Glutamate And Γ-aminobutyric Acid Levels Research Articles

Posterior cingulate and medial prefrontal excitation-inhibition balance in euthymic bipolar disorder.

Persistent cognitive deficits and functional impairments are associated with bipolar disorder (BD), even during the euthymic phase. The dysfunction of default mode network (DMN) is critical for self-referential and emotional mental processes and is implicated in BD. The current study aims to explore the balance of excitatory and inhibitory neurotransmitters, i.e. glutamate and γ-aminobutyric acid (GABA), in hubs of the DMN during the euthymic patients with BD (euBD). Thirty-four euBD and 55 healthy controls (HC) were recruited to the study. Using proton magnetic resonance spectroscopy (1H-MRS), glutamate (with PRESS sequence) and GABA levels (with MEGAPRESS sequence) were measured in the medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC) and the posterior cingulate gyrus (PCC). Measured concentrations of excitatory glutamate/glutamine (Glx) and inhibitory GABA were used to calculate the excitatory/inhibitory (E/I) ratio. Executive and attentional functions were respectively assessed using the Wisconsin card-sorting test and continuous performance test. euBD performed worse on attentional function than controls (p = 0.001). Compared to controls, euBD had higher E/I ratios in the PCC (p = 0.023), mainly driven by a higher Glx level in the PCC of euBD (p = 0.002). Only in the BD group, a marginally significant negative association between the mPFC E/I ratio (Glx/GABA) and executive function was observed (p = 0.068). Disturbed E/I balance, particularly elevated Glx/GABA ratio in PCC is observed in euBD. The E/I balance in hubs of DMN may serve as potential biomarkers for euBD, which may also contribute to their poorer executive function.

Parvalbumin in the metabolic pathway of glutamate and γ-aminobutyric acid: Influence on expression of GAD65 and GAD67

Parvalbumin-expressing neurons are a type of inhibitory intermediate neuron that play an important role in terminating seizures. The aim of the present study was to use lentiviral construction and packaging technology to overexpress and silence the parvalbumin gene in pheochromocytoma (PC12) cells, and to evaluate how parvalbumin influences the metabolic pathway involving glutamate and γ-aminobutyric acid (GABA). In this work, Immunofluorescence staining was used to verify the differentiation of PC12 cells into neurons after adding nerve growth factor (NGF). Western blotting and real-time quantitative polymerase chain reaction (qRT-PCR) were used to confirm lentivirus-mediated knockdown or overexpression of parvalbumin. Expression of parvalbumin, the 65-kDa GAD isoform (GAD65), and the 67-kDa GAD isoform (GAD67) in neuronal cells was examined at the mRNA and protein levels using qRT-PCR, western blotting and immunofluorescence staining, while intracellular glutamate and GABA levels were determined by high performance liquid chromatography (HPLC). We demonstrate that the expression of parvalbumin is associated with GAD65 and GAD67. Interestingly, overexpression of parvalbumin up-regulated GAD65 and GAD67, increased GABA concentration, and decreased glutamate concentration. Silencing of parvalbumin led to the opposite effects. Altogether, parvalbumin affected the expression of GAD65 and GAD67, thereby influencing the metabolic pathway involving glutamate and GABA.

Time of Day-Dependent Alterations in Hippocampal Kynurenic Acid, Glutamate, and GABA in Adult Rats Exposed to Elevated Kynurenic Acid During Neurodevelopment.

