Stahl's - Glutamate and Psychosis

Question 1

What is proposed by the glutamate theory of psychosis?

Answer 1

The NMDA (N-methyl-D-aspartate) subtype of glutamate receptor is hypofunctional at critical synapses in the prefontal cortex

Question 2

What hypothetically causes disruption of NMDA glutamate functioning?

Answer 2

1. Neurodevelopmental abnormalities in schizophrenia
2. Neurodegenerative abnormalities as seen in Alzheimer disease and other dementias
3. NMDA receptor blocking actions of drugs such as dissociative anesthetics (e.g. Ketamine, phencyclidine)

Question 3

How are glutamate’s actions stopped?

Answer 3

By removal by excitatory amino acid transporters (EAATs) on neurons or glia where they can be reprocessed and reused

Question 4

What is required of glutamate to function with NMDA receptors?

Answer 4

Companion transmitters (cotransmitters):
Glycine or D-serine

Question 5

What contributes glycine to glutamate synapses?

Answer 5

Glycine neurons (few)
Glia (many)

Question 6

How is glycine taken back up into glia?

Answer 6

Type 1 glycine transporter (GlyT1)

Question 7

How is glycine taken back up into glycine neurons?

Answer 7

Type 2 glycine transporter (GlyT2)

Question 8

Which glutamate cotransmitter is stored in a storage vesicle within glia?

Answer 8

D-serine

Question 9

Which glutamate cotransmitter is stored in the cytoplasm of glia?

Answer 9

Glycine

Question 10

How does glycine escape glial cells for cotransmission with glutamate?

Answer 10

On a reversed GlyT1 transporter

Question 11

What are the two types of glutamate receptors?

Answer 11

Metabotropic and Ionotropic (ligand-gated ion-channel receptors)

Question 12

What are the Group I metabotropic glutamate receptors?

Answer 12

1. mGluR1
2. mGluR5

Question 13

What are the Group II metabotropic glutamate receptors?

Answer 13

1. mGlu2
2. mGlu3

Question 14

What are the Group III metabotropic glutamate receptors?

Answer 14

1. mGlu4
2. mGlu6
3. mGlu7
4. mGlu8

Question 15

Which group(s) of metabotropic glutamate receptors can be found presynaptically and what is their function?

Answer 15

Group II and Group III; function as autoreceptors to block glutamate release

Question 16

What effect do Group II and Group III metabotropic glutamate receptors have on glutamate release?

Answer 16

REDUCE glutamate release

Question 17

What are the three functional classes of the ionotropic glutamate receptors?

Answer 17

1. alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors
2. Kainate receptors
3. N-methyl-D-aspartate (NMDA) receptors

Question 18

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?

Answer 18

1. Glutamate occupies its binding site on the NMDA receptor
2. Glycine or D-serine bind to its site on the NMDA receptor
3. Depolarization occurs, allowing the magnesium plug to be removed

Question 19

What are the seven glutamatergic pathways of particular relevance to psychopharmacology?

Answer 19

1. Cortico-brainstem
2. Cortico-striatal
3. Hippocampal-accumbens
4. Thalamo-cortical
5. Cortico-thalamic
6. Cortico-cortical (direct)
7. Cortico-cortical (indirect)

Question 20

The cortico-brainstem glutamate pathway projects to which brainstem neurotransmitter centers?

Answer 20

1. Raphe (serotonin)
2. Ventral tegmental area & substantia nigra (dopamine)
3. Locus coeruleus (norepinephrine)

Question 21

Where is the cortico-brainstem glutamate pathway located?

Answer 21

Projects from cortical pyramidal neurons to brainstem neurotransmitter centers

Question 22

Where is the cortico-striatal glutamate pathway located?

Answer 22

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

Question 23

Direct innervation of monoamine neurons in the brainstem by excitatory cortico-brainstem glutamate neurons has what effect on monoamine neurotransmitter release?

Answer 23

STIMULATES release

Question 24

Indirect innervation of monoamine neurons by excitatory cortico-brainstem glutamate neurons via GABA interneurons in the brainstem has what effect on monoamine neurotransmitter release?

Answer 24

BLOCKS release

Question 25

Where is the hippocampal-accumbens glutamate pathway located?

Answer 25

Projects from the hippocampus to the nucleus accumbens and, like the cortico-striatal pathway, terminates on GABA headed for the globus pallidus

Question 26

What is the function of the thalamo-cortical glutamate pathway?

Answer 26

Brings information from the thalamus back into the cortex, often to process sensory information

Question 27

What is the function of the cortico-thalamic glutamate pathway?

Answer 27

Projects directly to thalamus where it may direct the manner in which neurons react to sensory information

Question 28

What is the functional difference between the direct and indirect cortico-cortical glutamate pathways?

Answer 28

Through direct pathway, pyramidal neurons can excite each other within the cerebral cortex via direct synaptic input from their own glutamate

Through the indirect pathway, pyramidal neurons can inhibit one another via indirect input, namely via interneurons that release GABA