David Lodge | |
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 Lodge in 2016 | |
| Alma mater | University of Bristol (PhD, DSc) |
| Scientific career | |
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| Thesis | [ ProQuest 301323670 Neuropharmacological and physiological studies on central neurones in the rat] (1974) |
| Doctoral advisor | Tim Biscoe |
| Other academic advisors | David Curtis |
| Website | www |
David Lodge FRS FMedSci [1] is a research fellow in the Department of Physiology and Pharmacology at the University of Bristol. [2] [3]
Lodge was awarded a Bachelor of Veterinary Science degree in 1963[ where? ] and worked in University of Bristol as a surgeon and anaesthetist, before doing postgraduate research with Tim J. Biscoe [4] on the neuropharmacology of amino acids, he was awarded his PhD in 1974. [1] [5]
During postdoctoral studies at the Australian National University with David Curtis, he helped establish the role of glutamate as a central neurotransmitter and characterised its actions between AMPA, N-Methyl-D-aspartic acid (NMDA) and kainate receptor subtypes. At the Royal Veterinary College, Lodge linked his interests in anaesthesia and glutamate receptors by making the key discovery that the dissociative anaesthetics, ketamine and phencyclidine, [6] selectively blocked NMDA receptors. He related NMDA receptor antagonism to psychotomimetic effects. This provided a basis for the glutamate hypothesis of schizophrenia and redirected pharmaceutical search for schizophrenia therapies. David was recruited as a director of Eli Lilly's neuroscience program, where he helped develop glutamate receptor approaches to brain diseases, resulting in clinical trials, e.g. for schizophrenia, some of which are ongoing. As of 2016 [update] , Lodge's research concerns the mechanism of action of new ‘legal highs’ and the consequences of spontaneous mutations in glutamate receptors. [1]
Lodge was elected a Fellow of the Royal Society (FRS) in 2016 [1] and a Fellow of the Academy of Medical Sciences.[ when? ] He was awarded a Doctor of Science degree from the University of Bristol in 2002. [7]
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and pain management. It is a novel compound that was derived from phencyclidine in 1962 in pursuit of a safer anesthetic with fewer hallucinogenic effects.
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptions of sounds, and violent behavior. As a recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected. It may also be mixed with cannabis or tobacco.
N-methyl-D-aspartic acid or N-methyl-D-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors. NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.
The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
Dizocilpine (INN), also known as MK-801, is a pore blocker of the NMDA receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is normally blocked with a magnesium ion and requires depolarization of the neuron to remove the magnesium and allow the glutamate to open the channel, causing an influx of calcium, which then leads to subsequent depolarization. Dizocilpine binds inside the ion channel of the receptor at several of PCP's binding sites thus preventing the flow of ions, including calcium (Ca2+), through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it. The drug acts as a potent anti-convulsant and probably has dissociative anesthetic properties, but it is not used clinically for this purpose because of the discovery of brain lesions, called Olney's lesions (see below), in laboratory rats. Dizocilpine is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It inhibits the induction of long term potentiation and has been found to impair the acquisition of difficult, but not easy, learning tasks in rats and primates. Because of these effects of dizocilpine, the NMDA receptor pore blocker ketamine is used instead as a dissociative anesthetic in human medical procedures. While ketamine may also trigger temporary psychosis in certain individuals, its short half-life and lower potency make it a much safer clinical option. However, dizocilpine is the most frequently used uncompetitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for human and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.
Quisqualic acid is an agonist of the AMPA, kainate, and group I metabotropic glutamate receptors. It is one of the most potent AMPA receptor agonists known. It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord. Quisqualic acid occurs naturally in the seeds of Quisqualis species.
N-Acetylaspartylglutamic acid is a peptide neurotransmitter and the third-most-prevalent neurotransmitter in the mammalian nervous system. NAAG consists of N-acetylaspartic acid (NAA) and glutamic acid coupled via a peptide bond.
Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.
LY-379,268 is a drug that is used in neuroscience research, which acts as a potent and selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).
Stuart Graham Cull-Candy is a British neuroscientist. He holds the Gaddum Chair of Pharmacology and a personal Chair in Neuroscience at University College London. He is also a member of the Faculty of 1000 and held a Royal Society - Wolfson Research position.
7-Chlorokynurenic acid (7-CKA) is a tool compound that acts as a potent and selective competitive antagonist of the glycine site of the NMDA receptor. It produces ketamine-like rapid antidepressant effects in animal models of depression. However, 7-CKA is unable to cross the blood-brain-barrier, and for this reason, is unsuitable for clinical use. As a result, a centrally-penetrant prodrug of 7-CKA, 4-chlorokynurenine (AV-101), has been developed for use in humans, and is being studied in clinical trials as a potential treatment for major depressive disorder, and anti-nociception. In addition to antagonizing the NMDA receptor, 7-CKA also acts as a potent inhibitor of the reuptake of glutamate into synaptic vesicles, an action that it mediates via competitive blockade of vesicular glutamate transporters.
Annette Catherine Dolphin is a Professor of Pharmacology in the Department of Neuroscience, Physiology and Pharmacology at University College London (UCL).
Maria Fitzgerald is a professor in the Department of Neuroscience at University College London.
PD-137889 (N-methylhexahydrofluorenamine) is a chemical compound that is active as an NMDA receptor antagonist in the central nervous system at roughly 30 times the potency of the "flagship" of its class, ketamine, and substitutes for phencyclidine in animal studies. Ki [3H]TCP binding = 27 nM versus ketamine's Ki = 860 nM.
Mark Lee Mayer is scientist emeritus at the National Institutes of Health (NIH). His research investigates glutamate receptor ion channels, the major mediators of excitatory synapses in the brain. He has made numerous observations that have changed our view of receptor function and neurotransmission in the brain. Major findings include discovery of the block of NMDA receptors by extracellular Mg and their high Ca permeability; analysis of the permeation and block of Ca permeable AMPA and kainate receptors by cytoplasmic polyamines; and structural studies on ligand binding, allosteric modulation, and gating using X-ray diffraction and cryoelectron microscopy.
Fiona Hamilton Marshall is a British pharmacologist, founder and Senior Vice President of Discovery, Preclinical & Translational Medicine at Merck & Co. She will become the next president of the Novartis Institutes for BioMedical Research. She previously served as Chief Scientific Officer at Heptares Therapeutic, where she was Vice President of the Japanese biopharmaceutical company Sosei. She was elected Fellow of the Academy of Medical Sciences in 2016 and the Royal Society in 2021.
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