Browsing by Subject "Glutamate"
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Item Aggression Results in the Phosphorylation of ERK1/2 in the Nucleus Accumbens and the Dephosphorylation of mTOR in the Medial Prefrontal Cortex in Female Syrian Hamsters(MDPI, 2023-01-10) Borland, Johnathan M.; Dempsey, Desarae A.; Peyla, Anna C.; Hall, Megan A. L.; Kohut-Jackson, Abigail L.; Mermelstein, Paul G.; Meisel, Robert L.; Neurology, School of MedicineLike many social behaviors, aggression can be rewarding, leading to behavioral plasticity. One outcome of reward-induced aggression is the long-term increase in the speed in which future aggression-based encounters is initiated. This form of aggression impacts dendritic structure and excitatory synaptic neurotransmission in the nucleus accumbens, a brain region well known to regulate motivated behaviors. Yet, little is known about the intracellular signaling mechanisms that drive these structural/functional changes and long-term changes in aggressive behavior. This study set out to further elucidate the intracellular signaling mechanisms regulating the plasticity in neurophysiology and behavior that underlie the rewarding consequences of aggressive interactions. Female Syrian hamsters experienced zero, two or five aggressive interactions and the phosphorylation of proteins in reward-associated regions was analyzed. We report that aggressive interactions result in a transient increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) in the nucleus accumbens. We also report that aggressive interactions result in a transient decrease in the phosphorylation of mammalian target of rapamycin (mTOR) in the medial prefrontal cortex, a major input structure to the nucleus accumbens. Thus, this study identifies ERK1/2 and mTOR as potential signaling pathways for regulating the long-term rewarding consequences of aggressive interactions. Furthermore, the recruitment profile of the ERK1/2 and the mTOR pathways are distinct in different brain regions.Item Alcohol drinking increases the dopamine-stimulating effects of ethanol and reduces D2 auto-receptor and group II metabotropic glutamate receptor function within the posterior ventral tegmental area of alcohol preferring (P) rats(Elsevier, 2016-10) Ding, Zheng-Ming; Ingraham, Cynthia M.; Rodd, Zachary A.; McBride, William J.; Psychiatry, School of MedicineRepeated local administration of ethanol (EtOH) sensitized the posterior ventral tegmental area (pVTA) to the local dopamine (DA)-stimulating effects of EtOH. Chronic alcohol drinking increased nucleus accumbens (NAC) DA transmission and pVTA glutamate transmission in alcohol-preferring (P) rats. The objectives of the present study were to determine the effects of chronic alcohol drinking by P rats on the (a) sensitivity and response of the pVTA DA neurons to the DA-stimulating actions of EtOH, and (b) negative feedback control of DA (via D2 auto-receptors) and glutamate (via group II mGlu auto-receptors) release in the pVTA. EtOH (50 or 150 mg%) or the D2/3 receptor antagonist sulpiride (100 or 200 μM) was microinjected into the pVTA while DA was sampled with microdialysis in the NAC shell (NACsh). The mGluR2/3 antagonist LY341495 (1 or 10 μM) was perfused through the pVTA via reverse microdialysis and local extracellular glutamate and DA levels were measured. EtOH produced a more robust increase of NACsh DA in the ‘EtOH’ than ‘Water’ groups (e.g., 150 mg% EtOH: to ~ 210 vs 150% of baseline). In contrast, sulpiride increased DA release in the NACsh more in the ‘Water’ than ‘EtOH’ groups (e.g., 200 μM sulpiride: to ~ 190–240 vs 150–160% of baseline). LY341495 (at 10 μM) increased extracellular glutamate and DA levels in the ‘Water’ (to ~ 150–180% and 180–230% of baseline, respectively) but not the ‘EtOH’ groups. These results indicate that alcohol drinking enhanced the DA-stimulating effects of EtOH, and attenuated the functional activities of D2 auto-receptors and group II mGluRs within the pVTA.Item Altered excitatory transmission in striatal neurons after chronic ethanol consumption in selectively bred crossed high alcohol-preferring mice(Elsevier, 2021) Rangel-Barajas, Claudia; Boehm, Stephen L., II.; Logrip, Marian L.; Psychology, School of ScienceGenetic predisposition to heavy drinking is a risk factor for alcohol misuse. We used selectively bred crossed high alcohol-preferring (cHAP) mice to study sex differences in alcohol drinking and its effect on glutamatergic activity in dorsolateral (DLS) and dorsomedial (DMS) striatum. We