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Glutamate and GABA

  1. GLUTAMATE GABA Presentation: Dr. B Ooha Susmita Chairperson: Dr. Sarath
  2. • Glutamate or Glutamic acid is an amino acid neurotransmitter • Main role in the body- as a building block for other amino acids • As a neurotransmitter- excitatory function in up to 80% of brain synapses • Gamma-aminobutyric acid is a neurotransmitter found exclusively in the CNS • Principal inhibitory neurotransmitter in the brain GABA Glutamate
  3. Synthesis & Metabolism
  4. Vit B6 cofactor
  5. Receptors
  6. Glutamate GABA Metabotropic receptors • Group 1 • Group 2 • Group 3 GABA-a receptor complex Ionotropic receptors • AMPA • Kainate • NMDA GABA-b receptor GABA-c receptor complex
  7. Metabotropic receptors of Glutamate Group Group 1 mGluR1 mGluR5 • Postsynaptic • Facilitate and strengthen excitatory responses Group 2 mGluR2 mGluR3 • Presynaptic autoreceptors • Block glutamate release Group 3 mGluR4 mGluR6 mGluR7 mGluR8 • Presynaptic autoreceptors • Block glutamate release
  8. Ionotropic receptors of Glutamate Functional class Gene family Agonists Antagonists Action AMPA GluR1 GluR2 GluR3 GluR4 Glutamate AMPA Kainate • Postsynaptic • Fast, excitatory neurotransmission • Na+ channels Kainate GluR5 GluR6 GluR7 KA1 KA2 Glutamate Kainate • Postsynaptic • Fast, excitatory neurotransmission • Na+ channels NMDA NR1 NR2A NR2B NR2C NR2D Glutamate NMDA Aspartate MK801 PCP Ketamine • Postsynaptic • Excitatory neurotransmission • Ca2+ channels • Requires co-transmitter- Glycine/D-Serine • Blocked by Mg2+ in resting state • Involved in LTP and Synaptic plasticity
  9. NMDA Receptors • Blocked by Mg2+ in resting state • Requires “Coincidence detection” to open ligand-gated Ca2+ channels 1. Binding of Glutamate to its site 2. Binding of Glycine (co- transmitter) to its site 3. Depolarization of the postsynaptic neuron usually due to surrounding AMPA receptors • Transmission results in LTP and neuroplasticity functions
  10. Excitotoxicity • Excitotoxicity relates to the hypothesis that excessive stimulation of glutamate receptors leads to prolonged and excessive intraneuronal concentrations of calcium and NO. • Such conditions activate many enzymes (especially proteases) that are destructive to neuronal integrity.
  11. Alzheimer’s Disease • Glutamate hypothesis of cognitive deficiency in Alzheimer’s disease • Glutamate “leak” due to amyloid plaques and neurofibrillary tangles into the synaptic space • Overstimulate the NMDA receptors • Acute Chronic • Memory problems Free Radical accumulation Neuronal damage (Excitotoxicity)
  12. Memantine • Non-competitive, low affinity NMDA antagonist • Binds to Mg2+ binding site when the channel is open • Can be overcome by a burst of glutamate release seen during normal neurotransmission
  13. Glycine and Glutamate- relationship L-Serine Glycine (In glial cells) Glycine released from presynaptic glycine neuron reuptake Uptake into glial cell or presynaptic glutamate neuron Released into synapse to act as co-transmitter with Glutamate at NMDA receptor SHMT GlyT2 GlyT1 GlyT1
  14. Phobic disorder • The extinction of conditioned fear has been shown to be an active process mediated by the activation of NMDA receptors in the amygdala. • In a study, D-Cycloserine (partial agonist at Glycine binding site of NMDA receptor) plus CBT resulted in a highly significant reduction in acrophobic symptoms that persisted for at least 3 months as compared to placebo plus CBT. • Other placebo-controlled clinical trials support the notion that n- cycloserine is a robust enhancer of CBT, suggesting that pharmacologically augmenting neural plasticity may be used to bolster psychological interventions.
