Glutamate Levels In Prefrontal Cortex Research Articles

Glutamate levels in the ventromedial prefrontal cortex and resting-state functional connectivity within reward circuits in alcohol-dependent patients.

Great progress has been made in understanding the neural mechanisms associated with alcohol-dependent (AD) patients. However, the interactions within the reward circuits of the patients need further exploration. Glutamatergic projections from the prefrontal cortex to some brain regions are present in the reward circuit. However, little is known about the potential implications of glutamate levels in the prefrontal cortex on abnormal interactions within reward circuits in AD patients. To determine the potential roles of reward circuits in drinking, we investigated differences in resting-state functional connectivity (RSFC) and multivariate Granger causality analysis between 20 AD patients and 20 healthy controls (HC). The neuroimaging findings were then correlated with clinical variables (alcohol use disorder identification test). The ventromedial prefrontal cortex (VmPFC) is believed to play a critical role in addiction disorders, and glutamatergic projections from the prefrontal cortex to several regions of the brain are present in reward circuits. Proton magnetic resonance spectroscopy was also performed to assess the difference in glutamate levels in VmPFC between AD patients and HC. The results showed that the strength of functional connectivity in the reward circuit was generally attenuated in AD patients, and the reciprocal enhancement of activity between the right insula, left thalamus and VmPFC was found to be significantly greater in AD patients. It is worth noting that although glutamate levels in the VmPFC did not show significant differences between the two groups, the level of glutamate in the VmPFC was significantly correlated with RSFC. We hope that the current findings will help us to develop new intervention models based on the important role of the VmPFC in AD.

Altered relationship between prefrontal glutamate and activation during cognitive control in people with high trait anxiety

Trait anxiety can affect cognitive control resulting in ineffective and/or inefficient task performance. Moreover, previous functional Magnetic Resonance Imaging (fMRI) studies have reported altered dorsolateral prefrontal cortex (DLPFC) activity in anxious cohorts, particularly when executive control is required. Recently, it has been demonstrated that cortical glutamate levels can predict both functional activation during cognitive control, and anxiety levels. In the present study we sought to investigate the relationship between trait anxiety, prefrontal glutamate levels and functional activation in DLPFC during a cognitive control task. Thirty-nine participants assigned to either low trait anxiety (LTA) or high trait anxiety (HTA) groups underwent 1H-Magnetic Resonance Spectroscopy (1H-MRS) to measure levels of resting glutamate in the prefrontal cortex (PFC). Participants also completed fMRI during a Stroop task comprising congruent and incongruent colour word trials. The HTA group showed reduced task performance relative to the LTA group. In the LTA group, there was a positive association between PFC Glu levels and DLPFC activation during incongruent trials. This association was absent in the HTA group. Individual differences in trait anxiety affect the relationship between PFC glutamate levels and DLPFC activation, possibly contributing to ineffective task performance when cognitive control is required.

Glutamate homeostasis in the adult rat prefrontal cortex is altered by cortical docosahexaenoic acid accrual during adolescence: An in vivo1H MRS study

Major psychiatric disorders are associated with dysregulated glutamate homeostasis and deficits in the omega-3 fatty acid docosahexaenoic acid (DHA). This study determined the effects of dietary-induced alterations in brain DHA accrual on cortical glutamate homeostasis in the adult rat brain. Adolescent rats were fed a control diet (n = 20), a n-3 fatty acid-deficient diet (DEF, n = 20), or a fish oil-fortified diet containing preformed DHA (FO, n = 20). In adulthood 1H MRS scans were performed with voxels in the prefrontal cortex (PFC) and thalamus. Compared with controls, erythrocyte, PFC, and thalamus DHA levels were significantly lower in DEF rats and significantly higher in FO rats. In the PFC, but not the thalamus, glutamate was significantly elevated in DEF rats compared with controls and FO rats. Glutamine did not differ between groups and the glutamine/glutamate ratio was lower in DEF rats. No differences were observed for markers of excitotoxicity (NAA, GFAP), or astrocyte glutamate transporter (GLAST, GLT-1) or glutamine synthetase expression. Across diet groups, PFC DHA levels were inversely correlated with PFC glutamate levels and positively correlated with GLAST expression. Together these findings demonstrate that rat cortical DHA accrual during adolescence impacts glutamate homeostasis in the adult PFC.

Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1H magnetic resonance spectroscopy study.

