Basic systems Flashcards
How is glutamate synthesised and recycled? Name the transporters involved.
From glutamine in glia cells. Glutamine transporters pump glutamine from glia to neuron with SNAT (specific glial neutral amino acid
transporter), it is then converted to glutamate under influence of glutaminase and transported by vGlut into vesicles. After release, it is absorbed by glia via excitatory amino acid transporter (EAAT).
How many metabotropic glutamate receptor types are there?
At least 8, categorized into 3 groups.
- Group II and Group III: function presynaptically, as autoreceptors to block glutamate release.
-> Stimulating drugs therefore reduce glutamate release - Group I (mGluR1 and mGluR5): function on the post synapse, and interact with other postsynaptic glutamate receptors to facilitate response, mediated by ligad-gated ion-channel receptors during excitatory glutamatergic neurotransmission.
Name 7 glutamate pathways in the brain
- Cortico-brainstem glutamate pathway
- direct interaction of monoamine neurones in the brainstem including the raphe nuclei for serotonin, VTA and SN for dopamine and locus coeruleus for norepinephrine.
- Cortico-striatal glutamate pathways
- A second descending glutamatergic output from cortical pyramidal neurons to the striatal complex, terminating on GABA neurons that serve as a relay station in the globus pallidus. Involved in schizophernia glutamate hypothesis.
- Hippocampal-accumbens glutamate pathway
- Also terminates on GABA neurones that project to relay station in the globus pallidus. Involved in schizophernia glutamate hypothesis.
- Thalamo-cortical glutamate pathway
- cortico-thalamic glutamate pathway
- Direct cortico-cortical glutamate pathways
- Indirect cortico-cortical glutamate pathways
What are the inhibitory serotonin receptors? Describe their mechanism.
5HT1a, located postsynaptically on GABA neurons in the PFC. When stimulated, it inhibits NE, DA and ACh release in the PFC.
5HT1b, located presynaptically on non-serotonin (so, this is a heteroceptor) nerve terminals. When stimulated it inhibits the neurotransmitters plus histamine, originated from TMN.
What can you say about the 5HT2a and 5HT2c receptors ?
They are both excitatory.
5HT2a its downstream effect is dependent on its location, could be on GABA interneurons or glutamate pyramidal neurons in the PFC. Agonists of this receptor cause hallucinations (LSD and psilocybin)
5HT2c is located postsynaptically on GABA interneurons in the brain stem. Therefore, it has an inhibitory effect. Agonists can treat obesity. Antagonist treat psychosis and mood disorders, but are also involved in weight gain.
What can you say about 5HT3 receptors?
They are excitatory, located postsynaptically upon GABA interneurons in the PFC and basal forbrain. They are also involved in nausea and vomiting at the brainstem chemoreceptor outside BBB. Is also ionotropic.
What can you say about the 5HT7 receptors?
They are excitatory, and can inhibit the release of glutamate at the cortical level, and inhibit serotonin release at the level of the raphe nuclei, due to their presence on GABA interneurons. 5HT7 antagonists are used for the treatment of psychosis
and mood.
How is noradrenaline synsthesized and broken down?
Derived from tyrosine, which is converted into DOPA and then dopamine which is converted into noradrenaline. Noradrenaline is stored into vesicles but the VMAT2, and terminated intracellularly by MAO in the mitochondria and extracellularly by COMT. NE is transported via NET.
What are the most important noradrenerge receptors?
α2 -> high NE sensitivity, autoreceptor: suppression of NE release. Decreases BP and is important for focused attention.
α1 -> moderate NE sensitivity: important for flexible attention and distractibility, increase BP.
Alpha-1 antagonism can modulate downstream dopamine
release via two disinhibition of the nigrostriatal dopamine pathway. The increased dopamine release
in the motor striatum can reduce motor side effects caused by D2 antagonism because there is more dopamine to compete with the
D2 antagonist. Alpha-1 antagonism also causes disinhibition of the mesocortical dopamine pathway. Increased dopamine release in the prefrontal
cortex (PFC) can potentially improve mood and reduce affective and cognitive symptoms.
β1 -> low NE sensitivity: increases bloodpressure and involved in trauma memory.
How is GABA synthesized and transported?
GABA is produced from glutamate via the enzyme glutamatic acid decarboxylase (GAD) and transported into the veiscle by vescular inhibitory amino acid transporters (VIAATs). GABA is reuptaken by GAT and terminated by intracellular GABA-T.
What do you know about GABA receptor subtypes A and B.
GABAb receptors are G-protein-linked receptors that may be coupled with calcium or potassium channels. This is also the target of the drug GHB.
GABAa receptors are ionotropic and consists out of five subunits (isoforms) and each of four transmembrane regions.
GABA binding site between α and β
- γ isoforms tend to be synaptic, mediate phasic neurotransmission and are sensitive to benzodiazepines - benzo binding site between γ and α
- δ isoforms tend to by extrasynaptic, mediate tonic neurotransmission and are insensitive to benzodiazepines - neuroactive steroids (alcohol and anesthetics) between δ and α