performed whole-cell patch-clamp recording in neurons from male and female cHAP mice with 5-week alcohol drinking history and alcohol-naïve controls. In DMS, alcohol-naïve males' neurons displayed lower cell capacitance and higher membrane resistance than females' neurons, both effects reversed by drinking. Conversely, in DLS neurons, drinking history increased capacitance only in males and changed membrane resistance only in females. Altered biophysical membrane properties were accompanied by disrupted glutamatergic transmission. Drinking history increased spontaneous excitatory postsynaptic current (sEPSC) amplitude in DMS and frequency in DLS female neurons, compared to alcohol-naïve females, without effect in males. Acute ethanol differentially impacted DMS and DLS neurons by sex and drinking history. In DMS, acute alcohol significantly increased sEPSC frequency only in neurons from alcohol-naïve females, an effect that disappeared after drinking history. In DLS, acute alcohol had opposing effects in males and females based on drinking history. Estrous cycle also impacted DMS and DLS neurons differently: sEPSC amplitudes were higher in DMS cells from drinking history than alcohol-naïve females, whereas estrous cycle, not drinking history, modified DLS firing rate. Our data show sex differences in cHAP ethanol consumption and neurophysiology, suggesting differential dysregulation of glutamatergic drive onto DMS and DLS after chronic ethanol consumption.Item Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites - Neuroimaging results from the WELDOX II study(Elsevier, 2018-01) Casjens, Swaantje; Dydak, Urike; Dharmadhikari, Shalmali; Lotz, Anne; Lehnert, Martin; Quetscher, Clara; Stewig, Christoph; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Edmondson, David; Yeh, Chien-Lin; Weiss, Tobias; van Thriel, Christoph; Herrmann, Lennard; Muhlack, Siegfried; Woitalla, Dirk; Aschner, Michael; Brüning, Thomas; Pesch, Beate; Radiology and Imaging Sciences, School of MedicineOBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. MATERIAL AND METHODS: GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson's disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). RESULTS: The median shift exposure to respirable Mn and Fe in active welders was 23μg/m3 and 110μg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(β)=0.87, p<0.01) and choline (exp(β)=0.84, p=0.04). R2* was positively associated with glutamate-glutamine and negatively with myo-inositol. CONCLUSIONS: Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations.Item Associations between sensory processing and electrophysiological and neurochemical measures in children with ASD: an EEG-MRS study(BMC, 2021-01-06) Pierce, Sarah; Kadlaskar, Girija; Edmondson, David A.; McNally Keehn, Rebecca; Dydak, Ulrike; Keehn, Brandon; Pediatrics, School of MedicineBackground: Autism spectrum disorder (ASD) is associated with hyper- and/or hypo-sensitivity to sensory input. Spontaneous alpha power, which plays an important role in shaping responsivity to sensory information, is reduced across the lifespan in individuals with ASD. Furthermore, an excitatory/inhibitory imbalance has also been linked to sensory dysfunction in ASD and has been hypothesized to underlie atypical patterns of spontaneous brain activity. The present study examined whether resting-state alpha power differed in children with ASD as compared to TD children, and investigated the relationships between alpha levels, concentrations of excitatory and inhibitory neurotransmitters, and atypical sensory processing in ASD. Methods: Participants included thirty-one children and adolescents with ASD and thirty-one age- and IQ-matched typically developing (TD) participants. Resting-state electroencephalography (EEG) was used to obtain measures of alpha power. A subset of participants (ASD = 16; TD = 16) also completed a magnetic resonance spectroscopy (MRS) protocol in order to measure concentrations of excitatory (glutamate + glutamine; Glx) and inhibitory (GABA) neurotransmitters. Results: Children with ASD evidenced significantly decreased resting alpha power compared to their TD peers. MRS estimates of GABA and Glx did not differ between groups with the exception of Glx in the temporal-parietal junction. Inter-individual differences in alpha power within the ASD group were not associated with region-specific concentrations of GABA or Glx, nor were they associated with sensory processing differences. However, atypically decreased Glx was