Block 2 Lecture 2 -- DA, 5HT, and Amino Acids Flashcards
What are the 4 major brain DA pathways?
1) nigrostriatal
2) mesolimbic
3) mesocortical
4) tuberinfundibular
Describe the anatomy of the mesolimbic pathway.
VTA projects to:
- NAc
- HP
- Amy
Describe the anatomy of the mesocortical pathway.
VTA projects to PFc
Describe the anatomy of the tuberinfundibular pathway.
arcuate nucleus of HT projects to median eminence; median eminence projects to AP to decrease PRL release
What is the function of the mesocortical pathway?
executive function
- decision-making
- impulsivity
What is the function of the mesolimbic pathway?
1) positive reinforcement
2) learning/memory
3) emotional control
How do drugs of abuse cause addiction?
increase DA in mesolimbic pathway
– positive reinforcement, learning/memory, emotional control
Describe the anatomy of the nigrostriatal pathway.
Substantia nigra projects to striatum
What pathway is affected in PD?
nigrostriatal DA pathway
For what conditions are DAr agonists used?
1) PD
2) ADHD
3) hyper-PRL
4) RLS
For what conditions are DAr antagonists used?
1) anti-emetics
2) anti-psychotics
3) movement disorders (Huntingtons, Tourettes, dystonias)
What are the main receptor classes of DAr’s?
1) Gs (D1 and D5-like)
2) Gi (D2-, 3, and 4-like)
What is the function of D1/D5 Gs receptors?
- in CNS
- typically post-synaptic
- increase cAMP
What is the function of D2/3/4-like Gi receptors?
- in CNS
- pre and postsynatpic (like a2 and M2)
- decrease cAMP
Which DAr is cloned?
D5-like
What are the peripheral roles of 5-HT?
1) platelet aggregation (storage granules of platelets)
2) peristalsis, n/v (enterochromaffin)
3) blood vessels and cardiac valves
What are the central roles of 5-HT?
1) mood
2) appetite
3) sleep
4) n/v
5) nociception
In what conditions is 5-HT dysregulation implicated?
1) migraine
2) anxiety
3) schizophrenia
4) depression
5) n/v
6) aggression/hostility
7) OCD/phobias
Where is 5-HT synthesized?
from Trp in Raphe Nucleus
How is 5-HT broken down?
1) MAOb
2) synthesized into melatonin
Where is melatonin synthesized?
pineal gland
Where is serotonin stored?
serotonergic cell groups
Where are melatonin receptors located?
1) SCN
2) anterior pituitary
3) periphery
What are the 5-HT receptors?
1) 5HT1 (A,B,D) Gi
2) 5HT2 (A,B,D) Gq
3) 5HT3 LGIC
4) 5HT4 Gs
Where does LSD act?
5HT2 antagonist
Where do the triptans act?
5HT1 antagonist
5HT4 agonist
Which serotonin receptor is inhibitory?
5HT1 Gi
Which serotonin receptor is an LGIC?
5HT3
What are the signs/sxs of serotonin syndrome?
1) diarrhea
2) euphoria
3) drowsiness/dizziness
4) rapid eye movement and muscle contraction
5) hyperthermia
6) shivering, seizures
7) arrhythmia
8) loss of consciousness, death
What drugs can cause serotonin syndrome?
1) SSRIs
2) MAOIs
3) TCAs
4) triptans
For what reasons weren’t AAs accepted as NTs until 1980?
1) metabolic role
2) distribution
3) high concnetration
4) non-mammalian origin
What is the TA pair for glycine?
glyoxylate
What is the TA pair for glutamate?
alpha-KG
What is the TA pair for Asp?
OAA
What is the TA pair for GABA?
succinic-semialdehyde
Where does vigabatrin act?
inhibits GABA TA
What are the glutamate transporters?
1) EAAT1
2) EAAT2
3) EAAT3
4) EAAT4
Why are there so many Glu transporters?
high concentration of Glu as a NT
Where are EAAT1 GluTs located?
astrocytes
Where are EAAT2 GluTs located?
astrocytes
presynaptic
Where are EAAT3 GluTs located?
postsynaptic
Where are EAAT4 GluTs located?
postsynaptic
What are the predominant neurotransmitters in mammalian brains?
Glu + GABA
How are GluR’s classified?
1) metabotropic
2) ionotropic
What are the metabotropic GluRs?
1) Group 1 Gq
- - 1,5
2) Group 2 Gi
- - 2,3
3) Group 3 Gi
- - 4,6,8,7
What are the ionotropic GluRs?
1) kainic acid
2) AMPAr
3) NMDAr
What does NMDA stand for?
n-methyl-D-aspartate
What does AMPA stand for?
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
Describe the permeability of the kainic acid receptor?
Na
Describe the permeability of the AMPAr?
Na
Describe the permeability of the NMDAr?
Ca
How is the NMDAr activated?
Gly and Glu
– co-agonists
What are non-competitive antagonists of the NMDAr and where do they bind?
1) PCP/phencyclidine
2) ketamine
3) DM
4) memantine
- - bind in the channel
How is the NMDAr modulated?
1) directly by polyamines (spermine) and Zn
2) by increased activity, removing the Mg block
What is the function of the NMDAr Mg-block?
decreased activation of the NMDAr
Why does GABA have so many receptor subtypes?
highly flexible molecule with many different comformations
What are the GABA receptors?
1) GABAa (LGIC)
2) GABAb (Gi)
What are the subunits of the GABAa receptor?
many different alpha/beta
- alpha 1-6
- beta 1-3
- wildcard d, e, g, t, pi
What are the 5 main domains of the GABAa receptor?
1) Cl- channel
2) GABA binding site
3) BZD binding site
4) barb/EtOH binding site
5) neurosteroid/volatile anesthetic binding site
–also: picrotoxin-binding site
Where is the GABA binding site on GABAa?
between a and b
Where is the BZD binding site on GABAa?
between a and g
What GABAa modulators bind in the channel?
1) barbs
2) steroids
3) picrotoxin
What GABAa modulators bind outside the channel?
GABA
BZDs
What is a GABAa agonist?
muscimol
What is muscimol?
GABAa agonist
– poison native to KY
What are GABAa antagonists?
1) bicucline (competitive)
2) picrotoxin (non-competitive)
Describe the GABAb receptor.
metabotropic Gi
- similar to a2 and M2 (presynaptic to decrease NT release)
- high [GABAb] in spinal cord
What is a GABAb agonist?
baclofen
What is baclofen?
GABAb-selective GABAb agonist
What is glycine?
the main NT of renshaw cells in the vental horn of the spinal cord
– co-agonist of NMDAr
What is a renshaw cell?
interneuron in ventral horn of SC
– inhibits recurrent activity
Describe the glycine receptor, vesicular transport, and reuptake?
similar in structure/fx to GABAa
- LGIC Cl
- transported into vesicle via VGLYT
- reuptake mediated by GLYT
Where does glycine bind on the NMDAr?
Gly B-site (strychnine-insensitive binding site)
What is a GlyR antagonist?
strychnine
What is strychnine?
GlyR antagonist
- proconvulsant rat poison
- emetic response in humans
- does not act on Gly B-site of NMDAr
