Role of glutamate transporters in the modulation of stress-induced lactate metabolism in the rat brain

Uehara, Takashi; Sumiyoshi, Tomiki; Itoh, Hiroko; Kurachi, Masayoshi

doi:10.1007/s00213-007-0881-1

Cited by 18 publications

(16 citation statements)

References 28 publications

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“…For example, infusions of high doses of DHK into the hippocampus can elevate taurine levels (Lehmann and Hamberger, 1983) and taurine supplementation, alone, can increase anxiety (El Idrissi et al, 2009). Interestingly, infusion of DHK directly in the amygdala also increases lactate, which is indicative of increased neuronal activity and energy use (Uehara et al, 2007). Thus, we are unable to rule out other potential effects of DHK in inducing the observed effects.…”

Section: Discussionmentioning

confidence: 84%

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: Discussionmentioning

confidence: 84%

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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“…The measurements of lactate concentrations in dialysates were conducted according to our previous studies (Uehara et al,2003a, 2005, 2006, 2007a, b). About 42–48 h after surgery, the dialysis experiment was carried out on the freely moving rats.…”

Section: Methodsmentioning

confidence: 99%

“…Footshock stress was administered using a plastic communication box (CB5; Melquest, Toyama, Japan) according to the method described previously (Uehara et al, 2003b(Uehara et al, , 2006(Uehara et al, , 2007b. The box (L 3 W 3 H 5 51 cm 3 51 cm 3 40 cm) was equipped with a grid floor composed of stainless steel rods (6 mm diameter) placed 16 mm apart and was subdivided into nine compartments (17 cm 3 17 cm) by transparent plastic walls.…”

Section: Footshock Stressmentioning

confidence: 99%

Effect of transient blockade of N‐methyl‐D‐aspartate receptors at neonatal stage on stress‐induced lactate metabolism in the medial prefrontal cortex of adult rats: Role of 5‐HT1A receptor agonism

Uehara

Itoh

Matsuoka

et al. 2012

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Decreased activity of the medial prefrontal cortex (mPFC) has been considered a basis for core symptoms of schizophrenia, an illness associated with a neurodevelopmental origin. Evidence from preclinical and clinical studies indicates that serotonin (5-HT)1A receptors play a crucial role in the energy metabolism of the mPFC. This study was undertaken to determine (1) if transient blockade of N-methyl-D-aspartate receptors during the neonatal stage inhibit energy demands in response to stress, as measured by extracellular lactate concentrations, in the mPFC at the young adult stage, and (2) if tandospirone, a 5-HT1A partial agonist, reverses the effect of the neonatal insult on energy metabolism. Male pups received MK-801 (0.20 mg/kg) on postnatal days (PDs) 7-10. On PD 63, footshock stress-induced lactate levels were measured using in vivo microdialysis technique. Tandospirone (0.1, 1.0, and 5.0 mg/kg) was administered once daily for 14 days before the measurement of lactate levels. Neonatal MK-801 treatment suppressed footshock stress-induced lactate production in the mPFC, but not caudate-putamen, whereas basal lactate levels were not significantly changed in either brain region. The MK-801-induced suppression of footshock stress-induced lactate production in the mPFC was attenuated by tandospirone at 1.0mg/kg/day, but not 0.1 or 5.0 mg/kg/day, which is an effect antagonized by coadministration of WAY-100635, a selective 5-HT1A antagonist. These results suggest a role for impaired lactate metabolism in some of the core symptoms of schizophrenia, for example, negative symptoms and cognitive deficits. The implications for the ability of 5-HT1A agonism to ameliorate impaired lactate production in the mPFC of this animal model are discussed.

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“…Furthermore, transient blockade of NMDA‐Rs during the neonatal stage inhibits energy demands in response to stress, as measured by extracellular lactate concentrations in the mPFC but not caudate–putamen, on postpuberty (Uehara et al, ). It is interesting that lactate metabolism in the brain is largely affected by glutamatergic transmission through NMDA‐Rs and Glu transporters, such as the Glu‐aspartate transporter (GLAST) and glutamate transporter‐1 (GLU‐1) (Pellerin and Magistretti, ; Uehara et al, ).…”

Section: Introductionmentioning

confidence: 99%

Neonatal exposure to MK‐801 reduces mRNA expression of mGlu3 receptors in the medial prefrontal cortex of adolescent rats

Uehara

Sumiyoshi

Rujescu³

et al. 2014

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Schizophrenia is considered as a "neurodegenerative" and "neurodevelopmental" disorder, the pathophysiology of which may include hypofunction of the N-methyl-D-aspartate receptor (NMDA-R) or subsequent pathways. Accordingly, administration of NMDA-R antagonists to rodents during the perinatal period may emulate some core pathophysiological aspects of schizophrenia. The effect of 4-day (postnatal day; PD 7-10) administration of MK-801, a selective NMDA-R antagonist, on gene expression in the medial prefrontal cortex (mPFC), hippocampus, and amygdala was evaluated using quantitative polymerase chain reaction methods. Specifically, we sought to determine whether genes related to Glu transmissions, for example those encoding for NMDA-Rs, metabotropic Glu receptors (mGluRs), or Glu transporters, were altered by neonatal treatment with MK-801. Model rats showed downregulation of the mGluR3 subtype in the mPFC around puberty, especially at PD 35 in response to MK-801 or during ontogenesis without pharmacological manipulations. Genes encoding for other mGluRs subtypes, that is NMDA-Rs and Glu transporters, were not affected by the neonatal insult. These results suggest that NMDA-R antagonism in the early course of development modulates the expression of mGluR3 in mPFC around puberty. Thus, mGluR3 may serve as a potential target to prevent the onset and progression of schizophrenia.

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Role of glutamate transporters in the modulation of stress-induced lactate metabolism in the rat brain

Abstract: These results suggest that glutamate transporters regulate lactate availability in astrocytes and indicate that the rapid energy demand induced by glutamate contributes to local lactate production.

Cited by 18 publications

References 28 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

Effect of transient blockade of N‐methyl‐D‐aspartate receptors at neonatal stage on stress‐induced lactate metabolism in the medial prefrontal cortex of adult rats: Role of 5‐HT1A receptor agonism

Neonatal exposure to MK‐801 reduces mRNA expression of mGlu3 receptors in the medial prefrontal cortex of adolescent rats

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