  15. Action of D-Serine as Co-transmitter • Only amino acid in D-form • L-Serine D-Serine (In glial cells) Transported into synapse to act as co-transmitter with glutamate at NMDA receptors Hydroxypyruvate (end product after termination of action of D-Serine) D-Serine Racemase D-SER-T DAO
  16. GABA Receptors GABA- a GABA- b GABA- c Postsynaptic Postsynaptic and presynaptic Postsynaptic Ligand-gated G-protein coupled Ligand-gated Part of a macromolecular complex Dimer of two seven- transmembrane spanning subunits Part of a macromolecular complex Cl- channel Ca2+ channel K+ channel Cl- channel • Site of action for BZDs, sedative-hypnotics, Barbiturates and alcohol • Tonic and phasic inhibitory neurotransmission at GABAergic synapses • Postsynaptic hyperpolarization • Presynaptic autoregulation • Involved in pain, mood, memory and other CNS functions Antagonized by • Bicuculline • Picrotoxin • Penicillin • Pentylenetetrazol • Insensitive to the antagonistic properties of Bicuculline • Sensitive to agonist action of Baclofen
  17. Autism • GABA receptors occur in a cluster on chromosome 15 (region 15q11-13) and some evidence suggests that genes here might act as modifiers or susceptibility factors for an autism spectrum phenotype. • Duplications of this region are the most common cytogenetic abnormalities seen in autism cases (up to 6 percent of cases). • This region is also the critical region for Angelman and Prader-Willi syndromes. • However, research is still going on to establish a clear correlation between GABA and autism spectrum disorders.
  18. GABA-a receptor Benzodiazepine-sensitive receptors Benzodiazepine- insensitive receptors
  19. Benzodiazepines and GABA receptors • They are positive allosteric modulators (PAMs) • Have no activity on their own when GABA is not simultaneously binding to its agonist sites • The combination of benzodiazepines at the allosteric site plus GABA at its agonist sites increases the frequency of opening of the chloride channel to an extent not possible with GABA alone
  20. Anxiety • GABA is strongly implicated due to the efficacy of BZDs in the treatment of anxiety disorders • While low potency BZDs can be used to treat GAD, high potency BZDs like clonazepam may be required in panic disorder • Inverse agonists at BZD site of GABA-a receptors like BCCE and antagonists like Flumazenil have been known to induce anxiety and panic attacks in patients
  21. Sleep • GABA systems involved in maintaining sleep-wake cycle • First line treatment for insomnia include BZD and non-BZD agents that bind to the BZD-binding site of GABA-a receptors and enhance GABAergic inhibitory activity
  22. Barbiturates • Barbiturates allosterically increase the affinities of the binding sites for GABA and benzodiazepines • Barbiturates also affect channel dynamics by markedly increasing the long open state and reducing the short open state, thereby increasing Cl- inhibition
  23. Other GABAergic drugs • Progabide- GABA receptor agonist with good brain penetration • Tiagabine- inhibits the GABA transporter (GAT) • Vigabatrin- inhibits GABA-T • Topiramate- potentiates GABA activity by acting on the Cl- channels (and also acts as a glutamate receptor antagonist); has shown efficacy as an anti-craving agent in cocaine and METH dependence • Gabapentin- a GABA derivative with good brain penetration; yet, curiously, it has no activity at GABA receptors or the GABA transporter. • All of them are favoured for their anticonvulsant property
  24. Alcohol Addiction • Alcohol interferes with the synaptic transmission of glutamate, GABA and opioid neuron at VTA. • The net result being release of dopamine at the NAc. • Alcohol enhances inhibition at GABA synapses by blocking presynaptic GABA- b receptors and stimulating postsynaptic GABA-a receptors • It reduces excitation at glutamate synapses by acting at presynaptic metabotropic glutamate receptors (mGluRs) and presynaptic voltage sensitive calcium channels (VSCCs) to inhibit glutamate release.
  25. Alcohol Withdrawal • Acute administration of alcohol antagonizes NMDA receptors whereas chronic administration increases these receptor sites • This finding reflects the fact that alcohol withdrawal symptoms and other neurotoxic effects of alcohol are mediated by glutamate. • Furthermore, alcohol withdrawal appears to be associated with increased glutamate concentrations and decreased dopamine levels in the NAc. • Findings concerning the efficacy of Acamprosate (which exerts effects on the NMDA receptor) in the treatment of alcohol dependence suggest that this neurotransmitter system may have a major role in the disorder.
  26. Acamprosate • Thus, withdrawal from chronic alcohol use is a state of glutamate overexcitement and even excitotoxicity as well as GABA deficiency. • Acamprosate is a derivative of the amino acid taurine and interacts with both the glutamate system,to inhibit it, and with the GABA system, to enhance it, a bit like a form of “artificial alcohol”. • Acamprosate appears to have direct blocking actions on certain glutamate receptors, particularly mGlu receptors (specifically mGluR5 and perhaps mGluR2). • Actions at NMDA receptors and at GABA systems may be secondary downstream effects from Acamprosate’s actions on mGlu receptors.
  27. Mood Disorders - GABA • Reductions of GABA have been observed in plasma, CSF, and brain GABA levels in depression. • Low activity in frontal cortex and hippocampus in an animal model of depression (which is reversed by antidepressant treatment) has been noted. • Animal studies have also found that chronic stress can reduce and eventually deplete GABA levels. • By contrast, GABA receptors are upregulated by antidepressants, and some GABAergic medications have weak antidepressant effects.
