Catecholamines

What do all monoamine neurotransmitters have in common?

They share a similar chemical structure: one amino group linked to an aromatic ring

What are the 2 types of monoamines? Give examples of both

Catecholamines: Dopamine (DA), Norepinephrine (NE) , and Epinephrine (EPI)

Indolamines: serotonin (5-HT or 5-hydroxytryptamine), melatonin, and histamine

What does noradrenergic vs adrenergic mean vs dopaminergic?

Refers to neurons that release norepinephrine vs neurons that release epinephrine vs neurons that release dopamine

Where is most epinephrine secreted from?

From the adrenal medulla into the bloodstream (acts mainly as a hormone), but small amount is also found in the brain

Catecholamines are made from the amino acid ___ and share a “___” chemical group.

tyrosine; catechol

Indolamines are made from the amino acid ____ and have an “___” chemical structure.

tryptophan; indole

What is the main enzyme that controls catecholamine synthesis?

Tyrosine hydroxylase (TH)

What are the three short-term mechanisms that regulate catecholamine neurotransmitter levels?

End product inhibition, Neural activity, and substrate availability

What is end product inhibition?

When high levels of a NT inhibit further production of that same neurotransmitter.

How does neural activity affect catecholamine production?

High neural activity reduces end product inhibition and stimulates TH, increasing neurotransmitter synthesis.

How does substrate availability influence catecholamine levels?

More substrate (like tyrosine) allows the body to make more catecholamines, while less substrate reduces their production. Increasing tyrosine has a small effect, but giving L-DOPA increases catecholamine production more strongly.

What is trans-synaptic induction in catecholamine regulation?

When signals from the autonomic nervous system increase tyrosine hydroxylase levels in adrenal cells or neurons, boosting catecholamine production.

What drug blocks catecholamine synthesis?

α-methyl-para-tyrosine (AMPT), which inhibits tyrosine hydroxylase.

What is the effect of AMPT on neurotransmitters?

It prevents the synthesis of dopamine, norepinephrine, and epinephrine.

What is the role of VMAT2 in catecholamine neurons?

It packages catecholamines into vesicles for storage and release

What does Reserpine do?

It blocks VMAT2, preventing NT from being stored in vesicles, causing them to break down which leads to low levels of DA, NE, and EPI

What happens when Reserpine blocks VMAT2?

Catecholamine levels drop, leading to depression-like symptoms.

What was the monoamine hypothesis of depression?

The idea that depression is caused by too little monoamine activity (based on Reserpine’s effects)

What does it mean that Reserpine is an “irreversible inhibitor”

Once it blocks VMAT2, it can’t be undone; the cell must make new transporters to recover

How are catecholamines normally released from neurons?

By calcium-dependent vesicular exocytosis when a nerve impulse reaches the terminal.

What is tonic vs. phasic release?

Tonic = steady, baseline release; Phasic = burst release with higher frequency.

What does “Ca²⁺-independent release” mean?

Neurotransmitters can be released through reuptake transporters without vesicles or calcium.

How do amphetamine and meth cause dopamine or NE release?

They reverse reuptake transporters, pushing neurotransmitters out into the synapse (Ca²⁺-independent).

How does cocaine affect catecholamine release?

It blocks reuptake so neurotransmitters stay in the synapse longer

What is the main way dopamine and norepinephrine are cleared from the synapse?

By reuptake transporters that take them back into the presynaptic neuron

What happens when reuptake is blocked?

Neurotransmitters stay in the synapse longer, increasing their effects.

What drugs block dopamine and norepinephrine reuptake?

Methylphenidate (Ritalin) and amphetamine (Adderall).

What do tricyclic antidepressants block?

Reuptake of catecholamines (DA, NE) and serotonin (5-HT).

What does cocaine block?

Reuptake of dopamine, norepinephrine, and serotonin.

What are the two main enzymes that break down catecholamines?

Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

What do MAO inhibitors (MAOIs) do?

They block MAO, preventing monoamine breakdown and increasing neurotransmitter levels

What are the main metabolites of NE and DA?

NE → MHPG & VMA; DA → HVA.

What are the 4 dopamine pathways in the brain

Nigrostriatal tract, mesolimbic, Mesocortical, Tuberohypophyseal

Which dopamine pathway controls voluntary movement?

Nigrostriatal tract.

What is the pathway of dopamine in the nigrostriatal tract?

Dopamine is produced in the substantia nigra and sent to the striatum (caudate and putamen) to regulate voluntary movement.

Death of dopaminergic neurons in the substantia nigra causes?

Parkinsons disease

Which pathway is known as the “classic reward pathway”?

Mesolimbic dopamine pathway.

From where to where does the mesolimbic pathway project?

Ventral tegmental area (VTA) → nucleus accumbens.

Dysfunction of the mesolimbic pathway can contribute to?

addiction and psychosis

Which dopamine pathway is involved in cognition, motivation, and emotion?

Mesocortical pathway.

What are the main functions of the mesocortical pathway?

Cognition, motivation, emotion.

What kinds of clinical issues arise from mesocortical pathway dysfunction?

Negative symptoms of schizophrenia and cognitive deficits.

Where does the tuberohypophyseal pathway originate and terminate?

From hypothalamus → median eminence/pituitary gland.

What hormone does the tuberohypophyseal pathway regulate?

Prolactin

Does dopamine increase or decrease prolactin secretion?

Dopamine decreases/inhibits prolactin secretion.

What can happen if dopamine is blocked in the tuberohypophyseal pathway?

Hyperprolactinemia, which can cause milk production, absence of periods, or sexual dysfunction.

How many dopamine receptor subtypes are there?

Five (D1–D5).

Are dopamine receptors ionotropic or metabotropic?

