Amino Acid Neurotransmitters GABA Research Articles

Biogenic Amines and the Amino Acids GABA and Glutamate: Relationships with Pain and Depression.

Although it is well known that there is a high degree of comorbidity between chronic pain and mood and anxiety disorders, the mechanisms involved in these co-occurrences are not clear. It appears that numerous neurotransmitters and neuromodulators are involved, and this chapter focuses on the monoamine neurotransmitters noradrenaline, 5-hydroxytryptamine (5-HT, serotonin), and dopamine and the amino acid neurotransmitters GABA (γ-aminobutyric acid) and glutamate in chronic pain and depression. Numerous preclinical and clinical neurochemical, neuroanatomical, pharmacological and molecular biological studies as well as clinical pharmacological treatment investigations implicate noradrenaline, 5-HT and, to a lesser extent, dopamine in the etiology of pain and depression. Similarly, preclinical and clinical studies on GABAergic and glutamatergic mechanisms as well as reports on the actions of neuroactive steroids suggest that GABA and glutamate play an important role in the etiology of pain and depression and may contribute to comorbidity.

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

The neurotransmitter transporters (NTTs) belonging to the solute carrier 6 (SLC6) gene family (also referred to as the neurotransmitter-sodium-symporter family or Na(+)/Cl(-)-dependent transporters) comprise a group of nine sodium- and chloride-dependent plasma membrane transporters for the monoamine neurotransmitters serotonin (5-hydroxytryptamine), dopamine, and norepinephrine, and the amino acid neurotransmitters GABA and glycine. The SLC6 NTTs are widely expressed in the mammalian brain and play an essential role in regulating neurotransmitter signaling and homeostasis by mediating uptake of released neurotransmitters from the extracellular space into neurons and glial cells. The transporters are targets for a wide range of therapeutic drugs used in treatment of psychiatric diseases, including major depression, anxiety disorders, attention deficit hyperactivity disorder and epilepsy. Furthermore, psychostimulants such as cocaine and amphetamines have the SLC6 NTTs as primary targets. Beginning with the determination of a high-resolution structure of a prokaryotic homolog of the mammalian SLC6 transporters in 2005, the understanding of the molecular structure, function, and pharmacology of these proteins has advanced rapidly. Furthermore, intensive efforts have been directed toward understanding the molecular and cellular mechanisms involved in regulation of the activity of this important class of transporters, leading to new methodological developments and important insights. This review provides an update of these advances and their implications for the current understanding of the SLC6 NTTs.

Glutamatergic and GABAergic innervation of GnRH neurons in the human hypothalamus

Event Abstract Back to Event Glutamatergic and GABAergic innervation of GnRH neurons in the human hypothalamus E. Hrabovszky1*, C. S. Molnár1, I. Kallo2, B. Borsay3, L. Sarkadi3, L. Herczeg3, M. Watanabe4 and Z. Liposits1, 2 1 Hungarian Academy of Sciences, Institute of Experimental Medicine, Hungary 2 Pázmány Péter Catholic University, Department of Neuroscience, Hungary 3 University of Debrecen, Department of Forensic Medicine, Hungary 4 Hokkaido University School of Medicine, Department of Anatomy, Japan Neurosecretory projections of gonadotropin-releasing hormone (GnRH) neurons to the hypophysial portal capillaries represent the final common output way of the hypothalamus in the neuroendocrine control of reproduction. GnRH neurons receive afferent input from a variety of neurotransmitter systems which are only partly characterized in the human. In the present study we used immunohistochemical approaches to address the contribution of the amino acid neurotransmitters GABA and glutamate to the afferent regulation of human GnRH neurons. According to previous findings in rodents where GABA represents the main neurotransmitter in the afferent control of GnRH neurons, we found that vesicular GABA transporter-immunoreactive GABAergic axons abundantly innervated the cell bodies and the dendrites of human GnRH neurons. While in rats, only glutamatergic axons of the VGLUT2 phenotype innervate GnRH neurons, in human samples we observed both VGLUT1- and VGLUT2 immunoreactive afferent contacts on GnRH neurons, with a preferential accumulation on GnRH dendrites. These morphological observations implicate the classic amino acid neurotransmitters GABA and glutamate in the afferent regulation of human GnRH neurons. As in rodents, GABA-ergic and glutamatergic afferents may have important contributions to metabolic-, sex steroid-, circadian- and stress signaling to the reproductive axis. Acknowledgements Supported by: OTKA K69127, T73002 and K83710; ETT 122/2009; FP7/2007-2013 (n° 245009) Keywords: Neuroendocrinology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neuroendocrinology Citation: Hrabovszky E, Molnár CS, Kallo I, Borsay B, Sarkadi L, Herczeg L, Watanabe M and Liposits Z (2011). Glutamatergic and GABAergic innervation of GnRH neurons in the human hypothalamus. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00141 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. E. Hrabovszky, Hungarian Academy of Sciences, Institute of Experimental Medicine, Budapest, Hungary, hrabovszky.erik@koki.mta.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers E. Hrabovszky C. S Molnár I. Kallo B. Borsay L. Sarkadi L. Herczeg M. Watanabe Z. Liposits Google E. Hrabovszky C. S Molnár I. Kallo B. Borsay L. Sarkadi L. Herczeg M. Watanabe Z. Liposits Google Scholar E. Hrabovszky C. S Molnár I. Kallo B. Borsay L. Sarkadi L. Herczeg M. Watanabe Z. Liposits PubMed E. Hrabovszky C. S Molnár I. Kallo B. Borsay L. Sarkadi L. Herczeg M. Watanabe Z. Liposits Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Early Evolution of Ionotropic GABA Receptors and Selective Regimes Acting on the Mammalian-Specific Theta and Epsilon Subunits

