Browsing by Subject "GABA"

Now showing 1 - 10 of 22
  • Thumbnail Image
    Item
    Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus
    (Society for Neuroscience, 2006-09-06) Shekhar, Anantha; Johnson, Philip L.; Sajdyk, Tammy J.; Fitz, Stephanie D.; Keim, Stanley R.; Kelley, Pamela E.; Gehlert, Donald R.; DiMicco, Joseph A.; Psychiatry, School of Medicine
    Intravenous sodium lactate infusions or the noradrenergic agent yohimbine reliably induce panic attacks in humans with panic disorder but not in healthy controls. However, the exact mechanism of lactate eliciting a panic attack is still unknown. In rats with chronic disruption of GABA-mediated inhibition in the dorsomedial hypothalamus (DMH), achieved by chronic microinfusion of the glutamic acid decarboxylase inhibitor L-allylglycine, sodium lactate infusions or yohimbine elicits panic-like responses (i.e., anxiety, tachycardia, hypertension, and tachypnea). In the present study, previous injections of the angiotensin-II (A-II) type 1 receptor antagonist losartan and the nonspecific A-II receptor antagonist saralasin into the DMH of "panic-prone" rats blocked the anxiety-like and physiological components of lactate-induced panic-like responses. In addition, direct injections of A-II into the DMH of these panic-prone rats also elicited panic-like responses that were blocked by pretreatment with saralasin. Microinjections of saralasin into the DMH did not block the panic-like responses elicited by intravenous infusions of the noradrenergic agent yohimbine or by direct injections of NMDA into the DMH. The presence of the A-II type 1 receptors in the region of the DMH was demonstrated using immunohistochemistry. Thus, these results implicate A-II pathways and the A-II receptors in the hypothalamus as putative substrates for sodium lactate-induced panic-like responses in vulnerable subjects.
  • Thumbnail Image
    Item
    Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites
    (Elsevier, 2019-05) Mikkelsen, Mark; Rimbault, Daniel L.; Barker, Peter B.; Bhattacharyya, Pallab K.; Brix, Maiken K.; Buur, Pieter F.; Cecil, Kim M.; Chan, Kimberly L.; Chen, David Y.-T.; Craven, Alexander R.; Cuypers, Koen; Dacko, Michael; Duncan, Niall W.; Dydak, Ulrike; Edmondson, David A.; Ende, Gabriele; Ersland, Lars; Forbes, Megan A.; Gao, Fei; Greenhouse, Ian; Harris, Ashley D.; He, Naying; Heba, Stefanie; Hoggard, Nigel; Hsu, Tun-Wei; Jansen, Jacobus F. A.; Kangarlu, Alayar; Lange, Thomas; Lebel, R. Marc; Li, Yan; Lin, Chien-Yuan E.; Liou, Jy-Kang; Lirng, Jiing-Feng; Liu, Feng; Long, Joanna R.; Ma, Ruoyun; Maes, Celine; Moreno-Ortega, Marta; Murray, Scott O.; Noah, Sean; Noeske, Ralph; Noseworthy, Michael D.; Oeltzschner, Georg; Porges, Eric C.; Prisciandaro, James J.; Puts, Nicolaas A.; Roberts, Timothy P. L.; Sack, Markus; Sailasuta, Napapon; Saleh, Muhammad G.; Schallmo, Michael-Paul; Simard, Nicholas; Stoffers, Diederick; Swinnen, Stephan P.; Tegenthoff, Martin; Truong, Peter; Wang, Guangbin; Wilkinson, Iain D.; Wittsack, Hans-Jörg; Woods, Adam J.; Xu, Hongmin; Yan, Fuhua; Zhang, Chencheng; Zipunnikov, Vadim; Zöllner, Helge J.; Edden, Richard A. E.; Radiology and Imaging Sciences, School of Medicine
    Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.