Hypofunction of glutamatergic signaling is causally linked to neurodevelopmental disorders, including psychotic disorders like schizophrenia and bipolar disorder. Kynurenic acid (KYNA) has been found to be elevated in postmortem brain tissue and cerebrospinal fluid of patients with psychotic illnesses and may be involved in the hypoglutamatergia and cognitive dysfunction experienced by these patients. As insults during the prenatal period are hypothesized to be linked to the pathophysiology of psychotic disorders, we presently utilized the embryonic kynurenine (EKyn) paradigm to induce a prenatal hit. Pregnant Wistar dams were fed chow laced with kynurenine to stimulate fetal brain KYNA elevation from embryonic day 15 to embryonic day 22. Control dams (ECon) were fed unlaced chow. Plasma and hippocampal tissue from young adult (postnatal day 56) ECon and EKyn male and female offspring were collected at the beginning of the light (Zeitgeber time, ZT 0) and dark (ZT 12) phases to assess kynurenine pathway metabolites. Hippocampal tissue was also collected at ZT 6 and ZT 18. In separate animals, in vivo microdialysis was conducted in the dorsal hippocampus to assess extracellular KYNA, glutamate, and γ-aminobutyric acid (GABA). Biochemical analyses revealed no changes in peripheral metabolites, yet hippocampal tissue KYNA levels were significantly impacted by EKyn treatment, and increased in male EKyn offspring at ZT 6. Interestingly, extracellular hippocampal KYNA levels were only elevated in male EKyn offspring during the light phase. Decreases in extracellular glutamate levels were found in the dorsal hippocampus of EKyn male and female offspring, while decreased GABA levels were present only in males during the dark phase. The current findings suggest that the EKyn paradigm may be a useful tool for investigation of sex- and time-dependent changes in hippocampal neuromodulation elicited by prenatal KYNA elevation, which may influence behavioral phenotypes and have translational relevance to psychotic disorders.

Effect of Jian-Pi-Zhi-Dong Decoction on the Amino Acid Neurotransmitters in a Rat Model of Tourette Syndrome and Comorbid Anxiety Disorder.

Amino acid neurotransmitters have been shown to correlate with Tourette syndrome (TS) and its comorbidities. In this study, we investigated the effects of Jian-Pi-Zhi-Dong Decoction (JPZDD), a formula containing 10 different Chinese medical herbs, on amino acid neurotransmitters in rats. We established a rat model of Tourette syndrome and comorbid anxiety with an iminodipropionitrile injection plus uncertain empty water bottle stimulation for 3 weeks. Then the rats were randomly divided into four groups: control group and model group were gavaged with saline, while the remaining two treatment groups were gavaged with fluoxetine hydrochloride or JPZDD for four consecutive weeks. We recorded the behaviors of the rats with TS and comorbid anxiety by stereotypy recording, open field test, and elevated plus maze. We observed mitochondrial changes with transmission electron microscopy. We measured the content of glutamate (GLU) and γ-aminobutyric acid (GABA) both in the serum and striatum and the expression of their receptors by Western blot and real-time polymerase chain reaction. The study revealed that JPZDD was effective in alleviating the behavioral symptoms of both tic and anxiety in the rat model groups. These results might be associated with the increase in GABA levels and decrease in GLU levels in the serum, as well as an increase in striatal GABA level by the activation of GABA receptors Type A (GABAAR). JPZDD treatment also reversed the mitochondrial dysfunction both in the striatum and cortex in affected animals.

Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis.

Poor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs). Thirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response. Before treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ. Glutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.

F14. REDUCED DURATION MISMATCH NEGATIVITY ASSOCIATED WITH DECREASED GLUTAMATE+GLUTAMINE LEVEL IN SUBJECTS AT CLINICAL HIGH-RISK FOR PSYCHOSIS

