Chapter 4: psychosis and neurotransmitter networks Flashcards
3 subtypes of psychosis
paranoid
disorganized/excited
depressive
dopamine hypothesis of psychosis
caused by hyperactivity of D2 receptors in the mesolimbic pathway
how is dopamine synthesized
tyrosine is taken up into dopaminergic neurons and converted to DOPA which is then converted to dopamine to be stored in synaptic vesicles
what happens to excess dopamine
it can be destroyed in neuron by MAOA and MAOB
enzymes that convert tyrosine to DOPA and DOPA to dopamine
tyrosine hydroxylase
DOPA decarboxylase
primary pathway for dopamine termination
reuptake into presynaptic neuron via DAT
secondary inactivation of dopamine
extracellularly by COMT
what does COMT stand for
catechol-O-methyltransferase
how is dopamine terminated in the PFC where DATs are sparse
by COMT
how is dopamine inactivated when NO DATs are present
diffusion away from synapse to a noradrenergic neuron where it binds to NET and enters the neuron as a false substrate
how many groups of postsynaptic dopamine receptors are there
2 (D1-like receptors and D2-like receptors)
which dopamine receptors are D1-like postsynaptic receptors
D1 and D5
purposes for D1-like dopamine receptors
excitatory
positively linked to adenylate cyclase
stimulates the postsynaptic neuron
which dopamine receptors are included in the D2-like group
D2, D3, D4
main functions of D2-like postsynaptic dopamine receptors
inhibitory
negatively linked to adenylate cyclase
inhibits postsynaptic neuron
what dopamine receptors are also located presynaptically
D2, D3
function of presynaptic D2 and D3 receptors
act as autoreceptors to inhibit further dopamine release
which presynaptic dopamine receptor is LESS receptive to dopamine
D2
takes a higher concentration of dopamine to activate it
where are presynaptic D2 and D3 receptors located
axon terminal
somatodendritic area
location of mesocortical dopamine neurons
arise from ventral tegmental area (VTA) in the brain stem and project to the PFC
how is dopamine regulated in the VTA
by somatodendritic auto receptors D2 and D3 in axon terminals
what is different about dopamine autoreceptors in the PFC
not many of them to inhibit dopamine release and not many DATs for termination so it is free to diffuse further away from the synapse
what is true about dopamine’s diffusion radius
larger the radius the more concentrated dopamine becomes
location of mesolimbic dopamine neurons
project from VTA to striatum
how are mesolimbic dopamine neurons regulated in the VTA
somatodendritic D3 auto receptors
how are mesolimbic dopamine neurons regulated in the PFC
presynaptic D2 auto receptors
is dopamine excitatory or inhibitory
both. It depends on which receptor subtype it binds to
4 classic dopamine pathways
-tuberoinfundibular
-thalamic
-nigrostriatal
-mesolimbic
location of tuberoinfundibular dopamine pathway
project from the hypothalamus to the pituitary gland
function of dopamine neurons in the tuberoinfundibular dopamine pathway
inhibit prolactin release
location of thalamic dopamine pathway
arises from multiple sites
-periaqueductal gray matter
-ventral mesencephalon
-various hypothalamic nuclei
-lateral parabrachial nucleus
function of thalamic dopamine pathway
under investigation
no evidence that malfunctioning is present in schizophrenia
location of nigrostriatal dopamine pathway
projects from dopamine neurons in the brainstem substantia nigra to the striatum
main function of nigrostriatal dopamine pathway
part of the extrapyramidal motor system that controls motor function and movement
receptors, location, and results of direct nigrostriatal dopamine pathway
-D1 excitatory receptors
-projects from striatum to globus pallidus interna
-results in stimulation of movement
what causes movement disorders
too much or too little dopamine in the direct and indirect nigrostriatal dopamine pathway
receptors, location, and results of the indirect nigrostriatal dopamine pathway
-D2 receptors
-projects from globus pallidus externa and subthalamic nuclei to the globus pallidus interna
-blocks motor movements
what types of movement disorders are caused by excessive dopamine in the nigrostriatal pathway
chorea
dyskinesias
tics
what can happen with chronic blockade of D2 receptors
tardive dyskinesia
location of mesolimbic dopamine pathway
projects from midbrain VTA to the nucleus accumbens in the ventral striatum
what is the nucleus accumbens and what does it do
part of the limbic system involved in pleasurable sensations, euphoria or drug abuse, and delusions/hallucinations
what happens when there is too much or too little dopamine in the mesolimbic dopamine pathway
too much - causes positive symptoms of psychosis
too little - anhedonia, apathy, lack of energy, negative symptoms of schizophrenia
what is the classic dopamine hypothesis
dopamine hyperactivity in the mesolimbic pathway hypothetically accounts for positive symptoms of psychosis in any disorder in which they are present
what substances can cause dopamine hyperactivity in the mesolimbic pathway
psychostimulants
what is thought to cause cognitive, and negative symptoms of schizophrenia
hypoactivity of dopamine in the mesocortical pathway projections to the DLPFC
what is thought to cause the affective symptoms of schizophrenia
dopamine hypoactivity in the mesocortical pathway projections to the VMPFC