BackgroundThe amino acid neurotransmitter GABA is abundant in the central nervous system (CNS) of both invertebrates and vertebrates. Receptors of this neurotransmitter play a key role in important processes such as learning and memory. Yet, little is known about the mode and tempo of evolution of the receptors of this neurotransmitter. Here, we investigate the phylogenetic relationships of GABA receptor subunits across the chordates and detail their mode of evolution among mammals.Principal FindingsOur analyses support two major monophyletic clades: one clade containing GABAA receptor α, γ, and ε subunits, and another one containing GABAA receptor ρ, β, δ, θ, and π subunits. The presence of GABA receptor subunits from each of the major clades in the Ciona intestinalis genome suggests that these ancestral duplication events occurred before the divergence of urochordates. However, while gene divergence proceeded at similar rates on most receptor subunits, we show that the mammalian-specific subunits θ and ε experienced an episode of positive selection and of relaxed constraints, respectively, after the duplication event. Sites putatively under positive selection are placed on a three-dimensional model obtained by homology-modeling.ConclusionsOur results suggest an early divergence of the GABA receptor subunits, before the split from urochordates. We show that functional changes occurred in the lineages leading to the mammalian-specific subunit θ, and we identify the amino acid sites putatively responsible for the functional divergence. We discuss potential consequences for the evolution of mammals and of their CNS.

Estradiol-induced changes in the activity of hippocampal neurons in network culture are suppressed by co-incubation with gabapentin

The ovarian steroid hormone estradiol, in addition to its function in the maintenance and regulation of reproductive capacity, can alter neuronal excitability. Estradiol is proconvulsant, increases neuronal excitability and decreases the threshold for seizure activity. Over one-third to one-half of women with epilepsy experience catamenial seizures, which are seizures influenced by cyclical hormone changes. These hormone-sensitive seizures respond to the anti-epileptic drug gabapentin, which is a structural analogue of the inhibitory amino acid neurotransmitter GABA. We studied the effects of 17-β-estradiol alone and estradiol co-incubated with gabapentin on neuronal activity in network cultures of rat hippocampal neurons using a fluorescent calcium binding dye fluo-3 AM, FM 1-43 labeling of synaptic vesicles and electrophysiological recordings. Significant changes in the neuronal network activity were observed in the estradiol-treated neuronal cultures; the reactivity of the neurons to KCl depolarization induced intracellular calcium changes, and FM 1-43 destaining was increased as was the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSC). All these excitatory effects of estradiol were nullified by co-incubating the neurons with a combination of estradiol and gabapentin. This suggests that gabapentin can indeed affect the estradiol-induced changes in neuronal network hyperexcitability by influencing the neuronal calcium levels, exocytosis and synaptic activity. Our findings could provide an understanding of the cellular basis of hormone-sensitive seizure control by gabapentin.

The benzodiazepine site of the GABA A receptor: an old target with new potential?

