between anxiety and depression, we hypothesized that GLT-1 blockade in the CEA would induce symptoms of anhedonia and anxiety in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the CEA and examined effects on intracranial self-stimulation (ICSS) as an index of hedonic state, and on behavior in two anxiety paradigms, elevated plus maze (EPM) and fear conditioning. At lower doses, intra-CEA DHK produced modest increases in ICSS responding (T0). Higher doses resulted in complete cessation of responding for 15 min, suggesting an anhedonic or depressive-like effect. Intra-CEA DHK also increased anxiety-like behavior such that percent time in the open arms and total entries were decreased in the EPM and acquisition of freezing behavior to the tone was increased in a fear-conditioning paradigm. These effects did not appear to be explained by non-specific changes in activity, because effects on fear conditioning were assessed in a drug-free state, and a separate activity test showed no significant effects of intra-CEA DHK on locomotion. Taken together, these studies suggest that blockade of GLT-1 in the CEA is sufficient to induce both anhedonia and anxiety and therefore that a lack of glutamate uptake resulting from glial deficits may contribute to the comorbidity of depression and anxiety.

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Section: Discussionsupporting

confidence: 84%

Section: Effects Of Dhk On Icsssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 80%

Section: Drugsmentioning

confidence: 99%

Section: Intracranial Self-stimulationmentioning

confidence: 99%

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Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

John

Sypek

Carlezon

et al. 2015

Neuropsychopharmacol

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A single dose of S‐ketamine induces long‐term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation

Réus

Carlessi

Titus

et al. 2015

Developmental Neurobiology

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Ketamine, an antagonist of N-methyl-d-aspartate receptors, has produced rapid antidepressant effects in patients with depression, as well as in animal models. However, the extent and duration of the antidepressant effect over longer periods of time has not been considered. This study evaluated the effects of single dose of ketamine on behavior and oxidative stress, which is related to depression, in the brains of adult rats subjected to maternal deprivation. Deprived and nondeprived Wistar rats were divided into four groups nondeprived+saline; nondeprived+S-ketamine (15 mg/kg); deprived+saline; deprived+S-ketamine (15 mg/kg). A single dose of ketamine or saline was administrated during the adult phase, and 14 days later depressive-like behavior was assessed. In addition, lipid damage, protein damage, and antioxidant enzyme activities were evaluated in the rat brain. Maternal deprivation induces a depressive-like behavior, as verified by an increase in immobility and anhedonic behavior. However, a single dose of ketamine was able to reverse these alterations, showing long-term antidepressant effects. The brains of maternally deprived rats had an increase in protein oxidative damage and lipid peroxidation, but administration of a single dose of ketamine reversed this damage. The activities of antioxidant enzymes superoxide dismutase and catalase were reduced in the deprived rat brains. However, ketamine was also able to reverse these changes. In conclusion, these findings indicate that a single dose of ketamine is able to induce long-term antidepressant effects and protect against neural damage caused by oxidative stress in adulthood rats following maternal deprivation.

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An astroglial basis of major depressive disorder? An overview

Wang

Jie

Liu

et al. 2017

Glia

174

125

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Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding of the pharmacotherapy of depression for more than half a century; however, our understanding of the pathophysiology and pathogenesis of major depression has lagged far behind. Astrocytes are the most abundant and versatile cells in the brain, participating in most, if not all, of brain functions as both a passive housekeeper and an active player. Mounting evidence from clinical, preclinical and post-mortem studies has revealed a decrease in the number or density of astrocytes and morphological and functional astroglial atrophy in patients with major depressive disorder (MDD) and in animal models of depression. Furthermore, currently available antidepressant treatments at least partially exert their therapeutic effects on astrocytes. More importantly, dysfunctional astrocytes lead to depressive-like phenotypes in animals. Together, current studies point to astroglial pathology as the potential root cause of MDD. Thus, a shift from a neuron-centric to an astrocyte-centric cause of MDD has gained increasing attention during the past two decades. Here we will summarize the current evidence supporting the hypothesis that MDD is a disease of astrocyte pathology and highlight previous studies on promising strategies that directly target astrocytes for the development of novel antidepressant treatments.

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Blockade of Astrocytic Glutamate Uptake in the Prefrontal Cortex Induces Anhedonia

Cited by 117 publications

References 61 publications

Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

A single dose of S‐ketamine induces long‐term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation

An astroglial basis of major depressive disorder? An overview

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