There is ample evidence that the inhibitory GABA and the excitatory glutamate system are essential for an adequate response to stress. Both GABAergic and glutamatergic brain circuits modulate hypothalamus-pituitary-adrenal (HPA)-axis activity, and stress in turn affects glutamate and GABA levels in the rodent brain. However, studies examining stress-induced GABA and glutamate levels in the human brain are scarce. Therefore, we investigated the influence of acute psychosocial stress (using the Trier Social Stress Test) on glutamate and GABA levels in the medial prefrontal cortex of 29 healthy male individuals using 7 Tesla proton magnetic resonance spectroscopy. In vivo GABA and glutamate levels were measured before and 30 min after exposure to either the stress or the control condition. We found no associations between psychosocial stress or cortisol stress reactivity and changes over time in medial prefrontal glutamate and GABA levels. GABA and glutamate levels over time were significantly correlated in the control condition but not in the stress condition, suggesting that very subtle differential effects of stress on GABA and glutamate across individuals may occur. However, overall, acute psychosocial stress does not appear to affect in vivo medial prefrontal GABA and glutamate levels, at least this is not detectable with current practice 1H-MRS.

Role of glutamate and advantages of combining memantine with a 5HT6 ligand in a model of depression

BackgroundIt is a well-known fact that 5HT6 ligands increase glutamate levels. In the current study we investigated whether a 5HT6 antagonist, SB399885 would show antidepressant like property at a dose which would significantly increase the glutamate levels. Further we studied if the combination of a 5HT6 antagonist and N-methyl-d-asparate (NMDA) antagonist, memantine would restore the antidepressant property. As dementia and depression are co-morbid, we evaluated if this combination would have an effect on cognition. MethodsThe antidepressant like property of SB399885 alone and in combination with memantine was investigated using the forced swim test (FST). Object recognition task (ORT) was used to investigate the combination therapy on cognition. Additionally, glutamate levels in prefrontal cortex and corresponding brain concentration of SB399885 were determined. ResultsBrain concentrations of SB399885 equal to or greater than 553nM significantly increased brain glutamate levels and reduced immobility time in FST. When combined with memantine, glutamate levels and immobility time in FST was reduced. A dose dependent increase in the discriminative index was observed in ORT. ConclusionLoss of antidepressant like property seen at the highest tested dose of SB399885 could be due to increased glutamate levels which was reversed by memantine. Combining memantine and SB399885 offers the advantage of extending the therapeutic window of antidepressant like property of SB399885 as well as having procognitve effect. The combination therapy holds promise in treatment of dementia associated with depression.

Presymptomatic glutamate levels in prefrontal cortex in the Hdh(CAG150) mouse model of Huntington's disease.

Huntington's disease (HD) is a genetic neurodegenerative disorder with few available treatments. Clinical observations suggest prefrontal dysfunction in early stages of HD is associated with altered glutamate transport. Evidence from the R6/2 mouse model suggests an abnormal increase in glutamate signaling in the sensorimotor cortex and striatum. The present study was designed to determine if a similar deficit in glutamate function occurs in the prefrontal cortex (PFC) of Hdh(CAG150) mice. We used the following groups of 40 week old male and female Hdh(CAG150) mice: homozygote n = 7, heterozygote n = 7, wild type n = 6. Motor coordination was evaluated using a hanging wire grid test and a balance beam. Microdialysis measurements were taken from the PFC of freely moving mice while glutamate transporters were inhibited by L-trans-pyrrolidine-2, 4-dicarboxylate (PDC) and compared to baseline glutamate levels. RESULTS indicated an elevation in glutamate levels in response to PDC but no significant difference among genotype groups. When comparing wild type and homozygote alone, a significant difference in total extracellular glutamate was observed. Contrary to our original hypothesis, the homozygote group had lower glutamate levels compared to their wild type counterparts. Furthermore, there was a significant difference in GABA measurements across genotypes. Our results suggest a mechanistic dichotomy between R6/2 and Hdh(CAG150) mice and underscores the need to select the appropriate HD mouse model when assessing therapeutic interventions. In particular, the time when animals are evaluated can have a significant impact on behavioral and physiological measures and so should be carefully considered.