associated with increased sensory impairment in children with ASD. Conclusions: Although we replicated prior reports of decreased alpha power in ASD, atypically reduced alpha was not related to neurochemical differences or sensory symptoms in ASD. Instead, reduced Glx in the temporal-parietal cortex was associated with greater hyper-sensitivity in ASD. Together, these findings may provide insight into the neural underpinnings of sensory processing differences present in ASD.Item Collapsin response mediator protein 2 (CRMP2) interacts with N-methyl-D-aspartate (NMDA) receptor and Na+/Ca2+ exchanger and regulates their functional activity(ASBMB, 2014-03-14) Brustovetsky, Tatiana; Pellman, Jessica J.; Yang, Xiao-Fang; Khanna, Rajesh; Brustovetsky, Nickolay; Department of Pharmacology and Toxicology, IU School of MedicineCollapsin response mediator protein 2 (CRMP2) is traditionally viewed as an axonal growth protein involved in axon/dendrite specification. Here, we describe novel functions of CRMP2. A 15-amino acid peptide from CRMP2, fused to the TAT cell-penetrating motif of the HIV-1 protein, TAT-CBD3, but not CBD3 without TAT, attenuated N-methyl-d-aspartate receptor (NMDAR) activity and protected neurons against glutamate-induced Ca(2+) dysregulation, suggesting the key contribution of CRMP2 in these processes. In addition, TAT-CBD3, but not CBD3 without TAT or TAT-scramble peptide, inhibited increases in cytosolic Ca(2+) mediated by the plasmalemmal Na(+)/Ca(2+) exchanger (NCX) operating in the reverse mode. Co-immunoprecipitation experiments revealed an interaction between CRMP2 and NMDAR as well as NCX3 but not NCX1. TAT-CBD3 disrupted CRMP2-NMDAR interaction without change in NMDAR localization. In contrast, TAT-CBD3 augmented the CRMP2-NCX3 co-immunoprecipitation, indicating increased interaction or stabilization of a complex between these proteins. Immunostaining with an anti-NCX3 antibody revealed that TAT-CBD3 induced NCX3 internalization, suggesting that both reverse and forward modes of NCX might be affected. Indeed, the forward mode of NCX, evaluated in experiments with ionomycin-induced Ca(2+) influx into neurons, was strongly suppressed by TAT-CBD3. Knockdown of CRMP2 with short interfering RNA (siRNA) prevented NCX3 internalization in response to TAT-CBD3 exposure. Moreover, CRMP2 down-regulation strongly attenuated TAT-CBD3-induced inhibition of reverse NCX. Overall, our results demonstrate that CRMP2 interacts with NCX and NMDAR and that TAT-CBD3 protects against glutamate-induced Ca(2+) dysregulation most likely via suppression of both NMDAR and NCX activities. Our results further clarify the mechanism of action of TAT-CBD3 and identify a novel regulatory checkpoint for NMDAR and NCX function based on CRMP2 interaction with these proteins.Item Deep Network Pharmacology: Targeting Glutamate Systems as Integrative Treatments for Jump-Starting Neural Networks and Recovery Trajectories(Hapres, 2021) Chambers, R. Andrew; Toombs, Christopher; Psychiatry, School of MedicineSignificant advances in pharmacological treatments for mental illness and addiction will require abandoning old monoaminergic theories of psychiatric disorders and traditionally narrow approaches to how we conduct treatment research. Reframing our efforts with a view on integrative treatments that target core neural network function and plasticity may provide new approaches for lifting patients out of chronic psychiatric symptom sets and addiction. For example, we discuss new treatments that target brain glutamate systems at key transition points within longitudinal courses of care that integrate several treatment modalities. A reconsideration of what our novel and already available medications are intended to achieve and how and when we deliver them for patients with complex illness trajectories could be the key to unlocking new advances in general and addiction psychiatry.Item Effects of chronic ethanol consumption on the expression of GLT-1 and neuroplasticity-related proteins in the nucleus accumbens of alcohol-preferring rats(Elsevier, 2020-12) Alhaddad, Hasan; Alasmari, Fawaz; Alhamadani, Balsam; Wong, Woonyen; Bell, Richard L.; Sari, Youssef; Psychiatry, School of MedicineChronic ethanol exposure induces impairments in CNS excitatory and inhibitory activity. These impairments are associated with glutamatergic dysfunction, including altered neuroplasticity. This study examined the effects of 6-week ethanol (15% and 30% v/v) consumption, by male alcohol-preferring P rats, on protein