Metabotropic (activate intracellular signaling cascades).

Which receptors are D1-like? And which are D2-like?

D1 and D5 /// D2, D3, D4

Where are D1-like receptors especially found, and what kind of release do they rely on?

Prefrontal cortex (PFC); rely more on phasic dopamine release.

What is the role of D2 in the pituitary?

Pituitary gland activation of D2 inhibits prolactin (PRL) release

What is the role of D3 in the limbic system?

Regulates emotion and motivation

What does it mean that some D2-like receptors are autoreceptors?

They are on dopamine neurons themselves and help regulate dopamine release.

Which family generally increases cAMP and is excitatory? and which decreases cAMP and is inhibitory

D1-like (D1 & D5) /// D2-like (D2, D3, D4)

Which family generally decreases cAMP and is inhibitory?

D2-like (D2, D3, D4)

D2-like have a higher ___ to dopamine than D1-like

affinity

When dopamine activity is high it leads to ___ and ___ behavior

exploratory and locomotor

What are stereotyped behaviors, and what causes them?

Repetitive, purposeless movements caused by dopamine agonists (too much dopamine activity)

What is catalepsy, and what causes it?

A frozen, rigid state caused by blocking D₂ receptors—used to screen for antipsychotics

What happens in dopamine transporter knockout (KO) mice?

They are extremely hyperactive because dopamine isn’t cleared from the synapse.

What happens in D₂ receptor knockout mice?

They show impaired movement because dopamine’s motor control effects are lost.

What causes Parkinson’s disease?

Death of dopaminergic neurons in the substantia nigra → striatum (nigrostriatal tract)

What dopamine pathway is key for reward and reinforcement?

The mesolimbic pathway — VTA → nucleus accumbens (MFB).

What is the dopamine hypothesis of schizophrenia? All antipsychotics block which receptors to reduce this activity?

Too much dopamine activity (especially in the mesolimbic pathway) causes positive symptoms. All antipsychotics block D₂ receptors to reduce this activity.

Which receptors does apomorphine activate?

D1 and D2 receptors

What are the effects of apomorphine?

Stimulant-like effects similar to methamphetamine

What is DETQ?

A positive allosteric modulator (PAM) of D1 receptors — enhances D1 activity when dopamine is present.

What is bromocriptine (Parlodel) used for?

Parkinson’s disease (improves movement) 2) Reduces prolactin release.

Which receptor does bromocriptine mainly target?

D2 receptors

Where is norepinephrine primarily produced?

The Locus Coeruleus in the brainstem

Name three brain regions that receive NE projections.

Cortex, limbic system, thalamus (also hypothalamus, cerebellum, spinal cord).

What are NE’s main roles in the CNS?

Attention, goal-directed behaviors, sensory processing, mood, and anxiety regulation.

How does NE function in the PNS?

Regulates the autonomic nervous system — sympathetic “fight or flight” responses like increased HR and vasodilation/constriction.

Can NE act as a hormone?

Yes, when released into the bloodstream by the adrenal medulla.

What are the two major families of NE receptors? What are the subtypes of NE receptors?

Alpha (α) and Beta (β) receptors /// α₁, α₂, β₁, β₂.

Are NE receptors ionotropic or metabotropic?

Metabotropic — they signal through intracellular cascades.

Do NE receptors mediate neurotransmitter, hormonal, or both actions?

Both — CNS/PNS neurotransmission and adrenal hormone effects.

What type of receptor is α₂ and what does it do?

Presynaptic autoreceptor; reduces NE release

How does α₂ inhibit NE release?

Reduces cAMP synthesis and induces hyperpolarization.

How do α₁ receptors signal inside the cell?

Through the phosphoinositide second messenger system, increasing Ca²⁺

What is the general effect of α₁ receptors?

Excitatory; smooth muscle contraction, CNS activation.

How do β receptors signal?

Gs protein-coupled → stimulate cAMP formation.

What is the general effect of β receptors?

Excitatory; increases heart rate, smooth muscle relaxation (β₂), and metabolic effects.

Name a α₁ receptor agonist and its main effect?

Phenylephrine → vasoconstriction, ↑BP.

Name α₁ receptor antagonist and main effect?

Prazosin → vasodilation, ↓BP.

Name a α₂ receptor agonists and use?

Clonidine, Lofexidine → reduce NE release → lower HR/BP; used in opioid withdrawal.

α₂ receptor antagonist and effect?

Yohimbine → increases NE release → ↑HR, ↑BP, ↑anxiety

Nonselective β antagonist example and effect?

Propranolol → blocks β₁/β₂ → ↓HR, ↓contractility, antihypertensive; also used for anxiety/social phobia.

β₁ selective antagonist example and effect?

Metoprolol → mainly blocks β₁ in the heart → ↓HR and cardiac output → antihypertensive.

Which NE pathway promotes attention, arousal, and vigilance?

Locus Coeruleus pathway to→ telencephalon

When is Locus coeruleus (LC)  activity silent?

During REM sleep

Which behaviors or disorders are linked to NE dysregulation?

Anxiety, depression, ADHD

How does NE affect hunger and feeding?

Increases meal size and duration via α₂ receptors, mainly for carbs; frequency unchanged

Name a drug that acts on NE to reduce appetite.

Phentermine (sympathomimetic, part of Fen-phen)

Which receptor in the PFC improves working memory when activated?

α₂ receptors (e.g., by guanfacine).

What drug is an α₂ agonist used to improve working memory and ADHD?

Guanfacine.

What happens if NE overactivates α₁ receptors in the PFC?

anxiety and impaired working memory

How does NE/arousal affect memory?

Moderate NE → better memory; too much NE → worse memory.

What is the main use of β₂ agonists like albuterol?

Bronchodilation for asthma.