PHA5560: PPA-I Module 2.6 - Neurological Systems: Epinephrine and Norepinephrine

Understand key catecholamine biogenic amine neurotransmitters: Norepinephrine (NE) and Epinephrine (EPI).
Describe the synthesis, transport, and signaling mechanisms of these neurotransmitters and their receptors.
Illustrate how NE and EPI influence behavior and illness, and explain the actions of medications through these neurotransmitter systems.

Dopamine (DA): First member of the catecholamine neurotransmitter class.
Transport into Vesicles: Dopamine is transported into synaptic vesicles where:
- It is converted into norepinephrine (NE) and epinephrine (EPI) by neurons that contain specific enzymes.

DOPA Decarboxylase: Converts DOPA to dopamine.
Tyrosine Hydroxylase: Converts Tyrosine to DOPA.
Dopamine-β-hydroxylase: Converts dopamine to norepinephrine.
Phenylethanolamine N-methyltransferase: Methylates norepinephrine to form epinephrine.

Other Name: Noradrenaline.
Synthesis:
- NE is synthesized through oxidation from dopamine via dopamine β-hydroxylase in the cytosol.
- The reaction rate is limited by the availability of dopamine, which arises from a multi-step process.
Transport Mechanisms:
- Movement of NE across neuronal membranes requires active cotransport.
- NE is stored in synaptic vesicles via the vesicular monoamine transporter (VMAT1 or 2).
- Reuptake from the synaptic cleft is achieved through the norepinephrine transporter (NET), which terminates signaling.
- Ion co-transport is involved; NE entry is coupled with an influx of 1 sodium ion (Na+) and 1 chloride ion (Cl-).
- Approximately 90% of NE is recovered from the synaptic cleft.
- The prefix "nor-" signifies that NE is a demethylated version of epinephrine.

Other Name: Adrenaline.
Synthesis:
- EPI is synthesized through the methylation of norepinephrine by PNMT.
- PNMT is primarily found in endocrine cells, and its synthesis of EPI is indirectly increased by stress.
Transport Mechanisms:
- EPI's storage and reuptake occur via VMAT and NET, similar to NE.
- The PNMT reaction is limited by the availability of norepinephrine.
- EPI functions as a key neurotransmitter of the sympathetic nervous system.

NE and EPI act on adrenergic receptors, which are all metabotropic 7-transmembrane G protein-coupled receptors (GPCRs).

α2 Receptors:
- Subtypes: α2A, α2B, α2C.
- Inhibitory effects on pathways, Gi protein interactions.
β Receptors:
- Subtypes: β1, β2, β3.
- Associated with excitatory effects, Gs protein interactions.

Block amine transporters to increase neurotransmitter levels.
- Example: Atomoxetine, a medication for ADHD.

Substances that replace neurotransmitters in vesicles but exhibit weak or negligible receptor affinity, such as phenylethylamine.

Metabolized by the enzymes Monoamine Oxidase (MAO) and Catechol-O-methyl transferase (COMT).

α2 Agonism (e.g., Clonidine): Results in inhibitory tone in neurons.
β1 Agonism: Results in excitatory tone in neurons.
Examples of Drug Actions:
- Clonidine acts as an α2 agonist.
- Yohimbine is an α2 antagonist.
- Isoproterenol acts as a nonselective β agonist.
- Propranolol is a nonselective β antagonist, a beta blocker.
- Phenylephrine is an α1 agonist.
- Prazosin acts as an α1 blocker.

Neurons containing epinephrine identified by the presence of PNMT.
NE and EPI neurons play crucial roles in the Autonomic Nervous System (ANS), particularly in sympathetic activation.
Localization in Central Nervous System (CNS):
- Found in the medullary reticular formation and concentrated in two pons-medulla tracts, which may relate to stress responses, anxiety, and memory.

Increased heart rate (HR), respiration, glycogenolysis in the liver, and enhanced muscle contraction facilitated by NE/EPI signaling.

Regulates blood pressure through α2A receptors in the brainstem, enhancing baroreceptor reflex activity.
Controls nociception through descending pathways that inhibit pain signals in the spinal cord.

Arousal Regulation: NE from the reticular activating system (RAS) acts on α2A receptors in the prefrontal cortex, improving attention, focus, and sensory processing.
Memory Enhancement: NE enhances the formation and retrieval of both long-term and working memory.
Cognitive Performance: Enhances sensory processing and the brain's response time.
Reward Regulation: Mixed impact; while NE increases reward sensation, α1 activation can decrease appetite.
Mood Regulation:
- α2 agonists can help reduce anxiety, panic, and PTSD symptoms.
- α2 antagonists might present potential antidepressant qualities (like yohimbine).
- MAO inhibitors elevate levels of NE and dopamine and are known antidepressants.

Tyramine: A metabolic product of tyrosine found in fermented foods such as beer, cheese, and red wine.
Action: Functions as a false neurotransmitter with weak activity.
- Caution: Use of MAO inhibitors is contraindicated with tyramine, as it increases effect significantly.

Phenylephrine: α1 agonist used as a decongestant.
Prazosin: α1 blocker, inverse agonist; used for hypertension and possibly alcoholism.
Clonidine: α2 agonist; treated for hypertension, ADHD, anxiety, PTSD; shows modest analgesic properties.
Yohimbine: α2 antagonist studied as an antidepressant and for erectile dysfunction.
Isoproterenol: Nonselective β agonist; treated bradycardia, historically for asthma.
Propranolol: Nonselective β antagonist; used for hypertension, migraines, and anxiety.
Atomoxetine: NET inhibitor; used to treat ADHD.