The gamma-aminobutyric acid-A (GABA A) receptors is the target for the most widely prescribed sleep medicines. It is a ligand-gated ion channel, activated by the amino acid neurotransmitter GABA, which normally results in hyperpolarization of neurons leading to reduced action potential firing, and thereby a reduction in neuronal activity. It has a rich pharmacology with a number of separate modulator binding sites. The best studied of these is the benzodiazepine site. Modulation of GABA A receptor activity by benzodiazepines produces sedative, hypnotic, anxiolytic and anticonvulsant activities. Short half-life benzodiazepines such as triazolam have been particularly useful in treating insomnia, but concerns have been raised regarding tolerance potential and dependence liability of classical benzodiazepines, which has led to reduced prescribing of these agents. In recent years, the treatment of sleep disorders has moved towards the use of non-benzodiazepine sedative hypnotics. These agents act at the same site on the GABA A receptor, but feature less of the problems associated with classical benzodiazepines. Recent progress in our understanding of the diversity and pharmacology of GABA A receptor subtypes has provided a rational explanation for the efficacy of these compounds. Findings from preclinical studies reveal promising avenues for the design of better therapeutics in the near future.

Hypericum perforatum (St John's Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology

Hypericum possesses a unique pharmacology in that it displays the pharmacology of many classes of antidepressants and new mechanisms not typical of standard antidepressants. The most potent of all its action is the moderate to high potency for inhibition of the reuptake of monoamines, serotonin, dopamine and noradrenaline and the amino-acid neurotransmitters GABA and glutamate. Unlike standard reuptake inhibitors, hypericum exerts this reuptake inhibition non-competitively by enhancing intracellular Na+ ion concentrations. At a receptor level, chronic treatment with hypericum downregulates beta1-adrenoceptor, upregulates post-synaptic 5-HT1A receptors and 5-HT2 receptors. Although the major constituent responsible for the antidepressant effect is thought to be hyperforin, other constituents such as hypericin, pseudohypericin, flavonoids and oligomeric procyanidines may also play a direct or indirect role. While reuptake inhibition may more than likely be responsible for most of the antidepressant effect, other mechanisms may also contribute alone or in combination to exert the overall antidepressant action.

High-dose methamphetamine treatment alters presynaptic GABA and glutamate immunoreactivity

The goal of this study was to determine if high-dose methamphetamine treatment altered presynaptic immunoreactivity for the amino acid neurotransmitters GABA and glutamate within the basal ganglia. Methamphetamine (15 mg/kg every 6 h, four doses) treatment in rats resulted in severe hyperthermia and a long-lasting (four weeks) depletion of striatal dopamine content (>80%). Severe dopamine loss correlated with a decrease in the density of presynaptic immunolabeling for GABA one week post-drug, and an increase after four weeks. Although no changes were seen in presynaptic striatal glutamate immunoreactivity, there was a significant increase in the percentage of glutamate-immunopositive terminals associated with perforated postsynaptic densities. Rats given the same dose of methamphetamine but prevented from becoming hyperthermic showed less severe dopamine depletions and a lack of ultrastructural or immunocytochemical changes. In addition, induction of hyperthermia in the absence of drug decreased immunolabeling within mitochondria, but had no effect on dopamine content, morphology or nerve terminal immunoreactivity. Altered presynaptic GABA immunolabeling and terminal size were found in both the striatum and globus pallidus, suggesting that dynamic changes occur in the striatopallidal pathway following methamphetamine-induced dopamine loss. In addition, ultrastructural changes in glutamate-positive synapses which have been correlated with increased synaptic activity were found. These results are similar to changes in GABA and glutamate synapses that follow nigrostriatal dopamine loss in 6-hydroxydopamine-lesioned animals and in Parkinson's disease, and provide the first direct evidence that methamphetamine-induced dopamine loss alters the GABAergic striatopallidal pathway. Exposure to either methamphetamine or prolonged hyperpyrexia decreased mitochondrial immunoreactivity, indicating that hyperthermia may contribute to methamphetamine toxicity by affecting energy stores.