Evidence for involvement of nitric oxide and GABAB receptors in MK-801- stimulated release of glutamate in rat prefrontal cortex

Systemic administration of NMDA receptor antagonists elevates extracellular glutamate within prefrontal cortex. The cognitive and behavioral effects of NMDA receptor blockade have direct relevance to symptoms of schizophrenia, and recent studies demonstrate an important role for nitric oxide and GABAB receptors in mediating the effects of NMDA receptor blockade on these behaviors. We sought to extend those observations by directly measuring the effects of nitric oxide and GABAB receptor mechanisms on MK-801-induced glutamate release in the prefrontal cortex. Systemic MK-801 injection (0.3 mg/kg) to male Sprague–Dawley rats significantly increased extracellular glutamate levels in prefrontal cortex, as determined by microdialysis. This effect was blocked by pre-treatment with the nitric oxide synthase inhibitor l-NAME (60 mg/kg). Reverse dialysis of the nitric oxide donor SNAP (0.5–5 mM) directly into prefrontal cortex mimicked the effect of systemic MK-801, dose-dependently elevating cortical extracellular glutamate. The effect of MK-801 was also blocked by systemic treatment with the GABAB receptor agonist baclofen (5 mg/kg). In combination, these data suggest increased nitric oxide formation is necessary for NMDA antagonist-induced elevations of extracellular glutamate in the prefrontal cortex. Additionally, the data suggest GABAB receptor activation can modulate the NMDA antagonist-induced increase in cortical glutamate release.

Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine

Cognitive deficits represent a core symptom cluster in schizophrenia (SZ) that is predictive of outcome but not effectively treated by current antipsychotics. Thus, there is a need for validated animal models for testing potential pro-cognitive drugs. As kynurenic acid levels are increased in prefrontal cortex (PFC) of individuals with SZ, we acutely increased brain levels of this astrocyte-derived, negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs) by administration of its bioprecursor kynurenine and measured the effects on extracellular kynurenic acid and glutamate levels in PFC and also performance in a set-shifting task. Injections of kynurenine (100 mg/kg, i.p.) increased extracellular kynurenic acid (1,500%) and decreased glutamate levels (30%) in PFC. Kynurenine also produced selective deficits in set-shifting. Saline- and kynurenine-treated rats similarly acquired the compound discrimination and intra-dimensional shift (saline, 7.0 and 6.3 trials, respectively; kynurenine, 8.0 and 6.7). Both groups required more trials to acquire the initial reversal (saline, 15.3; kynurenine, 22.2). Only kynurenine-treated rats were impaired in acquiring the extra-dimensional shift (saline, 8.2; kynurenine, 21.3). These deficits were normalized by administering the α7nAChR positive allosteric modulator galantamine (3.0 mg/kg, i.p) prior to kynurenine, as trials were comparable between galantamine + kynurenine (7.8) and controls (8.2). Bilateral local perfusion of the PFC with galantamine (5.0 μM) also attenuated kynurenine-induced deficits. These results validate the use of animals with elevated brain kynurenic acid levels in SZ research and support studies of drugs that normalize brain kynurenic acid levels and/or positively modulate α7nAChRs as pro-cognitive treatments for SZ.

Nicotine Normalizes Increased Prefrontal Cortical Dopamine D1 Receptor Binding and Decreased Working Memory Performance Produced by Repeated Pretreatment with MK-801: A PET Study in Conscious Monkeys

The effects of acute nicotine were determined on dopamine (DA) D(1) (D(1)R) and D(2) (D(2)R) receptor binding in the neocortex of conscious monkeys under control conditions as well as after chronic pretreatment with MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Extrastriatal neocortical D(1)R and D(2)R binding was evaluated with [(11)C]NNC112 and [(11)C]FLB457 with high-specific radioactivity using positron emission tomography (PET). Acute administration of nicotine bitartrate, given as an intravenous (i.v.) bolus plus infusion for 30 min at doses of 32 microg/kg+0.8 microg/kg/min or 100 microg/kg+2.53 microg/kg/min as base, induced slight but significant dose-dependent increases of DA in the extracellular fluid of prefrontal cortex (PFC) as determined by microdialysis. However, acute nicotine did not affect either [(11)C]NNC112 or [(11)C]FLB457 binding to D(1)R or D(2)R, respectively, in any cortical region. Chronic MK-801 (0.03 mg/kg, intramuscularly (i.m.), twice daily for 13 days) increased [(11)C]NNC112 binding to D(1)R in PFC. No significant changes were detected in [(11)C]FLB457 binding to PFC D(2)R. Although chronic MK-801 lowered baseline DA and glutamate levels in PFC, acute nicotine normalized reduced DA to control levels. Acute nicotine dose-dependently normalized the increased binding of [(11)C]NNC112 to D(1)R produced by chronic MK-801 but [(11)C]FLB457 binding to PFC D(2)R did not change. Working memory performance, impaired after chronic MK-801, was partially improved by acute nicotine. These results demonstrate that acute nicotine normalizes MK-801-induced PFC abnormality of D(1)R in PFC.