BackgroundAbnormal mismatch negativity (MMN), thought to be a putative marker of glutamatergic function, has been reported in non-Asian, first episode schizophrenia and clinical high-risk for psychosis (CHR) individuals as indicative of impairments in pre-attentive processes. However, reports of abnormal MMN in Asian populations are sparse, as well as its relationships to glutamate and γ–aminobutyric acid (GABA) levels in medial prefrontal cortex. The present longitudinal study explored MMN differences between CHR subjects who will and who will not remit, and its relationships with prefrontal glutamate and GABA levels.MethodsAll subjects participated in the ShangHai At-Risk for Psychosis (SHARP) program. CHR subjects met the criteria defined by the Chinese version of the Structural Interview for Prodromal Syndromes (SIPS). From the SHARP sample, 76 CHR subjects (41 male, age 18.63 ± 5.02 years) and 53 HC (31 male, age 17.72 ± 3.18 years) completed both MMN test and proton magnetic resonance spectroscopy (1H MRS) scans using a MEGA-PRESS sequence at their initial visit. CHR subjects were divided into remitted (37) and non-remitted (34) individuals based on their clinical symptoms and functional scores at a one-year follow up. Duration MMN amplitude was measured at electrodes F1/2, Fz, FC1/2, FCz, C1/2 and Cz. Concentrations of glutamate+glutamine (Glx) and GABA in the medial prefrontal cortex (mPFC) were quantified using the LCModel software (version 6.3-0I).Repeated measures analysis of variance (ANOVA) with group (remitted CHR, non-remitted CHR and HC) as the between-group factor and electrodes (Fz, FCz and Cz) as the within-group factor were performed for the midline sites, and the ANOVA using F1/2, FC1/2 and C1/C2 with laterality (left and right hemisphere) as an additional within-group factor was performed for the lateral sites. Correlations of the dMMN amplitude (averaged over the 9 electrodes) and Glx and GABA concentrations were assessed by Pearson correlation tests for each group.ResultsThere was a significant main effect of group (F(2,121)=3.14, p<0.05) for the midline fronto-central dMMN amplitude. Post-hoc tests showed that non-remitted CHR subjects had lower baseline dMMN amplitude (-4.75 ± 0.37μv) than HC (-5.92 ± 0.30μv, p<0.05), whereas dMMN in remitted CHR (-5.22 ± 0.36μv, p=0.41) was comparable to dMMN in HC.The main effect of group was marginally significant at lateral sites (F(2,121)=2.83, p=0.06). DMMN amplitude in non-remitted CHR (-4.67 ± 0.37μv) tended to be lower than those in HC (-5.76 ± 0.29μv, p<0.1), while remitted CHR had dMMN amplitude (-5.11 ± 0.35μv, p=0.47) comparable to HC. There was no significant main effect of laterality or interaction of group × laterality.In non-remitted CHR subjects, dMMN amplitude was significantly correlated with Glx level (r=-0.47, p<0.01) and with GABA level (r=-0.38, p<0.05) in the mPFC. However, the correlation of dMMN amplitude with Glx or GABA levels was not significant among either HC or remitted CHR.DiscussionIn line with previous studies, reduced dMMN amplitude distinguished between remitted and non-remitted CHR subjects, with remitted CHR not different from HCs. Our finding further supports the idea that reduced dMMN amplitude could be a candidate biomarker for predicting outcome in CHR. More importantly, we linked the reduced dMMN amplitude in non-remitted CHR to their Glx and GABA levels in mPFC, the region identified as one of dMMN sources (responsible for attention switching) thus supporting the idea that NMDA-mediated disruptions may play a key role in predicting psychosis and functional outcome.

Parachlorophenylalanine-induced 5-HT depletion alters behavioral and brain neurotransmitters levels in 6-Hz psychomotor seizure model in mice.

The present study was designed to investigate the role of serotonin and other neurotransmitters namely dopamine (DA), histamine, nor-epinephrine (NE), glutamate, and γ-aminobutyric acid (GABA) in the 6-Hz-induced psychomotor seizures in Swiss albino mice. Parachlorophenylalanine (PCPA, 300 mg/kg/day, i.p for 3 days)-treated mice were given 6-Hz stimulation. Sodium valproate (SVP) (200 mg/kg/day, p.o for 3 days) was used as a reference antiepileptic drug. The behavioral changes induced by 6 Hz including increased rearing and grooming, Straub's tail, behavioral arrest, stun position were amplified by PCPA. The 6-Hz-induced seizures were accompanied by reduced brain 5-HT, DA, NE, histamine, GABA, and enhanced glutamate levels. PCPA facilitated further reduction of endogenous 5-HT and DA levels but not NE, histamine, GABA, and glutamate levels. Pre- and post-treatment with SVP protected the mice from 6-Hz seizures and attenuated PCPA-induced changes in the levels of 5-HT and DA in the mice brain suggesting the protective effect of SVP in the pharmacoresistant model of epilepsy involving mainly serotonergic mechanism. However, the study also suggests modulation of other neurotransmitters both in 6-Hz psychomotor seizures and in the action of SVP against such seizures.

