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Amino Acid Neurotransmitters

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Amino Acid Neurotransmitters. Paul Glue. Objectives. Review: Relative abundance of AAs vs monoamines Pharmacology of glutamate, GABA Postulated role of glutamate, GABA dysfunction in neuropsych disorders. Relative abundance of neurotransmitters. Glutamate ~60% of synapses - PowerPoint PPT Presentation

Text of Amino Acid Neurotransmitters

  • Amino Acid NeurotransmittersPaul Glue

  • ObjectivesReview:Relative abundance of AAs vs monoaminesPharmacology of glutamate, GABAPostulated role of glutamate, GABA dysfunction in neuropsych disorders

  • Relative abundance of neurotransmittersGlutamate ~60% of synapsesGABA ~30% of synapsesMonoamines, peptides, other AAs (e.g. glycine)
  • Glutamate PharmacologyGlutamate is one of the most common transmitters in the CNSFast, excitatory transmitter; receptors on almost all neurons. Transmitter in ~60% of neurons, esp cortex, limbic structures.Glutamate binds to 4 classes of receptorthree "ionotropic" receptor classes - ligand-gated ion channels which are characterized by the different ligands that bind to them:AMPAkainic acid N-methyl-D-aspartate or NMDA one G-protein coupled or "metabotropic" receptor class.H2NCOOHCOOH

  • The Glutamate SynapseNote significant Glu uptake (mainly astrocytes)Interconversion of glutamate to glutamine

  • Glutamate FunctionUnder physiological conditions, activation of ionotropic receptors in neurons initiates transient depolarization and excitation. AMPA-Rs mediate the fast component of excitatory postsynaptic currentsNMDA-Rs underlie a slower component. AMPA-Rs modulate Ca++ influx thru NMDA-Rs. Depolarization of the postsynaptic neuronal membrane via AMPA-Rs relieves the Mg++ block of the NMDA-R ion channel (this occurs in NMDA-R under resting conditions). This allows controlled Ca++ influx through the NMDA-R. This voltage-dependent modulation of the NMDA-R results in activity-driven synaptic modulation.Glutamate overactivity can lead to neuronal death due to Ca++ toxicity, other associated mechanisms. H2NCOOHCOOH

  • NMDA-ReceptorsStructure - tetramers of two NR1 subunits and two NR2 subunits (some brain areas have NR3 subunits).

    Binding sites on the extracellular domain: NR1: co-agonist glycine; NR2: glutamate. For efficient ion channel opening, the NMDA receptor requires both glutamate and the co-agonist glycine. Binding sites in the ion channel: Mg2+; PCP/ketamine site

    NMDA antagonists: Synthetic antagonists include: MK-801 (dizocilpine) Phencyclidine Ketamine Dextromethorphan Memantine, Amantadine Procyclidine NMDA modulators: Mg2+ blocks the NMDA channel in a voltage-dependent manner. - Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. Ketamineand- Zn2+ blocks the NMDA current in a non-competitive and voltage-independent manner. - The activity of NMDA receptors is also sensitive to the changes in H+ concentration, and is partially inhibited by the ambient concentration of H+ under physiological conditions.

  • Metabotropic glutamate receptorsMetabotropic receptors are coupled to their associated ion channel through a second messenger pathway. May be located pre-, post- or extra-synapticallyGlutamate binding activates a G-protein and initiates an intracellular cascade There are 8 cloned mGluRs (mGluR1-mGluR8) classified into three groups (I, II, and III) based on structural homology, agonist selectivity, and associated second messenger cascade Group I mGluRs (mGluR1 and mGluR5) are coupled to the hydrolysis of fatty acids and the release of calcium from internal stores. Quisqualate and trans-ACPD are Group I agonists. Group II (mGluR2 and mGluR3) and Group III (mGluRs 4, 6, 7, and 8) receptors are considered inhibitory because they are coupled to the downregulation of cyclic nucleotide synthesisAppear to have neuroprotective effects in animal models

  • mGluR1mGluR2mGluR3mGluR5mGluR4mGluR subtype mRNA distribution in rat brain

  • Glutamate hypothesis of schizophrenia (1)Is DA antagonism alone enough for an effective antipsychotic agent?DA antagonism has limited effects on negative symptomsDA antagonists take several weeks to show clinical antipsychotic activity; other pharmacological effects (PRL, EPSE) much more rapid.NMDA receptor antagonists (ketamine, PCP) are psychotogenic in normal individuals and schizophrenic patients; positive in animal models indicative of psychotogenic potential.Potency of antagonism correlates with ability to produce behavioral/ psychotogenic effects