Lysergic acid diethylamide and [−]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex

The ability of hallucinogens to increase extracellular glutamate in the prefrontal cortex (PFC) was assessed by in vivo microdialysis. The hallucinogen lysergic acid diethylamide (LSD; 0.1 mg/kg, i.p.) caused a time-dependent increase in PFC glutamate that was blocked by the 5-HT 2A antagonist M100907 (0.05 mg/kg, i.p.). Similarly, the 5-HT 2A/C agonist [−]-2,5-dimethoxy-4-methylamphetamine (DOM; 0.6 mg/kg, i.p.), which is a phenethylamine hallucinogen, increased glutamate to 206% above saline-treated controls. When LSD (10 μM) was directly applied to the PFC by reverse dialysis, a rapid increase in PFC glutamate levels was observed. Glutamate levels in the PFC remained elevated after the drug infusion was discontinued. These data provide direct evidence in vivo for the hypothesis that an enhanced release of glutamate is a common mechanism in the action of hallucinogens.

Extracellular glutamate levels in prefrontal cortex during the expression of associative responses to cocaine related stimuli

We conducted studies to examine the potential role of glutamate in the prefrontal cortex (PFC) during conditioned responses to stimuli (flashing light and metronome) previously associated with cocaine administration. During training, PAIRED subjects received cocaine injections (15 mg/kg) during stimuli sessions while UNPAIRED subjects received saline injections (but received cocaine in the home cage an hour later). We showed previously that PAIRED subjects exhibit conditioned locomotion when tested with the stimuli alone. In this study, we further demonstrated that the expression of behavioral sensitization in response to cocaine challenge is under conditioned control in PAIRED subjects. Then, we used microdialysis to examine extracellular levels of glutamate in the PFC in response to presentation of the conditioned stimuli alone and challenge with cocaine in the presence of the conditioned stimuli. Although PAIRED subjects demonstrated conditioned locomotion and conditioned control of sensitization during the microdialysis experiment, PFC glutamate levels were unaltered during the tests and did not differ between the PAIRED and UNPAIRED subjects.

Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: studies on the involvement of dopamine.

The effects of cocaine and d-amphetamine on extracellular glutamate and aspartate levels in the nucleus accumbens, prefrontal cortex, and striatum were studied by in vivo microdialysis in awake, freely moving rats. In the nucleus accumbens, glutamate levels were stimulated by cocaine (15-30 mg/kg, i.p.), GBR 12909 (15 mg/kg, i.p.), and d-amphetamine (2 mg/kg, i.p.), while aspartate levels were not affected. The increase in nucleus accumbens glutamate levels following cocaine (30 mg/kg) was calcium-dependent and was blocked by pretreatment with dopamine antagonists; haloperidol (0.2 mg/kg, i.p.), SCH 23390 (0.02 mg/kg, i.p.), and raclopride (1 mg/kg, i.p.), as well as local 6-OHDA lesions of the nucleus accumbens. In the prefrontal cortex, glutamate levels were stimulated by both cocaine (15-30 mg/kg, i.p.) and d-amphetamine (2 mg/kg, i.p.), while aspartate levels were moderately stimulated by d-amphetamine only. The increase in prefrontal cortex glutamate levels following cocaine (30 mg/kg) was calcium-dependent and was blocked by pretreatment with SCH 23390 (0.02 mg/kg, i.p.), but not haloperidol (0.2 mg/kg, i.p.) or raclopride (1 mg/kg, i.p.). In the striatum, glutamate and aspartate levels were not affected by either cocaine (15-30 mg/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). These findings demonstrate that stimulants enhance glutamate release in limbic brain structures, nucleus accumbens, and prefrontal cortex, but not extrapyamidal brain structures, striatum. Furthermore, the increase in glutamate release in the nucleus accumbens may be mediated by dopamine.