In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain

BackgroundPatients with chronic pain usually suffer from learning and memory impairment which may significantly decrease their quality of life. Despite laboratory and clinical studies, the mechanism underlying this memory impairment remains elusive. We evaluated the effect of chronic pain on the glutamate and GABA levels and BDNF expression in the CA1 region of hippocampus as a possible explanation for memory impairment related to neuropathic pain. MethodsIn this respect, 30 male rats were randomly allocated to 3 groups as control, sham and neuropathic. Neuropathic pain was induced by a chronic constriction injury of the sciatic nerve (CCI) and mechanical allodynia and the spatial memory was assessed using the Von Frey filaments and Morris water maze respectively. To determine the potential mechanisms, the in vivo extracellular levels of glutamate and γ-aminobutyric acid (GABA) were measured by microdialysis and the brain-derived neurotrophic factor (BDNF) expression was determined by using western blots technique in the hippocampus on days 14 and 21 post-CCI. ResultsWe showed that CCI impaired spatial learning and memory in Morris water maze (MWM) task. BDNF expression level and glutamate concentration significantly decreased in rats with chronic constriction injury of the sciatic nerve (P<0.001, F=7.3, F=23.23). In addition, GABA increased in hippocampal CA1 region (P<0.001, F=39.2) when the pain threshold was minimum. Nevertheless, these changes reversed while pain was relieved spontaneously. ConclusionChronic pain induced by constriction of the sciatic nerve impairs the spatial learning and memory function in rats. This effect exerts through the increase in GABA concentration and decrease in the glutamate and BDNF levels in the CA1 region of the hippocampus.

GABA and glutamate levels correlate with MTR and clinical disability: Insights from multiple sclerosis

Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key players in neuronal signalling and other central functions. Further research is needed, however, to identify microstructural and behavioral links to regional variability in levels of these neurometabolites, particularly in the presence of demyelinating disease. Thus, we sought to investigate the extent to which regional glutamate and GABA levels are related to a neuroimaging marker of microstructural damage and to motor and cognitive performance. Twenty-one healthy volunteers and 47 people with multiple sclerosis (all right-handed) participated in this study. Motor and cognitive abilities were assessed with standard tests used in the study of multiple sclerosis. Proton magnetic resonance spectroscopy data were acquired from sensorimotor and parietal regions of the brains’ left cerebral hemisphere using a MEGA-PRESS sequence. Our analysis protocol for the spectroscopy data was designed to account for confounding factors that could contaminate the measurement of neurometabolite levels due to disease, such as the macromolecule signal, partial volume effects, and relaxation effects. Glutamate levels in both regions of interest were lower in people with multiple sclerosis. In the sensorimotor (though not the parietal) region, GABA concentration was higher in the multiple sclerosis group compared to controls. Lower magnetization transfer ratio within grey and white matter regions from which spectroscopy data were acquired was linked to neurometabolite levels. When adjusting for age, normalized brain volume, MTR, total N-acetylaspartate level, and glutamate level, significant relationships were found between lower sensorimotor GABA level and worse performance on several tests, including one of upper limb motor function. This work highlights important methodological considerations relevant to analysis of spectroscopy data, particularly in the afflicted human brain. These findings support that regional neurotransmitter levels are linked to local microstructural integrity and specific behavioral abilities that can be affected in diseases such as multiple sclerosis.

Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: Microdialysis study of 79 patients at the yale epilepsy surgery program.

Aberrant glutamate and γ-aminobutyric acid (GABA) neurotransmission contribute to seizure generation and the epileptic state. However, whether levels of these neurochemicals are abnormal in epileptic patients is unknown. Here, we report on interictal levels of glutamate, glutamine, and GABA in epilepsy patients at seizure onset and nonepileptic sites, cortical lesions, and from patients with poorly localized neocortical epilepsies. Subjects (n = 79) were medically refractory epilepsy patients undergoing intracranial electroencephalogram evaluation. Microdialysis probes (n = 125) coupled to depth electrodes were implanted within suspected seizure onset sites and microdialysis samples were obtained during interictal periods. Glutamate, glutamine, and GABA were measured using high-performance liquid chromatography. Probe locations were subsequently classified by consensus of expert epileptologists. Glutamate levels were elevated in epileptogenic (p = 0.03; n = 7), nonlocalized (p < 0.001), and lesional cortical sites (p < 0.001) when compared to nonepileptogenic cortex. Glutamate was also elevated in epileptogenic (p < 0.001) compared to nonepileptogenic hippocampus. There were no statistical differences in GABA or glutamine, although GABA levels showed high variability across patients and groups. Our findings indicate that chronically elevated extracellular glutamate is a common pathological feature among epilepsies with different etiology. Contrary to our predictions, GABA and glutamine levels were not decreased in any of the measured areas. Whereas variability in GABA levels may in part be attributed to the use of GABAergic antiepileptic drugs, the stability in glutamine across patient groups indicate that extracellular glutamine levels are under tighter metabolic regulation than previously thought. Ann Neurol 2016;80:35-45.

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity.

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher-Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

Surface-Enhanced Raman Scattering Spectroscopy for the Detection of Glutamate and &lt;inline-formula&gt; &lt;tex-math notation="TeX"&gt;$\gamma$&lt;/tex-math&gt;&lt;/inline-formula&gt;-Aminobutyric Acid in Serum by Partial Least Squares Analysis

Glutamate (GLU) and γ-aminobutyric acid (GABA) are important amino acid neurotransmitters that, respectively, mediate rapid excitatory and inhibitory neurotransmission in the brain. Serum GLU and GABA levels could play a significant role in pathogenesis of the encephalopathic state, early detection of autism, and the neurobiology of depression. The optimal concentration ratio of GLU and GABA is vital for neuroendocrine control, and deviations in their synthesis are linked to epilepsy. Additionally, circulating GLU affects GABA levels in striatal extracellular fluid. The present work explores the feasibility of employing surface-enhanced Raman scattering spectroscopy, in conjunction with partial least squares (PLS) , for simultaneous measurement of physiological concentrations of GLU and GABA in their aqueous solution and blood serum. A PLS calibration model showed a high coefficient of determination (R <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> >0.98) between the spectral data of GLU and GABA and their respective concentrations. The low root mean square error of prediction (RMSEP) value was ~2.7 μM, and it established the accuracy of the calibration model. The present methodology enabled the detection of GLU and GABA as low as 8 μM. This provides a cost-effective alternative to existing techniques for quantification of neurotransmitters.

Environmental remodelling of GABAergic and glutamatergic neurotransmission: Rise of the anoxia-tolerant turtle brain

Climate cooling over the past one hundred thousand years has resulted in seasonal ice cover at northern and southern latitudes that has selected for hypoxia and anoxia tolerance in some species, such as freshwater turtles. At the northern reaches of their range, North American freshwater turtles spend 4 months or more buried in the mud bottom of ice covered lakes and ponds. From a comparative perspective this gives us the opportunity to understand how an extremely oxygen-sensitive organ, such as the vertebrate brain, can function without oxygen for long periods. Brain function is based on complex excitatory (on) and inhibitory (off) circuits involving the major neurotransmitters glutamate and, γ-aminobutyric acid (GABA) respectively. When a mammalian brain becomes anoxic, glutamate levels rise within minutes resulting in excitotoxic cell death which does not occur in anoxic turtle brain. The response in turtle brain has been remodelled – GABA levels rise rapidly resulting in large inhibitory GABA receptor currents and inhibition of glutamate receptor function that together depress neuronal activity.

Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis.

PurposeIn recent years in vivo microdialysis has become an important method in research studies investigating the alterations of neurotransmitters in the extracellular fluid of the brain. Based on the major involvement of glutamate and γ-aminobutyric acid (GABA) in mediating a variety of alcohol effects in the mammalian brain, numerous microdialysis studies have focused on the dynamical behavior of these systems in response to alcohol.MethodsHere we performed multiple meta-analyses on published datasets from the rat brain: (i) we studied basal extracellular concentrations of glutamate and GABA in brain regions that belong to a neurocircuitry involved in neuropsychiatric diseases, especially in alcoholism (Noori et al., Addict Biol 17:827-864, 2012); (ii) we examined the effect of acute ethanol administration on glutamate and GABA levels within this network and (iii) we studied alcohol withdrawal-induced alterations in glutamate and GABA levels within this neurocircuitry.ResultsFor extraction of basal concentrations of these neurotransmitters, datasets of 6932 rats were analyzed and the absolute basal glutamate and GABA levels were estimated for 18 different brain sites. In response to different doses of acute ethanol administration, datasets of 529 rats were analyzed and a non-linear dose response (glutamate and GABA release) relationship was observed in several brain sites. Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve. Finally, regression analysis of 11 published reports employing brain microdialysis experiments in 104 alcohol-dependent rats reveals very consistent augmented extracellular glutamate and GABA levels in various brain sites that correlate with the intensity of the withdrawal response were identified.ConclusionsIn summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release. Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data.

Accumbal and pallidal dopamine, glutamate and GABA overflow during cocaine self‐administration and its extinction in rats

We investigated the changes in dopamine (DA), glutamate and γ-aminobutyric acid (GABA) during cocaine self-administration in rats implanted with guide cannulae into the nucleus accumbens and ventral pallidum. After stabilized cocaine self-administration, separate groups of rats underwent extinction (10 days) procedure in which cocaine infusion was replaced by saline injections. With using a 'yoked' procedure, the effects of cocaine or its withdrawal on the level of neurotransmitters were evaluated by dual-probe microdialysis. Repeated cocaine administration reduced basal glutamate levels in the nucleus accumbens and ventral pallidum, whereas it did not affect basal accumbal DA levels. Only rats that self-administered cocaine had increased basal GABA overflow in both examined brain structures. Active or passive cocaine administration elevated extracellular accumbal DA, however, the extent of cocaine-evoked DA level was significantly higher in rats that self-administered cocaine while both groups of animals showed also an attenuation of GABA level in the nucleus accumbens. On day 10 of extinction training, rats previously given cocaine revealed decreases in the basal accumbal concentration of glutamate while the basal GABA levels were significantly enhanced as compared with baseline of saline-yoked controls. Potassium depolarization delayed the reduction of the accumbal and pallidal extracellular glutamate levels in the active and passive cocaine groups. The present data indicate that changes in DA and GABA neurotransmission during maintenance phase mirror the motivational aspects of cocaine intake. Depending on acute (24 hours) or late (10 days) cocaine withdrawal, different neurotransmitter systems (i.e. glutamate or GABA) seem to be involved.

