ch 5: catecholamines

catecholamines are (2)

1. monoamines: a catechol + amine group

2. include dopamine, norepinephrine, epinephrine

catecholamine synthesis pathway (3)

• synthesized by a multistep pathway in which tyrosine hydroxylase catalyzes the rate-limiting step

• tyrosine → dopa → dopamine → norepinephrine

• enzymes: tyrosine hydroxylase → aromatic amino acid decarboxylase (AADC) → dopamine ß-hydroxylase

factors affecting tyrosine hydroxylase (TH) activity (2)

1. DA + NE lvls in the nerve terminal → negative feedback

2. cell firing stimulates TH activity through phosphorylation of the enzyme by protein kinases 

how can catecholamine synthesis be increased/inhibited

• ↑sed: administering precursors → ie. tyrosine or L-DOPA

• ↓sed: inhibit one of the enzymes → α-methyl-para-tyrosine (AMPT) blocks TH

catecholamines are loaded into synaptic vesicles by ____ which can be blocked by _____ → an irreversible inhibitor that causes ____ and _____ symptoms

1. vesicular monoamine transporters (VMAT)

2. reserpine

3. sedation

4. depressive

reversible inhibitors of ____ are used to reduce uncontrolled movements in ____ disease + _____ dyskinesia

1. VMAT

2. Huntington’s

3. tardive (is a chronic, involuntary movement disorder that can develop as a side effect of taking certain medications)

How do amphetamine & methamphetamine affect catecholamine release, and what behaviors result? (3)

• Mechanism (presynaptic): enter terminals via DAT/NET, displace NT from vesicles (VMAT2), and reverse transporters → release without nerve firing (action potential–independent).

• Animals: ↑ general activity; high doses → stereotyped behaviors (repetitive sniffing/licking).

• Humans: ↑ alertness, ↑ energy, euphoria, insomnia.
  🧠 Takeaway: Psychostimulants can force DA/NE out even when the neuron isn’t firing—driving hyperactivity and, at high doses, stereotypies

What loads catecholamines into vesicles, and what happens if you block it? (3)

• VMAT2 moves DA/NE into synaptic vesicles

• Reserpine/tetrabenazine block VMAT → vesicular depletion, ↓ release

• Classic effect: akinesia/depression-like behavior in animals; L-DOPA can rescue
  🧠 Takeaway: No VMAT filling = no releasable DA/NE.

how does burst mode (phasic release) neuronal firing patter influence DA release compared to single-spiking mode? (tonic release)? (3)

• burst mode: trains of 2-20 spikes at higher frequency 

  • transmitter release occurring faster than it can be cleared and/or metabolized

  • enhanced release of transmitter + hangs around longer

Where is DA released—classic synapses vs volume transmission (3)

• Many DA axons have varicosities; only 30% show classic active-zone synapses

• Much signaling is volume transmission: DA diffuses to extra-/perisynaptic receptors

• Uptake by DAT/NET + local architecture sets the spread
  🧠 Takeaway: DA often broadcasts via varicosities, not just tight synapses.

how are catecholamines recycled after release? + how can inhibitors ∆ this? (3)

• DA + NE transporters return NTs to the releasing cell for breakdown or repackaging into vesicles

  • uptake by postsynaptic or glial cells

• transporter-blocking drugs enhance DA/NE transmission by ↑ing the amount of NT available

nonselective vs selective MAO inhibitors (4)

• non-selecetive: used to treat depression → had dangerous side effects

• selective:

  • MAO-A: moclobemide: depression 

  • MAO-B: selegiline (eldepryl) + rasagiline (azilect) → Parkinson’s disease

what two molecules are involved in the breakdown of catecholamines?

• monoamine oxidase (MAO)

• catechol-O-methyltrasnferase (COMT)

action of MAO and COMT produce what metabolites? what are these an indication of? (4)

• DA metabolites: homovanillic acid (HVA)

• NE metabolites:

  • 3-methoxy-4hydroxy-phenylglycol (MHPG) in brain

  • vanillymandelic acid (VMA) in PNS

• indication of catecholaminergic activity

what are the two important dopaminergic cell groups found in the midbrain? (4)

• A9 → in substancia nigra → axons project to dorsal striatum in forebrain

• A10 → in ventral tegmental area (VTA)

  • mesolimbic dopamine pathway

  • mesocortical dopamine pathway

info about the motor functions of DA in humans has been derived from (4)

1. Parkinson’s disease

2. mutations in henes for TH, AADC, TH cofactor

3. experimental lesions of the nigrostriatal tract by neurotoxins that damage/destroy midbrain DA neurons + lesion their pathways

4. mice genetically engineered to lack DA → DD mice

6-OHDA mice (3)

• neurotoxin that is injected directly into the brain 

• causes severe damage and/or death to nerve terminals

• animals result in sensory neglect, motivational deficits, motor impairments 

how do DD mice differ to 6-OHDA mice? (3)

1. DA neurons undamaged → they just can’t make DA

2. DD mice lack DA throughout development 

3. seem normal but after 1 week post birth: stop gaining weight, lack feeding + drinking behaviour, hypo-activity

what restores DD mice? (2)

1. temporarily: L-DOPA injection 

2. long-term: restoring DA synthesis just in caudate-putamen

mesolimbic pathway activates _____ +______ behaviour → different neurons mediate the effects of ____ + ____ stimuli

