NPP Exam 1 Review Ch.5 Catecholamines

What are catecholamines?

The monoamine neurotransmitters

- DA, dopamine

- NE, norepinephrine (adrenaline)

Similar neurotransmitter that play distinct roles

- DA: L&M, reward, motivation, and addiction.

- NE: L&M, stress, alertness, and attention

Neural systems

- NE (adrenergic or noradrenergic)

- DA (dopaminergic)

Where is EPI secreted?

Adrenal medulla

Where is NE synthesized?

One brain region

Locus Coeruleus (the blue place)

Where is DA synthesized?

2 brain regions

VTA & Substantia Nigra

What does Catecholamine synthesis begin with?

tyrosine amino acid

How are dopaminergic neurons synthesized?

Tyrosine → tyrosine hydroxylase → DOPA → aromatic amino acid decarboxylase (AADC) → Dopamine

How are noradrenergic neurons synthesized?

TH & AADC + dopamine β-hydroxylase (DBH)

What is the rate limiting step of dopaminergic neuron synthesis?

TH as it determines the overall rate of DA or NE synthesis

What modulates TH activity?

- stress, NE neurons are highly active, which stimulates TH for further synthesis of NE

- cell firing stimulates TH through phosphorylation of the enzyme by 2nd messengers and protein kinases

How can catecholamine synthesis be increased?

by administering precursors such as tyrosine or L-DOPA

How can catecholamine synthesis be prevented?

administering AMPT; blocks TH, thus preventing overall catecholamine synthesis

How are catecholamines stored and transported?

- packaged into vesicles

- job of vesicular monoamine transporter (VMAT)

How can VMATs be blocked?

Reserpine

Why is the storage of DA and NE into vesicles important?

broken down by monoamine oxidase (MAO), levels drop, causes strong sedation & depression

How can you reverse shutting off the mood system in the brain?

Administration of L-DOPA

Catecholamine Theory of Depression

too much norepinephrine and serotonin in the synapse leads to mania, while too little leads to depression

How are catecholamines released?

Normally released by exocytosis when a nerve impulse reaches the axon terminal

What drugs effect the release of catecholamines?

Amphetamines and methamphetamines

What can happen if you take amphetamines and methamphetamines at low doses?

increased locomotor activity

What can happen if you take amphetamines and methamphetamines at high doses?

Stereotyped behaviors

Amphetamine induced psychosis

Prolonged use can result in paranoia, hallucinations, and delusions, resembling symptoms of schizophrenia.

What is the mechanism that inhibits release of catecholamines?

Autoreceptors inhibit catecholamine release

Where are these autoreceptors located?

Pre-synaptic axon terminals as well as on the soma (cell body) and dendrites.

What is the function of pre-synaptic auto-receptors?

Enhances opening of voltage-gated K+ channels

Which G protein do pre-synaptic auto-receptors use?

Gi

What does the K+ channel activation do in relation to exocytosis?

reduces presynaptic Ca2+ influx via VGCCs (or VDCCs), thereby reducing vesicle exocytosis

What are the functions of somatic and dendritic auto-receptors?

Inhibit neurotransmitter release indirectly by reducing the firing rate of DA neurons

Single-spiking Mode:

Cells generate action potentials that appear at irregular intervals and produces tonic release of DA

Burst-spiking Mode:

involves bursts of 2-20 action potentials at a higher frequency, which produce phasic release of DA

Are DA receptors metabotropic or ionotropic? What G proteins do they use?

Metabotropic, Gi, Gs

Are NE receptors metabotropic or ionotropic? What G proteins do they use?

metabotropic; Gi, Gs, some Gq

Ways to manipulate NT's?

reuptake & breakdown

What subtype is the DA auto-receptor?

D2 dopaminergic

What subtype is the NE auto-receptor?

a2 adrenergic subtype

Auto-receptor agonists ______ catecholamine release

inhibit

Auto-receptor antagonists ______ catecholamine release

enhance

What drug is an auto-receptor agonist?

Clonidine; stimulate auto-receptors, thereby decreasing NE release.

What drug is an auto-receptor antagonist?

Yohimbine; blocks auto-receptors, thereby increasing NE release.

How do DA and NE move from the synaptic cleft to the axon terminal?

membrane transporters

How do tricyclic antidepressants inhibit?

they inhibit reuptake of both NE and 5-HT

How does cocaine inhibit?

inhibits reuptake of all monoamine transmitters

What do Reboxetine and Atomoxetine block?

