PPA Module 2a Lecture 2.6 on Catecholamines: Norepinephrine and Epinephrine

Introduction to Catecholamines

• Focus on neurotransmitters: epinephrine and norepinephrine

• Understanding synthesis, transport, signaling, and receptors

• Highlight the impact on behavior, illnesses, and how medications affect these neurotransmitters

Catecholamine Overview

• Catecholamines are biogenic amine neurotransmitters

  • Examples: Norepinephrine (also called noradrenaline) and Epinephrine (also known as adrenaline)

• Dopamine is the first catecholamine produced, serving as a precursor for both norepinephrine and epinephrine

  • Synthesis Pathway:

  • Tyrosine → DOPA (via tyrosine hydroxylase)

  • DOPA → Dopamine (via dopa decarboxylase)

  • Dopamine → Norepinephrine (via dopamine beta hydroxylase)

  • Norepinephrine → Epinephrine (via phenylethanolamine N-methyltransferase (PNMT))

Synthesis of Norepinephrine

• Also called: Noradrenaline

  • Demethylated version of epinephrine

• Synthesis Process:

  • Oxidation of dopamine to norepinephrine is conducted by dopamine beta hydroxylase

  • Rate-limiting step is the availability of dopamine, which is restricted by tyrosine hydroxylase

Synthesis of Epinephrine

• Also called: Adrenaline

• Key Points:

  • Synthesized from norepinephrine by PNMT

  • PNMT primarily found in endocrine cells

  • Stress increases epinephrine synthesis

  • Rate-limiting step is the availability of norepinephrine, which is itself limited by dopamine

Transport of Catecholamines

• Transport Mechanism: Active transport is required; not passively diffused

  • Vesicular Monoamine Transporters (VMAT1 and VMAT2): Active transport into vesicles

  • Transport involves proton exchange: Protons pumped into vesicles exchanged for norepinephrine

• Termination of signaling:

  • Norepinephrine transported back into presynaptic neurons via norepinephrine transporter (NET)

  • Approximately 90% recovered, repackaged, and reused

  • Na⁺ and Cl⁻ influx coupling is involved in transport mechanism

Adrenergic Receptors

• **Receptor Types:

  • Metabotropic, 7 transmembrane spanning G protein-coupled receptors**

• Types:

  • Alpha-1: Coupled to GQ (excitatory mechanism)

  • Alpha-2: Coupled to GI (inhibitory mechanism)

  • Beta: Coupled to GS (excitatory mechanism increasing cAMP production)

Key Drugs Acting on Adrenergic Receptors

• Alpha-1 drugs:

  • Phenylephrine: An agonist, used as a decongestant

  • Prazosin: An alpha-1 blocker; may treat high blood pressure and alcoholism

• Alpha-2 drugs:

  • Clonidine: An agonist; treats high blood pressure, ADHD, anxiety, PTSD, and acts as a modest analgesic

  • Yohimbine: Antagonist; potential antidepressant and erectile dysfunction treatment but associated with anxiety

• Beta receptor drugs:

  • Isoproterenol: A nonselective beta agonist for treating bradycardia and historically used for asthma

  • Propranolol: A nonselective beta blocker for high blood pressure, migraines, and anxiety

• Uptake inhibitors:

  • Atomoxetine: A norepinephrine transporter inhibitor, treats ADHD

False Neurotransmitters

• Defined as substances that are recognized and packaged like normal neurotransmitters but fail to activate receptors effectively

  • Example: Phenylethylamine

  • Tyramine: A false neurotransmitter derived from tyrosine, found in fermented foods; problematic when MAO inhibitors are used because of increased levels interfering with neurotransmitter function

Metabolism of Catecholamines

• Degradation enzymes:

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

• Importance in breaking down norepinephrine and epinephrine

Physiological and Behavioral Effects of Norepinephrine and Epinephrine

• Critical roles in the autonomic nervous system; especially sympathetic nervous system

  • Functions include:

  • Fight or Flight Response:

    • Increase in heart rate, respiration, and muscle contraction

    • Increase in glycogenolysis (conversion of glycogen to glucose) in the liver

• Central Nervous System Effects:

  • Epinephrine neurons identified by PNMT, located in the medullary reticular formation in the hindbrain

  • Roles in stress response and potentially memory enhancement

  • Norepinephrine neurons concentrated in the locus coeruleus and lateral tegmentum

  • Locus coeruleus manages blood pressure and the baroreceptor reflex; projects extensively throughout the brain

  • Regulates arousal, attention, sensory processing, cognition, and memory

  • Involvement in PTSD and mood regulation

Conclusion

• Comprehensive understanding of catecholamines, their synthesis, transport, receptor mechanisms, and clinical implications

• Importance of understanding effects on behavior and pharmacological treatments in various psychiatric and physiological conditions

• Remaining objectives from the lecture should be reviewed and understood thoroughly.