  • Thumbnail Image
    Item
    The circumventricular organs form a potential neural pathway for lactate sensitivity: implications for panic disorder
    (Society for Neuroscience, 1997-12-15) Shekhar, Anantha; Keim, Stanley R.; Psychiatry, School of Medicine
    Patients with panic disorder experience panic attacks after intravenous sodium lactate infusions by an as yet unexplained mechanism. Lactate elicits a panic-like response in rats with chronic dysfunction of GABA neurotransmission in the dorsomedial hypothalamus (DMH). The circumventricular organs, organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), are potential sites that could detect increases in plasma lactate levels and activate the DMH. To test this, we obtained baseline heart rate (HR) and blood pressure (BP) responses to lactate infusions in rats fit with femoral arterial and venous catheters. Next, unilateral chronic injection cannulae connected to an Alzet infusion pump filled with the GABA synthesis inhibitor L-allylglycine (L-AG) were implanted into the DMH. Another chronic injection cannula was implanted into the region of the OVLT, SFO, or an adjacent control site, the median preoptic area (MePOA). These rats were tested once again with lactate infusions after injection of either artificial cerebrospinal fluid (ACSF) or tetrodotoxin (TTX) into the CVO sites. Injecting TTX into the OVLT completely blocked the lactate-induced response, whereas TTX injections into the SFO or MePOA did not. Also, direct injections of lactate (100 or 500 nl) into the OVLT elicited robust anxiety-like responses in these rats. These results suggest that the OVLT may be the primary site that detects lactate infusions, activating an anxiety-like response in a compromised DMH, and provide the first neuroanatomical basis for lactate response in panic disorder.
  • Thumbnail Image
    Item
    Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting
    (APS Journals, 2016-10-01) Morozova, Ekaterina O.; Myroshnychenko, Maxym; Zakharov, Denis; di Volo, Matteo; Gutkin, Boris; Lapish, Christopher C.; Kuznetsov, Alexey; Mathematical Sciences, School of Science
    Presented herein ventral tegmental area microcircuit model challenges the classical view that GABA neurons exclusively reduce dopamine neuron firing and bursting. Rather, high levels of synchrony amongst GABA neurons can produce increases in firing and bursting of the dopamine neuron. Dopamine bursting can be produced in the absence of bursty excitatory input, if the neuron receives transiently synchronized GABA input. We provide an explanation of the mechanisms whereby GABA neurons could contribute to dopamine neuron burst firing., In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca2+) concentration, thus reducing the Ca2+-dependent potassium (K+) current. In this way, the GABA-mediated hyperpolarization replaces Ca2+-dependent K+ current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally.
  • Thumbnail Image
    Item
    The effects of 3-mercaptopropionic acid on the cardiovascular system and the content of GABA in specific areas of the brain: further evidence for GABAergic involvement in central cardiovascular control
    (1984) Alsip, Nancy L.
    A role has been proposed for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in central cardiovascular control. This proposa 1 was based on the cardiovascular effects of agents which block or mimic the action of GABA on the post-synaptic membrane. This dissertation reported the cardiovascular effects of 3-mercaptopropionic acid (3-MP), an agent which inhibits GABA biosynthesis in the pre-synaptic nerve terminal in anesthetized guinea pigs. 3-MP interrupts GABAergic transmission by decreasing the amount of GABA in the brain. The effect of 3-MP on mean arterial pressure, heart rate and barorflex-induced bradycardia was determined as well as the mechanism(s) involved in observed changes. The content of GABA in four regions of the brain (hypothalamus, medulla, cerebellum and occipital cortex) was determined at the end of each experiment. In anesthetized guinea pigs, 3-MP (195 mg/kg, i.p.) elicited a biphasic response (Type I) in the majority of animals. This response consisted of sympathetically-mediated hypertension and tachycardia superseded by vagally-mediated bradycardia. The other response (Type II) consisted of only the sympathetically-mediated effects. The Type II response was associated with animals in which the vagus nerves were functionally impaired. In all brain regions measured, the GABA levels of both Types I and II were significantly lower than those of control animals. The sympathetically-mediated effects of 3-MP were reversed by chlordiazepoxide, a GABA-facilitory agent. Therefore, the 3-MP-induced cardiovascular effects appeared to reflect GABAergic activity in the bra in which resulted from a reduction of GABA content. The two phases of the Type I response may have resulted from a reduction of GABA content in specific brain regions. A reduction in hypothalamic GABA levels appeared to be related to the sympathetic activation and a reduction in medullary GABA levels appeared to be related to the vagal activation. In unparalyzed animals, 3-MP elicited convulsive movements as well as the described effects on the cardiovascular system. The centrally acting anticonvulsant phenytoin stopped 3-MP-induced motor manifestations of seizure activity without altering either blood pressure or heart rate. Therefore, the cardiovascular effects of 3-MP appeared to occur independent of the convulsive effect of this agent. These results support the hypothesis of GABAergic involvement in the central control of autonomic outflow to the cardiovascular system. The inability of phenytoin to reverse the cardiovascular effects of 3-MP suggests that these effects were independent of 3-MP-induced seizures.