NE transporters

Enzyme-mediated breakdown

COMT & MAO

COMT inhibitors

Pentacapone and tolcapone enhance L-DOPA's effectiveness for the treatment of Parkinson's disease by preventing breakdown

MAO

phenelzine and tranylcypromine are used to treat clinical depression

What 2 brain regions do dopamine neurons originate from?

Substantia Nigra (SN) & Ventral tegmental area (VTA)

What pathways do DA neurons form?

- Nigrostriatal

- Mesolimbic

- Mesocortical

Nigrostriatal pathway

axons from SN extend to the caudate-putamen

What is the function of the nigrostriatal pathway?

- Facilitates voluntary movement

- Parkinson's disease involves loss of DA neurons in the SN, resulting in denervation of the striatum

Mesolimbic pathway

- From VTA to the nucleus accumbens

- Also from VTA to various regions of the limbic system, including the hippocampus (HPC) and amygdala (AMYG)

What is the function of the mesolimbic pathway?

- Projection to NAc - reward learning

- Projection to HPC and AMYG - other functions that include learning, anxiety, and depression

Mesocortical pathway

From VTA to cortical areas

What is the function of the mesocortical pathway?

Aversive learning

DA receptor subtypes (D1-D5)

All are metabotropic, thus they

interact with G proteins

What is the function are D1-D5 receptors associated with?

2nd messengers

What second messengers do D1 & D5 use? Are they excitatory or inhibitory? What G protein do they use?

excitatory; They use cAMP and phospholipase C (PLC); Gs

What second messengers do D2, D3, and D4 use? Are they excitatory or inhibitory? What G protein do they use?

Inhibitory, inhibits cAMP; Gi

D1 subtype

- found in post synaptic cells

- Activate via Gs proteins

Does D1 inhibit or stimulate adenylyl cyclase?

Stimulates adenylyl cyclase and synthesizes cAMP

D2 subtype

- found in post synaptic sites, but also in pre-synaptic sites as autoreceptors

- acts via Gi proteins

Does D2 inhibit or stimulate adenylyl cyclase?

Inhibits therefore reduces cAMP synthesis

What else do D2 receptors regulate?

K+ channels to produce hyperpolarization of post-synaptic cell membranes

What happens if cell membranes hyperpolarize?

Decreases the excitability and firing of cells

What is a non selective drug that affects dopaminergic post synaptic receptors?

Apomorphine

Apomorphine

Agonist that stimulates both D1 and D2 receptors

* causes similar effect to cocaine and amphetamine

What is a D2 selective drug(s) that affects dopaminergic post synaptic receptors?

Quinpirole & Haloperidol

Quinpirole

Selective agonist for D2 and D3 receptors

Haloperidol

Selective antagonist for D2 receptors

*Also suppresses exploratory and locomotor behavior, and catalepsy at higher doses

Where do noradrenergic neurons send axons?

brain, cerebellum, and spinal cord

What kind of receptors are NE receptors?

- also known as adrenergic receptors

- metabotropic: there are two subtypes α & β

what is the mechanism of α2-receptors?

to inhibit adenylyl cyclase and reduce synthesis of cAMP (like D2 receptors)

what is the mechanism of α1-receptors?

to operate via phosphoinositide second messenger system

what is the mechanism of β1 & β2 receptors?

to stimulate adenylyl cyclase and enhance synthesis of cAMP (like D1 receptors)

What are the roles of NE (adrenergic) receptors?

- Behavior functions

- Arousal

- Cognition

- Memory consolidation

- Emotional experiences (Stress)

- Wakefulness

Phenylephrine

- Commonly decongestant

- Selective α1-receptor agonist

Isoproterenol

- Commonly used to treat certain types of heart problems

- Non-selective β-receptor agonist

What role to LC projections to the prefrontal cortex (PFC) play?

Cognitive functions such as attention and working memory

α2-receptor drugs

Clonidine and guanfacine

What do clonidine and guanfacine do in the body?

they activate α2-receptors

- enhances working memory when infused directly to the PFC

What G proteins do α2-receptors use?

Gi to inhibit adenylyl cyclase

What effect do α1 receptor drugs cause when they activate them in the PFC?

activation of α1-receptors in PFC has a deleterious effect on cognitive functions.

What effects do injections of NE itself have on the PFC?

NE injections facilitate PFC and cognitive functions under normal conditions.

Memory consolidation

Common process in the brain to convert short-term memories to long-term

How does NE play an important role in memory consolidation?

Because of the one-trial passive avoidance learning task

What is the one passive trial avoidance learning task?

Commonly used in rats & mice to evaluate memory consolidation for events with emotional / traumatic / aversive meaning.