ch 5-8 Flashcards
catecholamines
hormones made by adrenal glands
monoamines
transmitters that possess one amine group
biogenic amines
compounds made by living organisms
adrenergic
adrenaline/ epinephrine (EPI)
noradrenergic
noradrenaline/norepinephrine (NE)
EPI and NE are secreted by…
adrenal medulla
dopaminergic
dopamine (DA)
synthesis of dopamine/norepinehrine
tyrosine –> L- DOPA –> dopamine –> norepinephrine
enzymes required for synthesis (DA, NE)
tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AACD)
for NE, needs dopamine-β-hydroxylase (DBH) too
rate-limiting enzyme (DA,NE)
determines overall rate of formation because it is the slowest (e.g. TH)
TH inhibition and stimulation
high catecholamine levels inhibit TH (don’t need more), rate of cell firing stimulates TH (more synthesis due to more enzyme activity)
release of catecholamines
synaptic vesicles, important for protection from degrading enzymes and predetermining amount required
vesicular monoamine transporter (VMAT)
responsible for vesicular monoamine reuptake
VMAT1: found in adrenal medulla
VMAT2: found in brain
blocked by reserpin (DA and NE are no longer protected making levels drop)
when do (catecholamine) vesicles open
nerve impulse, but some drugs can cause this effect without needing s nerve impulse (amphetamine, methamphetamine)
release inhibition (catecholamines)
by autoreceptors who either;
1. directly reduce Ca2+ influx needed for exocytosis
2. indirectly reduces Ca2+ by shortening duration of APs entering the terminal
tonic release
DA released in single-spiking mode
phasic release
DA released in burst mode
varicosities
in-passing synpases in which the fibers exhibit repeated swellings
drugs on catecholamine autoreceptors
agonists: stimulate autoreceptors (inhibit release)
antagonists: stimulate release by inhibiting the inhibitory affects of autoreceptors
DA and NE transporters
induce reuptake
DA and NE transporter-blocking drugs
increase transmission in the synapse by not allowing reuptake
breakdown of NE
catechol-O-methyltransferase (COMT) and monoamine oxidase (MOA-A)
breakdown of DA
catechol-O-methyltransferase (COMT) and monoamine oxidase (MOA-B)
metabolites of catecholamines
DA:
- homovanillic acid (HVA)
NE:
- 3-methyl-4-hydroxy-phenylglycol (MHPG) in brain
- vanillymandelic acid in PNS
2 cell groups in midbrain
A1-A7= NE pathways
A8-A16= DA pathways
DA pathway function
from dorsal striatum to substantia nigra facilitates voluntary mvmt
DA pathway lesions
- behavioral dysfunction
- sensory neglect
- motivational deficits
- motor impairment
dopamine deficient mice (DD mice)
- still can produce NE
- lacked DA whole life
- dopaminergic neurons werent damaged, just couldnt produce DA
- all symptoms of lacking DA were fixed momentarily with L-DOPA injection
5 subtypes of DA receptors
- metabotropic (interact with G protein and second messengers
D1 and D2 are most common
D1 and D5 are similar
D2,D3,D4 are similar
D2 receptors
- autoreceptors
- found on pituitary gland that makes prolactin (activation inhibits prolactin)
- can influence K+ channels causing hyperpolarization (inhibiting APs)
- higher affinity for DA than D1
- decrease cAMP
D1
- increases cAMP
- lower affinity for DA
dopamine agonists
apomorphine: agonist for D1 and D2 (classical stimulant)
SKF 38393: agonist for D1 (self grooming in mice)
quinpirole: increase locomotion
dopamine antagonists
suppress exploratory and locomotor behavior
(D2: catalepsy)
NE containing neurons (CNS)
pons and medulla, more specifically in locus coeruleus (A6 cell group)
- provides nearly all NE in the forebrain
NE in PNS
autonomic actions
BBB and NE
blood born NE cannot cross BBB
(blood born NE helps EPI with fight or flight response)
NE and EPI receptors
- metabotropic
- mediates NT (NE) and hormonal (EPI) actions of the catecholamines
a1 and a2
β1 and β2
a1 receptors
increase Ca2+ ion sin postsynaptic cells
a2 receptors
- located on noradrenergic terminals (autoreceptor)
- reduces cAMP
- causes hyperpolarization
β1 and β2 receptors
increases cAMP
synthesis of serotonin
amino acid tryptophan
L-tryptophan -> L-5-hydroxytryptophan –> 5-hydroxytryptamine (5-HT)
enzymes of serotonin synthesis
tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (AACD)
rate limiting enzyme of serotonin synthesis
TPH
tryptophan loading
administration of pure tryptophan
tryptophan- large neutral amino acids ratio
modest increase will not have any effect
large increase will positively enhance mood and cognition
extremely high increase will have negative effects
release of serotonin
released into synapse by VMAT2
-reserpin depletes serotonergic neurons of 5-HT
