Stahl's - Glutamate and Psychosis Flashcards
What is proposed by the glutamate theory of psychosis?
The NMDA (N-methyl-D-aspartate) subtype of glutamate receptor is hypofunctional at critical synapses in the prefontal cortex
What hypothetically causes disruption of NMDA glutamate functioning?
- Neurodevelopmental abnormalities in schizophrenia
- Neurodegenerative abnormalities as seen in Alzheimer disease and other dementias
- NMDA receptor blocking actions of drugs such as dissociative anesthetics (e.g. Ketamine, phencyclidine)
How are glutamate’s actions stopped?
By removal by excitatory amino acid transporters (EAATs) on neurons or glia where they can be reprocessed and reused
What is required of glutamate to function with NMDA receptors?
Companion transmitters (cotransmitters):
Glycine or D-serine
What contributes glycine to glutamate synapses?
Glycine neurons (few)
Glia (many)
How is glycine taken back up into glia?
Type 1 glycine transporter (GlyT1)
How is glycine taken back up into glycine neurons?
Type 2 glycine transporter (GlyT2)
Which glutamate cotransmitter is stored in a storage vesicle within glia?
D-serine
Which glutamate cotransmitter is stored in the cytoplasm of glia?
Glycine
How does glycine escape glial cells for cotransmission with glutamate?
On a reversed GlyT1 transporter
What are the two types of glutamate receptors?
Metabotropic and Ionotropic (ligand-gated ion-channel receptors)
What are the Group I metabotropic glutamate receptors?
- mGluR1
- mGluR5
What are the Group II metabotropic glutamate receptors?
- mGlu2
- mGlu3
What are the Group III metabotropic glutamate receptors?
- mGlu4
- mGlu6
- mGlu7
- mGlu8
Which group(s) of metabotropic glutamate receptors can be found presynaptically and what is their function?
Group II and Group III; function as autoreceptors to block glutamate release
What effect do Group II and Group III metabotropic glutamate receptors have on glutamate release?
REDUCE glutamate release
What are the three functional classes of the ionotropic glutamate receptors?
- alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors
- Kainate receptors
- N-methyl-D-aspartate (NMDA) receptors
What are the three required “coincidences” that must occur for NMDA receptors to remove magnesium from blocking the calcium channel to let calcium in and trigger postsynaptic actions from glutamate neurotransmission?
- Glutamate occupies its binding site on the NMDA receptor
- Glycine or D-serine bind to its site on the NMDA receptor
- Depolarization occurs, allowing the magnesium plug to be removed
What are the seven glutamatergic pathways of particular relevance to psychopharmacology?
- Cortico-brainstem
- Cortico-striatal
- Hippocampal-accumbens
- Thalamo-cortical
- Cortico-thalamic
- Cortico-cortical (direct)
- Cortico-cortical (indirect)
The cortico-brainstem glutamate pathway projects to which brainstem neurotransmitter centers?
- Raphe (serotonin)
- Ventral tegmental area & substantia nigra (dopamine)
- Locus coeruleus (norepinephrine)
Where is the cortico-brainstem glutamate pathway located?
Projects from cortical pyramidal neurons to brainstem neurotransmitter centers
Where is the cortico-striatal glutamate pathway located?
Projects from cortical pyramidal neurons to the striatal complex and terminates on GABA neurons destined for a relay station in the striatal complex called the globus pallidus
Direct innervation of monoamine neurons in the brainstem by excitatory cortico-brainstem glutamate neurons has what effect on monoamine neurotransmitter release?
STIMULATES release
Indirect innervation of monoamine neurons by excitatory cortico-brainstem glutamate neurons via GABA interneurons in the brainstem has what effect on monoamine neurotransmitter release?
BLOCKS release