Polysubstance and alcohol dependence: Unique abnormalities of magnetic resonance-derived brain metabolite levels

BackgroundAlthough comorbid substance misuse is common in alcohol dependence, and polysubstance abusers (PSU) represent the largest group of individuals seeking treatment for drug abuse today, we know little about potential brain abnormalities in this population. Brain magnetic resonance spectroscopy studies of mono-substance use disorders (e.g., alcohol or cocaine) reveal abnormal levels of cortical metabolites (reflecting neuronal integrity, cell membrane turnover/synthesis, cellular bioenergetics, gliosis) and altered concentrations of glutamate and γ-aminobutyric acid (GABA). The concurrent misuse of several substances may have unique and different effects on brain biology and function compared to any mono-substance misuse. MethodsHigh field brain magnetic resonance spectroscopy at 4T and neurocognitive testing were performed at one month of abstinence in 40 alcohol dependent individuals (ALC), 28 alcohol dependent PSU and 16 drug-free controls. Absolute metabolite concentrations were calculated in anterior cingulate (ACC), parieto-occipital (POC) and dorso-lateral prefrontal cortices (DLPFC). ResultsCompared to ALC, PSU demonstrated significant metabolic abnormalities in the DLPFC and strong trends to lower GABA in the ACC. Metabolite levels in ALC and light drinking controls were statistically equivalent. Within PSU, lower DLPFC GABA levels are related to greater cocaine consumption. Several cortical metabolite concentrations were associated with cognitive performance. ConclusionsWhile metabolite concentrations in ALC at one month of abstinence were largely normal, PSU showed persistent and functionally significant metabolic abnormalities, primarily in the DLPFC. Our results point to specific metabolic deficits as biomarkers in polysubstance misuse and as targets for pharmacological and behavioral PSU-specific treatment.

Transcranial Focused Ultrasound to the Thalamus Is Associated with Reduced Extracellular GABA Levels in Rats

Objective: Transcranial focused ultrasound (FUS), with its ability to non-invasively modulate the excitability of region-specific brain areas, is gaining attention as a potential neurotherapeutic modality. The aim of this study was to examine whether or not FUS administered to the brain could alter the extracellular levels of glutamate and γ-aminobutyric acid (GABA), which are representative excitatory and inhibitory amino acid neurotransmitters, respectively. Methods: FUS, delivered in the form of a train of pulses, was applied to the thalamus of Sprague-Dawley rats transcranially. Glutamate and GABA were directly sampled from the frontal lobe of the rat brain via a direct microdialysis technique before, during, and after the sonication. The dialysate concentrations were determined by high-performance liquid chromatography. Results: The individual levels of the neurotransmitters sampled were normalized to the baseline level for each rat. In terms of the changes in extracellular glutamate levels, there was no difference between the FUS-treated group and the unsonicated control group. However, extracellular GABA levels started to decrease upon sonication and remained reduced (approximately 20% below baseline; repeated-measures ANOVA, p < 0.05, adjusted for multiple comparisons) compared to the control group. Conclusion: The ability to modulate region-specific brain activity, along with the present evidence of the ability to modulate neurotransmission, demonstrates the potential utility of FUS as a completely new non-invasive therapeutic modality.

Genetic differences in the modulation of accumbal glutamate and γ-amino butyric acid levels after cocaine-induced reinstatement

The Lewis (LEW) and Fischer 344 (F344) inbred rat strains are frequently used to study the role of genetic factors in vulnerability to drug addiction and relapse. Glutamate and γ-amino butyric acid (GABA) transmission are significantly altered after cocaine-induced reinstatement, although whether LEW and F344 rats differ in their accumbal glutamate and GABA responsiveness to cocaine-induced reinstatement remains unknown. To investigate this, we measured by in vivo microdialysis extracellular glutamate and GABA levels in the core division of the nucleus accumbens after extinction of cocaine self-administration and during cocaine-induced reinstatement (7.5mg/kg, i.p.) in these two strains of rats. No strain differences were evident in cocaine self-administration or extinction behavior, although cocaine priming did induce a higher rate of lever pressing in LEW compared with F344 rats. After extinction, F344 rats that self-administered cocaine had less GABA than the saline controls, while the glutamate levels remained constant in both strains. There was more accumbal glutamate after cocaine priming in LEW rats that self-administered cocaine, while GABA levels were unaffected. By contrast, GABA increased transiently in F344 rats that self-administered cocaine, while glutamate levels were unaltered. In F344 saline controls, cocaine priming provoked contrasting effects in glutamate and GABA levels, inducing a delayed increase in glutamate and a delayed decrease in GABA levels. These amino acids were unaffected by cocaine priming in LEW saline rats. Together, these results suggest that genetic differences in cocaine-induced reinstatement reflect different responses of the accumbal GABA and glutamate systems to cocaine priming.