expression associated with neuroplasticity and glutamate transporter-1 (GLT-1) function. The latter regulates intra- and extra-synaptic glutamate levels. We focused on the shell and core subregions of the nucleus accumbens (Acb); i.e., shell (AcbSh) and core (AcbCo), for these measures. Chronic ethanol exposure increased the expression of BDNF, Arc and phosphorylated (p)-post-synaptic density protein-95 (p-PSD-95) in the AcbSh of P rats. Moreover, the ratio of phospho-neuronal nitric oxide synthase (p-nNOS) to total nNOS was also increased in the AcbSh. These changes in BDNF, Arc and p-nNOS/nNOS ratio were not observed in the AcbCo. Furthermore, chronic ethanol consumption reduced GLT-1 expression in the AcbSh. Alternatively, treatment with ceftriaxone (CEF), a known GLT-1 upregulator, abolished the effect of chronic ethanol consumption on BDNF expression in the AcbSh. Overall, the present findings confirm that chronic ethanol consumption modulates activity-associated synaptic proteins, including BDNF, Arc and nNOS in a subregion-specific (i.e., in the AcbSh but not AcbCo) manner. Thus, alterations in mesocorticolimbic glutamatergic homeostasis and neuroplasticity are possible functional targets for the treatment of alcohol use disorders.Item Glutamate homeostasis and dopamine signaling: Implications for psychostimulant addiction behavior(Elsevier, 2021) Fischer, Kathryn D.; Knackstedt, Lori A.; Rosenberg, Paul A.; Pharmacology and Toxicology, School of MedicineCocaine, amphetamine, and methamphetamine abuse disorders are serious worldwide health problems. To date, there are no FDA-approved medications for the treatment of these disorders. Elucidation of the biochemical underpinnings contributing to psychostimulant addiction is critical for the development of effective therapies. Excitatory signaling and glutamate homeostasis are well known pathophysiological substrates underlying addiction-related behaviors spanning multiple types of psychostimulants. To alleviate relapse behavior to psychostimulants, considerable interest has focused on GLT-1, the major glutamate transporter in the brain. While many brain regions are implicated in addiction behavior, this review focuses on two regions well known for their role in mediating the effects of cocaine and amphetamines, namely the nucleus accumbens (NAc) and the ventral tegmental area (VTA). In addition, because many investigators have utilized Cre-driver lines to selectively control gene expression in defined cell populations relevant for psychostimulant addiction, we discuss potential off-target effects of Cre-recombinase that should be considered in the design and interpretation of such experiments.Item An Investigation of Neurochemical Changes in Chronic Cannabis Users(Frontiers Media, 2019-09-19) Newman, Sharlene D.; Cheng, Hu; Martin, Ashley Schnakenberg; Dydak, Ulrike; Dharmadhikari, Shalmali; Hetrick, William; O’Donnell, Brian; Radiology and Imaging Sciences, School of MedicineWith the legalization of recreational cannabis (CB) the characterization of how it may impact brain chemistry is essential. Magnetic resonance spectroscopy (MRS) was used to examine neurometabolite concentrations in the dorsal anterior cingulate (dACC) in chronic CB users (N = 26; 10 females) and controls (N = 24; 10 females). The concentrations of glutamate (Glu), total creatine (tCr), choline (Cho), total N-acetylaspartate (tNAA), and myo-inositol (mI) were estimated using LCModel. The ANCOVAs failed to show significant differences between controls and CB users. Regression analyses were then performed on the CB group to model each neurometabolite to determine its relationship to monthly CB use, sex, the interaction between CB use and sex. tCr was found to be predicted by both monthly CB use and sex. While the regression model was not significant the relationship between monthly CB use and Glu appears to be modulated by sex with the effect of monthly use (dose) being stronger in males. tNAA failed to show an effect of CB use but did reveal an effect of sex with females showing larger tNAA levels. Although the results presented are preliminary due to the small sample size they do guide future research. The results presented provide direction for further studies as they suggest that dose may significantly influence the observance of CB effects and that those effects may be modulated by sex. Studies with significantly larger sample sizes designed specifically to examine individuals with varying usage as well as sex effects are necessary.