GABA augments basal and electrically stimulated 3H-norepinephrine release in hypothalamic, preoptic area and cortical slices of female rats

These studies examined the regulation by GABA of norepinephrine release from hypothalamus, preoptic area and frontal cortex. Using superfused brain slicesfrom female rats, we show that 100 μM GABA enhances both basal and electrically stimulated release of 3H-norepinephrine in all three brain regions. The GABA A agonist muscimol (100 μM) significantly augments 3H-norepinephrine release, but it is somewhat less effective than GABA. The GABA B agonist baclofen has little or no effect on basal 3H-norepinephrine efflux. GABA also augments both the magnitude and duration of electrically evoked 3H-norepinephrine release in slices from all three brain regions. GABA facilitation of electrically stimulated 3H-norepinephrine release is mediated through GABA A receptors as evidenced by its blockad by 10 μM bicuculline, a GABA A antagonist, but not by 200 μM 2-OH-saclofen, a GABA B antagonist. These data show that the inhibitory amino acid neurotransmitter GABA enhances both basal and evoked release of 3H-norepinephrine in brain slices from female rats. These effects are predominantly mediated by GABA A receptors. GABA modulation of hypothalamic norepinephrine release may play a role in the regulation of gonadotropin secretion and reproductive behaviors such as lordosis.

Chapter 22 Pre- and postnatal expression of amino acid neurotransmitters, calcium binding proteins, and nitric oxide synthase in the developing superior colliculus

Neurons within the superior colliculus (SC) contain a variety of neurochemicals, including the amino acid neurotransmitters GABA and glutamate, the calcium binding proteins calbindin and parvalbumin, and the neuromodulator nitric oxide. We have examined the development of expression of these substances using antibody immunocytochemistry. These results are summarized in Fig. 10. GABA and calbindin are expressed very early in development, at a time when cells are still dividing and migrating from the subventricular zone. The expression of both GABA and CB is maximal at around E40-46, the age at which these cells have just established their adult lamination and extrinsic afferents have begun to grow into the tectum. GABA and CB likely play diverse roles during this stage of development, including the regulation of intracellular calcium during cell migration and neurite outgrowth. Glutamate is expressed somewhat later in development while parvalbumin immunoreactivity does not appear until shortly after birth. These two substances continue to increase in density throughout the period of postnatal growth, at a time when synapse formation and evoked electrical activity are beginning to develop. Both PV and glutamate may be involved in one or both of these activity-dependent processes. Nitric oxide synthase (NOS) is expressed at different times in different cell groups. NOS appears very early in prenatal development in cells within the SVZ and in the deep gray layer of SC. On the other hands, cells within the intermediate gray layer of SC do not express NOS until shortly before birth. The igl cells that express NOS at this age are clustered neurons similar to those that project to the CFR in the adult. NOS expression occurs in these cells at precisely the time when axons begin to form patches that innervate these clusters. Based upon this temporal correlation, we hypothesize that nitric oxide may regulate synapse formation in this cell group.

Differential effects of vigabatrin, gamma-acetylenic GABA, aminooxyacetic acid, and valproate on levels of various amino acids in rat brain regions and plasma.

Drugs which elevate brain levels of the inhibitory amino acid neurotransmitter GABA by inhibiting the GABA catabolizing enzyme GABA transaminase (GABA-T) have been developed for treatment of brain disease, such as epilepsy. Among all GABA-T inhibitors available, vigabatrin is thought to be the most selective compound, and this drug is the only GABA-T inhibitor in clinical use. However, some previous studies have indicated that vigabatrin might affect the metabolism of several amino acids not directly linked to the GABA shunt. In the present study, various amino acids, involving inhibitory and excitatory neurotransmitters, were determined in 12 brain regions and plasma of rats after treatment with anticonvulsant doses of vigabatrin and the less selective GABA-T inhibitors aminooxyacetic acid (AOAA) and gamma-acetylenic GABA (GAG). Furthermore, the antiepileptic drug valproate, which is also thought to act via the GABA system, was included for comparison. The GABA-T inhibitors markedly enhanced GABA levels in all brain regions examined, while valproate induced only moderate increases in some regions. All drugs, including valproate, significantly decreased aspartate in the brain to a similar extent, and the GABA-T inhibitors but not valproate decreased levels of glutamate. The decreases in aspartate and glutamate levels were not correlated with the different magnitudes of GABA increase produced by GABA-T inhibitors, suggesting that these effects were not simply due to the altered GABA degradation. In addition to glutamate and aspartate, alanine levels were decreased by GABA-T inhibitors but not valproate in several regions. Brain levels of glutamine were decreased by GAG and vigabatrin but increased by valproate and partly also by AOAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Appearance of putative amino acid neurotransmitters during differentiation of neurons in embryonic turtle cerebral cortex