  • Glutamate hypothesis of schizophrenia (2)Glutamate may have a significant role in the control of dopamine transmission in the striatum. Dopamine transmission occurs in two different temporal modes, phasic and tonic.Phasic DA release is transient and rapidly terminated, and selectively affects only receptors within or near the synapse. Phasic transmission is primarily dopamine dependent.Tonic release of dopamine results in a constant level of dopamine in the extracellular, extrasynaptic space and is regulated mainly by glutamate.Not all GluRs are realistic targets Ionotropic GluRs mediate most fast synaptic transmission in the CNS - too ubiquitousExcess Glu is neurotoxic; NMDA antagonism is psychotogenic Metabotropic glutamate receptors may be better targetsThese modulate synaptic neurotransmissionmGluR2 and 3 are primarily distributed in forebrain regions. Stimulation of these mediates presynaptic depression and decreases evoked release of glutamate. PCP and other NMDA antagonists increase glutamate efflux; this may increase DA activity (amongst others)Reduction of presynaptic glutamatergic activity by targeting group II mGluRs may be a novel approach to treating schizophrenia

  • DopamineClinical Trial:LY2140023:(mGluR 2/3agonist inacute SCZ) (Nat Med 2007)LY=OLZ, >pbo for:PANSS, CGI

    LY=pbo, >OLZ for:Weight, PRL

  • Glutamate Antagonists in Major DepressionRationale: NMDA-antagonists are effective in animal models of depressionElevated glutamate levels in occipital cortex of depressed patientsChronic antidepressants may work indirectly on NMDA systems (altered subunit transcription, binding density)Inhibitors of glutamate release (lamotrigine, riluzole) have antidepressant properties

    Clinical studies using single dose ketamine infusions Placebo-controlled, crossover, double-blindMay work through effects on mTOR (promotes synapse development) (Science 2010)

  • Single Dose Ketamine Infusion Studies (1)Diazgranados; Arch Gen Psych 2010

    Treatment refractory bipolar depression, unmedicated

    Randomized, double blind, 2 period crossover

    Ketamine (0.5mg/kg) or placebo via 40 minute IV infusions

    Assessments to 14 days

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    040 80 110 230 24 48 72 168- - - - -mins- - - - - - - - - - - - - -hours- - - - - - (time)40 80 110 230 24 48 72 168- - - - -mins- - - - - - - - - - - - - -hours- - - - - - (time) Ketamine PlaceboPercent of responders (>50% HAMD) Percent in remission (HAMD

  • Glutamate and other disordersAll effective mood stabilizers influence glutamate signalling (generally )Li Glu transport; LTG Glu release, etcExcess Glu signalling in alcohol withdrawal, epilepsy, ? anxiety

  • GABAInhibitory amino acid neurotransmitter; both pre- and post-synaptic receptors2 receptors GABA-A ion channelGABA-B G-protein coupled receptor

    (heterodimer)Besides CNS, GABA also found in liver, GI tract, uterus, ovary, testis, lung, etc

  • BDZs bind to the GABA-A Receptor -Ligand-gated receptor complex-Made up of 5 helical columns surrounding a chloride channel-Separate binding sites for GABA, GABA agonists/ antagonists benzodiazepinesbarbituratesethanol neurosteroids (pregnanolone)convulsants (picrotoxin, PTZ) outside

    Cell membrane

    insidevideo

  • Benzodiazepine pharmacologyPartial Partial InverseInverseAgonistsAgonistsAntagonistsAgonistsAgonists

    AnxiolyticNeutral/AnxiogenicAnticonvulsantno effectConvulsantAmnesticPromnesticSedatingArousing

    DiazepamAbecarnilFlumazenilFG7142LorazepamBretazenilDMCMClonazepam(all BDZs and Z-drugs in clinical use)

  • Pharmacological theories of Anxiety (1) - GABA theoriesObservations: positive modulators of GABA-A receptor are anxiolytic (BDZs; barbiturates; ethanol)negative modulators are anxiogenic (FG7142; metrazol) in normalsflumazenil (BDZ antagonist) is anxiogenic in panic disorder but not in healthy controls; BDZs are less sedating/impairing in anxious patients than in controls

  • Pharmacological theories of Anxiety (1) - GABA theoriesObservations (contd): Altered GABA-A PET binding in panic disorder15-BDZ nave, drug free patients with panic disorder and 18 controlsStatistical parametric map illustrating an area where benzodiazepine receptor binding (11C-flumazenil) was decreased in subjects with panic disorder vs control subjects (R dorsal anterolateral prefrontal cortex). Arch Gen Psych 2008:1166

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