Catecholamines Flashcards
Catecholamine Synthesis
Precursor: Tyrosine
Step 2: Rate limiting step- tyrosine converted to DOPA via tyrosine hydroxylase
Step 3: DOPA –> DA via AADC
Drug: L DOPA is used as precursor therapy for parkinsons disease.
Step 4: DA –> NE via DBH
Tyrosine Hydroxylase
Converts tyrosine to DOPA in 2nd step / rate limiting step of cat synthesis..
TH can be regulated in several ways:
- high cat levels tend to inhibit TH
- rate of cell firing influences TH activity (more firing, more TH activity)
Feedback allows for neuronal control on rate of NT formation.
Drug AMPT can block TH.
Catecholamines
Subset of monoamines: DA, NE, Epi
Where stimulants act -amph and meth release cats into the synapse
VMAT
Vesicular monoamine transporter -
VMAT 1 = adrenal medulla
VMAT 2 = Brain
–> Drug: Reserpine; blocks both VMAT 1 and 2 (creates depressive symptoms in humans from breakdown of DA and NE in the nerve terminal that can be reduced by DOPA admin)
Catecholamine Autoreceptors
DA: usually D2
NE: usually alpha2
synaptic = control amount of NT released in the terminal.
somatodendritic = may influence transmission by decreasing cell firing rather than NT release.
Catecholamine Inactivation
Reuptake: DA or NE transporters (drugs that act here are TCAS, reboxetrine and atromexetrine - adhd)
Metabolism: 2 enzymes
- COMT (com ti’s used to increase l dopa in parkinson’s)
- MAO – 2 types: mao-a and mao-b
- -> DA metab: 1 metabolite: HVA
- -> NE metab: 2 metabolites depending on where breakdown takes place: MHGP (CNS), and VMA (PNS)
Organization and Function of DA in Brain
2 Important cell groups: SN(A9) (to striatum) and VTA (A10)(mesolimbic and mesocortical paths)
- -> therefore 3 major ascending DA pathways:
- Nigrostriatal tract (SN –> striatum, caudate-putamen, GP)
- Mesolimbic (VTA –> NA, Amg, Hippo)
- Mesocortical (VTA –> cortex, prefrontal)
Ascending paths needed for:
- voluntary behavior
- sensory attention
- motivation
DA receptors
5 Main Types - D1-D5 - all METABOTROPIC
D1 and D5 are similar - ‘D1-like’
the rest are ‘D2-like’
D1 = stim adenylyl cyclase and increase cAMP by activating Gs D2 = inhibit adenylyl cyclase and decrease cAMP by activating Gi. -- D2's are also auto receptors.
Apomorphine - D1/D2 agonist – erectile dysfunction,
Antagonists cause decreased locomotion, and catalepsy at high doses (long term treatment can create behavioral super sensitivity)
Organization and Function of NE
Central and Peripheral components:
role in wakefulness, vigilance, and regulation of HPA axis
Central:
- LC (A6) = projects to all areas of brain; arousal, cognition, emotional memory enhancement
- PVN (hypothal) = stimulates feeding
Peripheral: used by sympathetic ganglia, control of internal organs, released by adrenal glands into blood.
NE Receptors
2 Major Types: All metabotropic
Beta Receptors:
-B1/B2 - stimulate adenylyl cyclase and increase cAMP, peripherally relax smooth muscle
Alpha Receptors:
- a2: inhibit adenylyl cyclase and decrease cAMP, and increase K+ channel opening; peripherally constricts smooth muscles (antagonist can provide asthma relief)
- a1: Increase concentration of free Ca2+ via phosphoinositide 2nd messenger system (this may cause significant synaptic changes).
NE and Arousal
Increased LC firing during waking than during sleep
(especially the medial septal)
–> sensory stimuli and alertness activate the LC, consuming, grooming and sleeping inhibit the LC
a1 agonist (phenylephrine) and b agonists (isoproterenol) administered to medial septal of LC increase the amount of time spent awake in rats –> therefore both b and a1 receptors are involved in arousal.
NE and Cognition
LC projections to PFC —>
PFC contains a2 and a1 receptors which are important for attn and learning and WM
-activate a2 - increase WM
-activate a1 - reduced cognitive functioning (Think: stress stims ne to pfd and reduces the functioning there)
In PFC, NE has higher affinity for a2 than for a1– so a 2 is responsible for the PFC dependent cognitive tasks
NE and Enhancement of Emotional Memory
As shown through inhibitory/passive avoidance paradigm. –> causes increased emotional mem consolidation mainly through b activation and cAMP.