  28. • Animal models have demonstrated that blockade of glutamate activity also blocks the learned helplessness response, • Elevated levels of cortical glutamate were demonstrated using MRI spectroscopy of depressed individuals and direct chemical assay from the brains of suicide victims. • There is also evidence for the antidepressant effects of antiglutamate agents such as Ketamine, Riluzole and Lamotrigine (which has some antiglutamate action). Mood Disorders - Glutamate
  29. Treatment Resistant Depression • Antiglutamate drugs as augmenting agents for TRD with the rationale that treatment resistance in depressive disorders may arise from excess inhibitory function. • Mainly- Ketamine • A single intravenous infusion of ketamine results in remission of depression in up to 75% of TRD patients, although its effects wane rapidly, usually over the course of days. • Repeated ketamine infusions have been shown to maintain benefit for up to 2 weeks, and a few case reports have suggested even longer remissions with continuing repeated administrations. • Research is ongoing.
  30. Other Antiglutamate drugs • Lamotrigine- action on VSSC to inhibit glutamate release • Riluzole- binds to VSSCs and prevents glutamate release in an action similar to that postulated for lamotrigine. The idea is that diminishing glutamate release in ALS would prevent the postulated excitotoxicity that may be causing death of motor neurons in ALS.
  31. Pathways
  32. Glutamate is the primary neurotransmitter in: • Cerebellar granule cells, • Striatum • Cells of hippocampal molecular layer • Entorhinal cortex • Pyramidal cells of cortex • Thalamocortical and corticostriatal projections GABA is found in: • Midbrain • Diencephalon • Cerebral hemispheres • Pons • Medulla • Intrinsic neurons that function as local mediators for the inhibitory feedback loops • Coexists with biogenic amine neurotransmitters, glycine and peptide neurotransmitters
  33. a. Cortico-Brainstem b. Cortico-Striatal c. Hippocampal- Accumbens d. Thalamo-Cortical e. Cortico-Thalamic f. Cortico-Cortical (direct) g. Cortico-Cortical (indirect)
  34. Cortico-Brainstem pathway • Pyramidal neurons of cortex  Neurotransmitter centres of brainstem • Raphe nucleus- Serotonin • VTA- Dopamine • Locus coeruleus- Norepinephrine • Regulates neurotransmitter release • Direct innervation- stimulates release • Indirect innervation via GABAnergic neurons- inhibits release
  35. Schizophrenia • NMDA hypofunction hypothesis of schizophrenia • Postulated due to psychotomimetic effects observed with NMDA antagonists like PCP and Ketamine • Can explain positive symptoms and negative symptoms and the dopamine hypothesis as a result of downstream regulation • Involved pathway – cortico-brainstem glutamate pathway • Cause: Neurodevelopmental abnormalities of GABA interneurons which synapse with Glutamate in the prefrontal cortex
  36. • Defective synaptic transmission between glutamate and GABA neurons • Lack of adequate inhibition of glutaminergic transmission • Hyperactivity of glutamate pyramidal neurons • Dysfunction of downstream neuronal pathways via GABA interneurons Mesolimbic pathway Mesocortical pathway Positive symptoms Negative symptoms
  37. Cortico-Striatal pathway • Pyramidal neurons of cortex  Dorsal striatum • Pyramidal neurons of cortex  Nucleus accumbens (ventral striatum) (aka cortico-accumbens pathway) • Terminate on GABAnergic neurons destined for Globus Pallidus
  38. Hippocampal-Accumbens pathway • Hippocampus  Nucleus Accumbens  GABA neurons  Globus pallidus • Involved in development of new memories
  39. Thalamo-Cortical pathway & Cortico-Thalamic pathway • Involved in processing of sensory information • Complex of many pathways • Excitatory via direct synaptic input • Inhibitory via indirect (GABA interneurons) input Cortico-Cortical pathways
  40. References • Stahl’s essential psychopharmacology : neuroscientific basis and practical application / Stephen M. Stahl ; with illustrations by Nancy Muntner. – 4th ed. • Kaplan & Sadock's synopsis of psychiatry : behavioral sciences/clinical psychiatry.-Eleventh edition I Benjamin James Sadock, Virginia Alcott Sadock, Pedro Ruiz. • Psychiatry / edited by Allan Tasman, Jerald Kay, Jeffrey A. Lieberman, Michael B. First, Michelle B. Riba.–Fourth edition. • Thank You

Editor's Notes

  1. Excitatory amino acid transporter
  2. Vesicular inhibitory amino acid transporter Glutamic acid decarboxylase GABA transaminase
  3. Serine hydroxymethyl transferase
  4. D-amino acid oxidase
  5. Voltage sensitive sodium channels
  6. Found to contain a Ca2+ binding protein called PARVALBUMIN