1. arousal

2. locomotor

3. rewarding

4. aversive

mesocortical pathway: input to the ___, helps regulate cognitive functions ie. ____ and _____

1. PFC

2. attention

3. working memory 

main subtypes of DA receptors (2)

1. all are metabotropic → 5 main subtypes

   1. D1 and D2 are most common

D1 vs D2 receptors (5)

1. D1 stimulate adenylyl cyclase → ↑ing rate of cAMP synthesis

2. D2 receptors inhibit adenylyl cyclase → ↓ing the rate of cAMP synthesis

   1. also regulate membrane ion channels for K+

   2. higher affinity for DA than D1

   3. function as autoreceptors + postsynaptic receptors

hypothesis: tonic DA release activates higher-affinity D2 receptors resulting in 

• an increase in DA lvls produced by phasic release

what do dopamine receptor agonists typically do behaviorally? (3)

• Increase locomotor activity and behavioral activation 

• Non-selective agonists (e.g., apomorphine) stimulate D₁ & D₂ receptors 

• Receptor-selective agonists help map which behaviors each subtype controls 

give one D₁ agonist and one D₂/D₃ agonist used in research/clinic + what they’re used for (3)

• D₁ agonist: SKF-38393 (research; receptor mapping; limited clinical use due to tolerance/tachyphylaxis)

• D₂/D₃ agonists: bromocriptine / cabergoline / quinpirole

  • Uses: Parkinson’s (stimulate striatal DA), hyperprolactinemia (restore prolactin inhibition)

what do dopamine receptor antagonists do, and what happens at high doses? (3)

• Block D₂ (± D₁) receptors → reduce dopaminergic behaviors

• Antipsychotics (e.g., haloperidol) = D₂ blockers for schizophrenia

• High doses → catalepsy / motor suppression (nigrostriatal D₂ block)

explain behavioral supersensitivity after chronic D₂ blockade (3)

• Long-term D₂ antagonists (e.g., haloperidol) → up-regulation / increased sensitivity of postsynaptic D₂

• After stopping the drug, animals show exaggerated responses to D₂ agonists

• Mechanism base: receptor up-regulation in striatum

what do DAT knockout studies show about dopamine function? (3)

• DAT −/− mice: hyperactive (persistent extracellular DA → ongoing receptor activation)

• Show impulsivity/cognitive changes reminiscent of ADHD traits

• Molecular genetics lets us knock in/out components to link DA pathways to behaviour

a non-selective dopamine agonist that activates both D₁ and D₂ receptors is _____, which typically _____ locomotor activity

• apomorphine

• increases

a research D₁ receptor agonist is _____; repeated dosing can lead to _____ (loss of effect)

• SKF-38393

• tachyphylaxis / tolerance

NE neurons are located in the ____ + medulla → especially in the ____. Here all neurons express the enzyme ____ + synthesize NE. This structure send fibers to ______ → areas mainly involved in _______ + cerebellum + spinal cord

1. pons

2. locus coerluleus (LC)

3. DBH

4. almost all areas of the forebrain

5. sensory information processing

D₂ receptor blockade by antipsychotics like _____ can cause _____ at high doses and may lead to _____ after chronic use

1. haloperidol

2. catalepsy / motor suppression

3. behavioral supersensitivity (D₂ up-regulation)

D₂/D₃ agonists such as _____ or _____ are used to treat _____ and _____ by stimulating dopamine receptors

• bromocriptine

• cabergoline (quinpirole = research)

• Parkinson’s disease

• hyperprolactinemia

deleting the dopamine transporter (DAT−/−) causes _____ behavior because extracellular DA _____

• hyperactive/impulsive

• stays elevated (reuptake impaired)

What do D1/D2/D3 KOs and DAT changes show about stimulant effects?

Receptor KOs blunt cocaine/amphetamine locomotion; DAT level (KO/over-expression) alters response → DA receptors + DAT are essential for stimulant behaviors.

Signaling for α1, α2, β1/β2/β3? (3)

• α1: Gq ↑IP₃/DAG/Ca²⁺

• α2: Gi ↓cAMP, opens K⁺ (often autoreceptor ↓ release)

• β: Gs ↑cAMP.

How do α2 drugs change NE output & behavior? (2)

• Clonidine/lofexidine (α2 agonists) ↓ LC firing → ease opioid withdrawal/HTN.

• Yohimbine (α2 antagonist) ↑ NE release → anxiety/craving.

How does NE affect working memory in PFC?

Moderate NE via α2A → best WM; low NE (fatigue) and high NE (stress via α1/β) impair—classic inverted-U.

Why does stress strengthen emotional memories?

↑ LC NE + adrenal EPI/cortisol engages amygdala (BLA) → boosts hippocampus/PFC consolidation.

Key adrenergic agonist uses? (5)

• β2 (albuterol/levalbuterol): bronchodilation (asthma/COPD).

• Phenylephrine (α1): vasoconstriction/decongestant.

• Isoproterenol (β1/β2): treats bradycardia.

• Midodrine (α1): raises BP in orthostatic hypotension.

• Dexmedetomidine (α2): ICU sedation/analgesia with minimal respiratory depression.

Key adrenergic antagonist uses? (3)

• Prazosin (α1 block): HTN, PTSD nightmares.

• Propranolol (β1/β2): ↓ HR, performance anxiety;

• Metoprolol (β1-selective): cardiac control with fewer bronchospasm risks.