location of mesocortical dopamine pathway
project from cells in the VTA to areas of the PFC
glutamate hypothesis of schizophrenia and psychosis
NMDA glutamate receptors at critical synapses in the PFC are hypofunctional
what are some things that can disrupt NMDA glutamate receptors
-neurodevelopmental abnormalities in schizophrenia
-neurodegenerative abnormalities in dementia
-receptor blocking by dissociative anesthetics like ketamine and PCP
where is glutamate synthesized when used as a neurotransmitter
synthesized from glutamine in glia cells
intracellular transporter to return glutamate to glia for storage
EAAT
how is glutamate synthesized
glutamate is converted to glutamine in glia and then released by reverse transporter SNAT. when SNAT reverses back into the cell glutamine catches a ride back in and is then converted back to glutamate and transported into synaptic vesicles via VGluT for release during neurotransmission
what is the enzyme that converts glutamate to glutamine
glutamine synthetase
which enzyme converts glutamine back into glutamate
glutaminase
how is glutamate terminated
when EEATs move it into glia for the cycle to begin again; not via enzymatic breakdown
what are the two glutamate cotransmitters
amino acids:
glycine
D-serine
what is required for glutamate to utilize NMDA receptors
a cotransmitter
where does glycine come from
glycine neurons (little)
glia (most)
synthesized from L-serine
derived directly from dietary amino acids
2 ways D-serine cotransmitter is synthesized
-L-serine is converted to D-serine by enzyme D-serine racemase in glia
-SHMT converts glycine to L-serine which is then converted to D-serine by racemase
name of presynaptic uptake pump for glutamate
EAAT - clears excess glutamate out of the synapse
name of intracellular vesicular transporter for glutamat
vGluT
what are glutamate receptors that are linked to G proteins called
metabotropic glutamate receptors
2 types of glutamate receptors
metabotropic
ionotropic
what is the NMDA glutamate hypofunction hypothesis
psychosis may be caused by dysfunction of glutamate synapses at certain GABA interneurons in the PFC
what happens when glutamate neurons that innervate the VTA/mesostriatal dopamine neurons lose their GABA inhibition
they become hyperactive and stimulate excessive dopamine release causing positive symptoms of psychosis
what happens when glutamate neurons that innervate the VTA/mesocortical dopamine neurons become hyperactive
dopamine release is inhibited and can lead to the negative symptoms of psychosis
what is the serotonin hypothesis of psychosis
psychosis results from hyperactivity/imbalance of serotonin activity (mainly at 5HT2A)
how is serotonin synthesized
amino acid tryptophan is transported from plasma into brain where it is converted to 5HTP by tryptophan hydroxylase. AAADC then converts 5HTP to 5HT which is then taken up to be stored in synaptic vesicles
how is serotonin action terminated
-when it is destroyed by MAO enzymes
-when it is taken back up into neuron by SERT
which receptor is the axon terminal autoreceptor to shut down serotonin activity
5HT1B/D
presynaptic serotonin receptors
5HT1B/D
5HT1A
5HT2B
which receptors are somatodendritic serotonin autoreceptors
5HT1A
5HT2B
difference between when serotonin binds with 5HT1A and 5HT2B receptors
when it binds with 5HT1A it shuts down serotonin impulse flow and when it binds to 5HT2B it increases serotonin impulse flow
where are 5HT1A and 5HT2B primarily located
midbrain raphe
which 5HT1A receptors promote the release of other neurotransmitters
ones located primarily on postsynaptic GABA interneurons
how do 5HT1A receptors located on GABA neurons promote the release of other neurotransmitters
serotonin action at these receptors inhibit the GABA interneurons which increases the release of downstream norepinephrine, dopamine, and acetylcholine
is 5HT1B excitatory or inhibitory
inhibitory
are 5HT2A receptors excitatory or inhibitory
excitatory
what is a heteroreceptor
receptor for a neurotransmitter other than the one the neuron uses as its own (a serotonin receptor on a GABA neuron)
are 5HT2A receptors excitatory or inhibitory
excitatory
how does action at 5HT2A sites affect the release of other neurotransmitters
depends on their location. If receptors are located on glutamate neurons excitatory glutamate is released onto downstream targets. When localized on GABA neurons inhibitory GABA release is promoted
are 5HT2C receptors excitatory or inhibitory
excitatory but since they are mostly located on GABA neurons, they promote GABA release, which inhibits any neuron it innervates downstream
where are 5HT3 receptors located
on a particular type of GABA interneuron in the PFC
are 5HT3 receptors inhibitory or excitatory
excitatory on GABA neurons so it has a net inhibitory effect
which neurotransmitters specifically does action at 5HT3 receptors on GABA neurons inhibit
inhibits release of acetylcholine and norepinephrine
are 5HT7 receptors inhibitory or excitatory
excitatory on GABA neurons so there is a net inhibitory effect
what are the three pathways linked to hallucinations/delusions
-dopamine hyperactivity at D2 in mesolimbic/mesostriatal pathway
-NMDA receptor hypoactivity at GABAergic interneurons with a loss of GABAergic inhibition in the PFC
-serotonin hyperactivity/imbalance at 5HT2A receptors on glutamate neurons in the cerebral cortex