Effects of high frequency electrical stimulation and R-verapamil on seizure susceptibility and glutamate and GABA release in a model of phenytoin-resistant seizures

The present study was focused to characterize the effects of intrahippocampal application of R-verapamil, a P-glycoprotein blocker, and High Frequency Electrical Stimulation (HFS) at 130 Hz, on seizure susceptibility and extracellular concentrations of glutamate and γ-aminobutyric acid (GABA) in hippocampus of kindled rats with drug-resistant seizures. Fully kindled rats classified in responsive and non-responsive to phenytoin were used for this purpose. In contrast with responsive animals, non-responsive rats showed lower afterdischarge threshold (ADT) values in pre-kindling conditions and required less number of kindling trials to achieve the kindled state. Once the animals attained the kindled state, both epileptic groups presented high glutamate and low GABA interictal release, effect more evident in non-responsive rats. In hippocampus of responsive animals, GABA levels demonstrated two increases at 120 and 240 min after the ictal event, a situation no detected for non-responsive rats. Kindled animals receiving hippocampal HFS showed augmented ADT, an effect associated with enhanced GABA release in responsive rats. Intrahippocampal perfusion of R-verapamil (5 mM) decreased the seizure susceptibility (high ADT values), enhanced the interictal GABA release and the postictal levels of glutamate and GABA in responsive and non-responsive rats. It is conclude that alterations of glutamate and GABA release in the epileptic hippocampus of non-responsive animals resemble those found in hippocampus of patients with refractory TLE. In addition, intrahippocampal application of HFS and R-verapamil modifies the amino acid release and reduces the seizure susceptibility of both, responsive and non-responsive rats.

Neurochemical effects of benzodiazepine and morphine on freshwater mussels

The purpose of this study was to examine the neurochemical effects of morphine, diazepam, a common benzodiazepine, and an effluent concentrate on the endemic freshwater mussel Elliptio complanata. Mussels were exposed to the drugs and to the solid-phase concentrate of a municipal effluent and left to stand at 15°C for 48h. Neurochemical effects were determined by monitoring changes in dopamine, serotonin, glutamate and γ-aminobutyric acid (GABA) levels in the visceral mass (containing the nerve ganglia) of mussels. The activities of acetylcholinesterase (AChE), dopamine and serotonin-dependent adenylyl cyclase (ADC) were also determined in the mussels. Oxidative stress was determined by tracking changes in lipid peroxidation (LPO) in the mitochondrial and post-mitochondrial fractions. The results revealed that the drugs and the effluent extract were biologically active in mussels. Morphine reduced serotonin and increased dopamine in mussel tissues while reducing AChE activity and increasing GABA levels. This suggests the induction of a relaxation state in mussels. Diazepam also reduced serotonin levels but produced no change in dopamine levels. However, dopamine-sensitive ADC activity was readily activated, indicating the potential effect on opiate signaling. Diazepam increased glutamate levels slightly, but AChE remained stable. The increase in both dopamine ADC activity and glutamate concentrations was also associated with greater oxidative stress on the mitochondrial and post-mitochondrial fractions in cells. A comparison of the global response pattern of these drugs with those of the effluent extract revealed only a relative proximity to morphine. In conclusion, the data warrant more studies on the analysis of opiates and benzodiazepines in municipal effluents to better address the potential environmental hazard of these neuroactive drug classes to aquatic organisms.