  • Thumbnail Image
    Item
    GABA and Glutamate Levels in Occlusal Splint-Wearing Males with Possible Bruxism
    (Elsevier B.V., 2015-07) Dharmadhikari, Shalmali; Romito, Laura M.; Dzemidzic, Mario; Dydak, Ulrike; Xu, Jun; Bodkin, Cynthia L.; Manchanda, Shalini; Byrd, Kenneth E.; Department of Oral Biology, IU School of Dentistry
    Objective The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the pathophysiology of anxiety behavioural disorders such as panic disorder and post-traumatic stress disorder and is also implicated in the manifestation of tooth-grinding and clenching behaviours generally known as bruxism. In order to test whether the stress-related behaviours of tooth-grinding and clenching share similar underlying mechanisms involving GABA and other metabolites as do anxiety-related behavioural disorders, we performed a Magnetic Resonance Spectroscopy (MRS) study for accurate, in vivo metabolite quantification in anxiety-related brain regions. Design MRS was performed in the right hippocampus and right thalamus involved in the hypothalamic−pituitary−adrenal axis system, together with a motor planning region (dorsal anterior cingulate cortex/pre-supplementary motor area) and right dorsolateral prefrontal cortex (DLPFC). Eight occlusal splint-wearing men (OCS) with possible tooth-grinding and clenching behaviours and nine male controls (CON) with no such behaviour were studied. Results Repeated-measures ANOVA showed significant Group × Region interaction for GABA+ (p = 0.001) and glutamate (Glu) (p = 0.031). Between-group post hoc ANOVA showed significantly lower levels of GABA+ (p = 0.003) and higher levels of Glu (p = 0.002) in DLPFC of OCS subjects. These GABA+ and Glu group differences remained significant (GABA+, p = 0.049; Glu, p = 0.039) after the inclusion of anxiety as a covariate. Additionally, GABA and Glu levels in the DLPFC of all subjects were negatively related (Pearson's r = −0.75, p = 0.003). Conclusions These findings indicate that the oral behaviours of tooth-grinding and clenching, generally known as bruxism, may be associated with disturbances in brain GABAergic and glutamatergic systems.