Pyramidal and nonpyramidal neurons can be recognized early in the development of the cerebral cortex in both reptiles and mammals, and the neurotransmitters likely utilized by these cells, glutamate and gamma-aminobutyric acid, or GABA, have been suggested to play critical developmental roles. Information concerning the timing and topography of neurotransmitter synthesis by specific classes of cortical neurons is important for understanding developmental roles of neurotransmitters and for identifying potential zones of neurotransmitter action in the developing brain. We therefore analyzed the appearance of GABA and glutamate in the cerebral cortex of embryonic turtles using polyclonal antisera raised against GABA and glutamate. Neuronal subtypes become immunoreactive for the putative amino acid neurotransmitters GABA and glutamate early in the embryonic development of turtle cerebral cortex, with nonpyramidal cells immunoreactive for GABA and pyramidal cells immunoreactive for glutamate. The results of controls strongly suggest that the immunocytochemical staining in tissue sections by the GABA and glutamate antisera corresponds to fixed endogenous GABA and glutamate. Horizontally oriented cells in the early marginal zone (stages 15-16) that are GABA-immunoreactive (GABA-IR) resemble nonpyramidal cells in morphology and distribution. GABA-IR neurons exhibit increasingly diverse morphologies and become distributed in all cortical layers as the cortex matures. Glutamate-immunoreactive (Glu-IR) cells dominate the cellular layer throughout development and are also common in the subcellular layer at early stages, a distribution like that of pyramidal neurons and distinct from that of GABA-IR nonpyramidal cells. The early organization of embryonic turtle cortex in reptiles resembles that of embryonic mammalian cortex, and the immunocytochemical results underline several shared as well as distinguishing features. Early GABA-IR nonpyramidal cells flank the developing cortical plate, composed primarily of pyramidal cells, shown here to be Glu-IR. The earliest GABA-IR cells in turtles likely correspond to Cajal-Retzius cells, a ubiquitous and precocious cell type in vertebrate cortex. Glutamate-IR projection neurons in vertebrates may also be related. The distinctly different topographies of GABA and glutamate containing cells in reptiles and mammals indicate that even if the basic amino acid transmitter-containing cell types are conserved in higher vertebrates, the local interactions mediated by these transmitters may differ. The potential role of GABA and glutamate in nonsynaptic interactions early in cortical development is reinforced by the precocious expression of these neurotransmitters in turtles, well before they are required for synaptic transmission.(ABSTRACT TRUNCATED AT 400 WORDS)

GABA: A dominant neurotransmitter in the hypothalamus

To study the organization and distribution of the inhibitory amino acid neurotransmitter GABA in the medial hypothalamus, we used a postembedding immunocytochemical approach with colloidal gold. Quantitative analysis showed that half (49%) of all synapsing boutons studied were immunoreactive for GABA, based on immunogold staining of the suprachiasmatic, arcuate, supraoptic, and paraventricular nuclei. This was corroborated with pre-embedding peroxidase immunostaining with antisera against glutamate decarboxylase, the GABA synthetic enzyme. These data suggest that GABA is the numerically dominant neurotransmitter in the hypothalamus, and emphasize the importance of inhibitory circuits in the hypothalamus. Serial ultrathin sections were used to reconstruct GABA immunoreactive boutons and axons in three dimensions. With this type of analysis we found less morphological heterogeneity between GABA immunoreactive boutons than with single ultrathin sections. Single sections sometimes showed boutons containing only small clear vesicles, and other with both clear vesicles and small dense core vesicles. However, with serial sections through individual boutons, dense core vesicles were consistently found at the periphery of the pre-synaptic GABA immunoreactive boutons, suggesting probable co-localization of GABA with unidentified peptides in most if not all boutons throughout the hypothalamus. A positive correlation was found between the density of small clear vesicles and the intensity of immunostaining with colloidal gold particles. GABA immunoreactive axons generally made symmetrical type synaptic specializations, although a small percentage made strongly asymmetrical synaptic specializations. Vesicles in GABA immunoreactive boutons were slightly smaller than those in non-reactive boutons. Synaptic efficacy is related to the position of the synapse on the post-synaptic neuron. While the majority of GABA immunoreactive axons made synaptic contact with dendrites, the distribution of GABA immunoreactive synapses on somata and dendrites was the same as would be expected from a random distribution of all boutons. No preferential innervation of cell bodies by GABA immunoreactive terminals was found. Serial ultrathin sections showed that a GABA immunoreactive axon would sometimes make repeated synaptic contacts with a single postsynaptic neuron, indicating a high degree of direct control by the presynaptic GABAergic cell. Other immunoreactive axons made synaptic contact with a number of adjacent dendrites and cells, suggesting a role for GABA in synchronizing the activity of hypothalamic neurons. Based on the density of immunogold particles per unit area, varying concentrations of immunoreactive GABA were found in different presynaptic boutons in the hypothalamus.