serontonergic autoreceptors
control 5-HT release; terminal autoreceptors directly inhibit release, other autoreceptors indirectly inhibit release by slowing down rate of firing
5-HT1a receptor
somatodenritic autoreceptors
5-HT1b and 5-HT1d receptors
terminal autoreceptors
drugs that stimulate 5-HT release
para-chloroamphetamine, fenfluramine, 3,4-methylenedioxymethamphetamine (MDMA)
inactivation of 5-HT
- 5-HT transporters (SERT) reuptake (SSRIs block reuptake)
- metabolized by MOA-A
metabolite of 5-HT
5-hydroxyindoleacetic acid (HIAA) used as a measure of serontonergic neurons in the brain
(more rapid neuron firing= more 5-HT= more HIAA
serotonergic neuron orgination
brainstem, projects to all forebrain areas
CNS serontonergic neurons
found along midline of brainstem (medulla, pons, raphe nuchlei)
cell groups (5-HT)
B1-B9
raphe nuclei (dorsal , median)
give rise to most serotonergic fibers in the forebrain
dorsal raphe nucleus neuronal firing
- slow, regular (tonic) while awake
- slower, irregular while asleep
> almost stops completely during REM
phasic firing of 5-HT
triggered by activity in excitatory synaptic inputs to the cells (most come from GABA, glutamate, and acetylcholine, sometimes DA, NE and orexin)
serotonin receptors
- 5-HT1a, 1b, 1d, 1e, 1f
- 5-HT2a, 2b, 2c
- 5-HT3, 4, 5a, 5b (not in humans)
- 5-HT6, 7
all are metabotropic except 5-HT3 which is excitatory ionotropic
5-HT1a functions
- particularly concentrated in hippocampus, septal area, amygdala, raphe nuclei
- reduces cAMP
- increase K+ opening (hyperpolarization)
5-HT2a functions
- more in cerebral cortex
- activate second messenger systems (increase Ca2+ levels)
5-HT2a agonist and antagonist
agonist: hallucinogenic
antagonist: used for schizophrenia treatment
5-HT1b, 1d agonists
constricts blood vessels providing relief from migraine symptoms
5-HT3 agonists and antagonists
agonists: induces vomiting
antagonist: counteracts vomiting and nausea
serontonergic lesions
5,7-dihydroxytryptamine (5,7-DHT): massive damage to serotonergic axons and nerve terminals in the forebrain yet raphe nuclei cell bodies are usually spared (cannot cross BBB)
- changes in hunger, anxiety, aggresion, pain sensitivity, learning and memory
TPH2 knockout
leaves serotonergic neurons intact but they chan’t synthesize 5-HT
TPH2 knockout effects
- causes almost complete loss of 5-HT in the brain but preserves 5-HT in the bloodstream and peripheral organs
- can reverse effects w 5-HTP injection
- reduced body mass, increased mortality, aggresive, impulsive, poor thermoregulation, abnormal respiration but survives gestation and birth (unlike DD mice)
5-HT2a involvement in death
SIDS and SUDEP
hypophagia (reduced food intake) involves what receptors
5-HT1b, 2c agonists
5-HT6 antagonists
anxiety involves what receptors
5-HT1a partial agonists for anti-anxiety
5-HT2a, 2c agonists induce anxiety
5-HT6 partial agonists induce anxiety
pain involves what receptors
5-HT1a, 1b, 2c, 7 agonists reduce pain
5-HT2a, 4 agonists exacerbate pain
learning and memory involves what receptors
5-HT1a agonists, 4 partial agonists improves performance in spatial learning and memory
5-HT6 antagonists improves learning and memory
serotonin in the gut
- 90-95% of bodily 5-HT is in the gut
- synthesized by enterochromaffin cells using TPH1 enzyme
- 5-HT increases when food is ingested
5-HT and IBS
5-HT3 partial agonists can treat IBS-C and IBS-D symptoms
5-HT4 helps with IBS-C
5-HT7 slows peristaltic activity
synthesis of ACh
acetyl CoA + choline –> acetylcholine
- enzyme choline acetyltranferase
rate of synthesis of ACh
controlled by amount of reactants present/available and cell firing
release of ACh
vesicular transporter VAChT
- can be blocked by vesamicol (decreases cytoplasm ACh)
vesicular blocker vesamicol (ACh)
actual exocytosis process doesnt change, only amount of ACh available within the vesicles decreases
animal and bacterial toxins and release of ACh
dramatically affected
overactive ACh
muscle pain in abdomen/chest, tremors, nausea, vomiting, salivation, sweating
inhibited ACh
muscle paralysis
inactivation of ACh
acetylcholinesterase (AChE) breaks it down into acetic acid and choline
- found inside presynaptic, postsynaptic cell, neuromuscular junctions
choline reuptake
choline transporter
- drugs that block choline transporters decrease ACh production by inhibiting choline reuptake
drugs blocking AChE
prevent inhibition of ACh creating an excess
- sometimes used mildly for alzheimers, and glaucome treatment (applied directly to eyes)
physostigmine
- AChE inhibitor
- synthetic analogs do not cross BBB
- reversible AChE inhibitors