  • Thumbnail Image
    Item
    The GABA(A) receptor alpha1 subtype in the ventral pallidum regulates alcohol-seeking behaviors
    (Society for Neuroscience, 2002-05-01) Harvey, Scott C.; Foster, Katrina L.; McKay, Pete F.; Carroll, Michelle R.; Seyoum, Regat; Woods, James E., II; Grey, Collette; Jones, Cecily M.; McCane, Shannan; Cummings, Rancia; Mason, Dynesha; Ma, Chunrong; Cook, James M.; June, Harry L.; Psychology, School of Science
    We investigated the potential role of the alpha1-containing GABA(A) receptor in regulating the reinforcing properties of alcohol. To accomplish this, we developed 3-propoxy-beta-carboline hydrochloride (3-PBC), a mixed agonist-antagonist benzodiazepine site ligand with binding selectivity at the alpha1 receptor. We then tested the capacity of 3-PBC to block alcohol-maintained responding in the ventral pallidum (VP), a novel alcohol reward substrate, which primarily expresses the alpha1-receptor isoform. Our results demonstrated that bilateral microinfusion of 3-PBC (0.5-40 microg) in the anterior and medial VP produced marked reductions in alcohol-maintained responding in a genetically selected rodent model of alcohol drinking. The VP infusions showed both neuroanatomical and reinforcer specificity because no effects were seen in sites dorsal to the VP (e.g., nucleus accumbens, caudate putamen). The saccharin-maintained responding was reduced only with the highest dose (40 microg). Parenteral injections of 3-PBC (1-20 mg/kg) also showed a similar selectivity on alcohol-maintained responding. Complementary in vitro studies revealed that 3-PBC exhibited a low partial agonist efficacy profile at recombinant diazepam-sensitive receptors (e.g., alpha1beta3gamma2, alpha2beta3gamma, and alpha3beta3gamma2). The selective suppression of 3-PBC on alcohol-maintained responding after central and parenteral administrations, together with its low-efficacy agonist profile, suggest that the reduction in alcohol-maintained behaviors was not attributable to a general suppression on consummatory behaviors. These results demonstrate that the alpha1-containing GABA(A) receptors in both the anterior and medial VP are important in regulating the reinforcing properties of alcohol. These receptors represent novel targets in the design and development of pharmacotherapies for alcohol-dependent subjects.
  • Thumbnail Image
    Item
    GABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry
    (Society for Neuroscience, 2001-03-15) June, Harry L.; Harvey, Scott C.; Foster, Katrina L.; McKay, Peter F.; Cummings, Rancia; Garcia, Marin; Mason, Dynesha; Grey, Collette; McCane, Shannan; Williams, La Shone; Johnson, Timothy B.; He, Xiaohui; Rock, Stephanie; Cook, James M.; Psychology, School of Science
    GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABA(A) receptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an alpha5 subunit-selective ( approximately 75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5-20 microgram) and unilateral (0.01-40 microgram) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 microgram). The competitive BDZ antagonist ZK 93426 (ZK) (7 microgram) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABA(A) receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of alpha1 and alpha2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all alpha receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the alpha5-containing GABA(A) receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors.
  • Thumbnail Image
    Item
  • Thumbnail Image
    Item
    Impairment of Motor Function Correlates with Neurometabolite and Brain Iron Alterations in Parkinson’s Disease
    (MDPI, 2019-01-29) Pesch, Beate; Casjens, Swaantje; Woitalla, Dirk; Dharmadhikari, Shalmali; Edmondson, David A.; Zella, Maria Angela Samis; Lehnert, Martin; Lotz, Anne; Herrmann, Lennard; Muhlack, Siegfried; Kraus, Peter; Yeh, Chien-Lin; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Gold, Ralf; van Thriel, Christoph; Brüning, Thomas; Tönges, Lars; Dydak, Ulrike; Department of Radiology and Imaging Sciences, Indiana University School of Medicine
    We took advantage of magnetic resonance imaging (MRI) and spectroscopy (MRS) as non-invasive methods to quantify brain iron and neurometabolites, which were analyzed along with other predictors of motor dysfunction in Parkinson's disease (PD). Tapping hits, tremor amplitude, and the scores derived from part III of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS3 scores) were determined in 35 male PD patients and 35 controls. The iron-sensitive MRI relaxation rate R2* was measured in the globus pallidus and substantia nigra. γ-aminobutyric acid (GABA)-edited and short echo-time MRS was used for the quantification of neurometabolites in the striatum and thalamus. Associations of R2*, neurometabolites, and other factors with motor function were estimated with Spearman correlations and mixed regression models to account for repeated measurements (hands, hemispheres). In PD patients, R2* and striatal GABA correlated with MDS-UPDRS3 scores if not adjusted for age. Patients with akinetic-rigid PD subtype (N = 19) presented with lower creatine and striatal glutamate and glutamine (Glx) but elevated thalamic GABA compared to controls or mixed PD subtype. In PD patients, Glx correlated with an impaired dexterity when adjusted for covariates. Elevated myo-inositol was associated with more tapping hits and lower MDS-UPDRS3 scores. Our neuroimaging study provides evidence that motor dysfunction in PD correlates with alterations in brain iron and neurometabolites.