Biochemical and histological modifications of the rat retina induced by the cholinergic neurotoxin AF64A

Intraocular injections of ethylcholine mustard aziridinium ion (AF64A) in the rat depressed retinal choline actyltransferase (ChaT) activity in a dose-dependent manner without any significant change in the content of amino acid neurotransmitters GABA, glycine, aspartate and glutamate. ChAT reduction was already detected 24 h after the injection and persisted for at least one month. In vitro AF64A also inhibited retinal ChAT activity. No changes in muscarinic receptor sites were detected. The histological study showed light cells, characterized by cytoplasmic swelling in the innermost part of the inner nuclear layer and in the ganglion cell layer. We suggest that these light cells are the cholinergic retinal neurons affected by the toxin. In addition, dark cells in the inner nuclear layer, large empty spaces in the outer nuclear layer, inflammatory infiltrate and vascular alterations were also observed in treated retinas. Choline uptake systems in photoreceptors and in endothclial cells or cholinergic perivascular nerve endings may explain the lesions observed in the outer layer and the vascular alterations.

Locally applied progesterone metabolites alter neuronal responsiveness in the cerebellum

Ongoing studies in this laboratory have demonstrated that both systemically and locally administered sex steroids 17β estradiol (E 2) and progesterone (P) alter cerebellar Purkinje cell responses to microiontophoretically applied amino acid neurotransmitters GABA and glutamate (GLUT) in the urethane-anesthetized, ovariectomized adult rat. In the present study, we have examined the effects of several locally pressure ejected P metabolites on Purkinje cell responsiveness to GABA and GLUT: 5α-pregnane-20-one (5α DHP), 5α-pregnane-3α-ol-20-one (3α OH-DHP) and 5α-pregnane-3β-ol-20-one (3β OH-DHP). GABA-induced inhibition was markedly enhanced immediately after onset of local application of 3α OH-DHP or 5α DHP, unaccompanied by alterations in background discharge. Both metabolites also attenuated excitatory responses to GLUT by 0–3 min after initiation of steroid application. In both cases, recovery to control levels of response was observed 6–9 min after termination of pressure application. These results are similar to those seen after local or systemic injection of P. In contrast, 3β OH-DHP did not produce any alteration in Purkinje cell responses to either amino acid. As 5α DHP and 3α OH-DHP can be localized in cerebellar tissue after P administration, the results presented here suggest that the neuronal effects of systemic P may be mediated by local membrane actions of P or its metabolites.

Short-lived isotopes in central chemical control of ventilation.

Central chemical ventilatory drive is dependent on electrolyte and acid-base status of brain ECF, as well as the interaction between H+ metabolism and CO2 fixation and metabolism of amino acid neurotransmitters-GABA and glutamate. In the anesthetized dogs, using the short-lived positron emitting isotope of carbon (11C) either in the form of molecular CO2 or as HCO3- injected intraarterially it was demonstrated that there is first pass uptake of 16% of HCO3- from blood into brain and 86% uptake of molecular CO2, thus indicating that the brain-blood barrier is permeable to HCO3-, but that HCO3- content in the CNS is regulated as a function of dissociation of strong ions such as Cl- and Na+. Relationship between CO2 fixation and brain glutamine was studied with intraarterial injection of 13N-ammonia and its turnover into glutamine when PCO2 was increased. Ammonia turnover into glutamine was increased by a factor of 2 when PaCO2 was increased by 35 torr, and this rise in glutamine was linearly related to the rise in CSF [HCO3-]. Glutamine is then converted into the active neurotransmitters GABA and glutamate. Thus, the short-lived isotopes allow for assessment of the interaction of biochemical events in the CNS in the central respiratory drive.