Lecture 7: Catecholamines 1 Flashcards
Explain Catecholamine Synthesis
Explain Catecholamine Release
Explain Catecholamine Inactivation
Describe the Organization of the Dopaminergic System
Describe the Function of the Dopaminergic System
Describe the processes involved in catecholamine synthesis
Describe the processes involved in catecholamine storage
Describe the processes involved in catecholamine release.
Explain how catecholamines are inactivated using reuptake.
Explain how catecholamines are inactivated using metabolism.
List and explain the clinical uses of drugs that act on catecholamine metabolism.
List and explain the clinical uses of drugs that act on catecholamine reuptake.
Name the major ascending dopaminergic pathways that originate in the midbrain
Identify the locations of the cell bodies and the projection areas of each dopaminergic pathway.
Explain the role of DA in behavioral regulation, using initiation and control of voluntary movement
Explain the role of DA in behavioral regulation using responses to rewarding stimuli
Explain the role of DA in behavioral regulation using cognitive functioning.
What are the members of the family of DA receptors
Describe the family of DA receptors’ various subtypes
Describe the family of DA receptors’ signaling mechanisms
Describe the family of DA receptors’ roles as postsynaptic receptors
Describe the family of DA receptors’ roles as autoreceptors.
Describe the behavioral effects of DA receptor agonists
Describe the behavioral effects of DA receptor antagonists
Describe the physiological effects of DA receptor agonists
Describe the physiological effects of DA receptor antagonists
Describe DA receptor clinical applications
What are catecholamines?
Catecholamines are monamines: a catechol + amine group
What are the different types of catecholamines?
- Dopamine (DA)
- Norepinephrine (NE)
- Epinephrine (EPI)
What are the adjective forms of the catecholamines?
dopaminergic, noradrenergic, and adrenergic
What secretes from the adrenal medulla and what do they act as?
Adrenal medulla secretes EPI and NE into the bloodstream where they act as hormones.
How are catecholamines synthesized?
By a multistep pathway in which tyrosine hydroxylase catalyzes the rate-limiting step
What are catecholamines synthesized from?
tyrosine
What is Tyrosine hydroxylase (TH)
the rate-limiting enzyme
What factor affects TH activity with negative feedback?
DA and NE levels in the nerve terminal
What factor stimulates TH activity?
Cell firing stimulates TH activity through phosphorylation of the enzyme by protein kinases
How is tyrosine obtained?
Tyrosine is obtained from dietary protein, transported from blood to brain
How can catecholamine synthesis be increased?
By administering precursors such as tyrosine or l-DOPA
What is used to treat Parkinson’s disease?
l-DOPA
What is each step of synthesis dependent on?
specific enzymes – dependent on neuron
EX: If neurons use DA as NT, only contain TH and AAAD
If neurons need NE, also possess DBH
What do drugs that reduce synthesis do?
inhibit one of the enzymes
What is the drug that blocks TH?
α-methyl-para-tyrosine (AMPT)
What are the steps in synthesis called?
synthetic pathways
What do synthetic pathways do?
provides a mechanism for regulating the amount of transmitter available for release
What opportunity is possible with synthetic pathways?
to intervene with drugs that alter transmitter synthesis in specific ways.
What catalyzes conversion of dopamine to norepinephrine?
dopamine β-hydroxylase (DBH)
What catalyzes conversion of DOPA to dopamine?
Aromatic amino acid decarboxylase (AADC)
What is catecholamine storage and release regulated by?
vesicular uptake
autoreceptor activity
cell firing rate
What are catecholamines loaded into synaptic vesicles by?
vesicular monoamine transporters (VMAT)
What can VMAT be blocked by?
reserpine (snake root)
What is snake root and what symptoms can it cause?
an irreversible inhibitor; (reduces the amount of NT at the terminal) causes sedation and depressive symptoms
What are reversible inhibitors of VMAT used for?
To reduce uncontrolled movements in Huntington’s disease and tardive dyskinesia.
Where is VMAT1 found?
adrenal medulla
Where is VMAT2?
present in the brain
What do VMAT1 and VMAT2 have in common?
Both can be blocked by reserpine.
What are some reversible VMAT2 inhibitors?
tetrabenazine (trade name Xenazine), deutetrabenazine (Austedo), and valbenazine (Ingrezza)
What makes TH the rate limiting enzyme?
Tyrosine to DOPA by TH occurs slower
What stimulates TH activity?
Neuronal firing
What determines the overall rate of DA or NE formation?
Tyrosine Hydroxylase
What regulates the activity in the neurons of the dopaminergic system?
the amount of DA/NE present at the terminal, negative feedback when high.
What is done to TH by second messengers, what are they, and what do they do?
TH can be phosphorylated by a number of secondary messengers (PKA, PKC, CaMKII). Generally increases the enzyme activity.
How can you increase the formation of TH?
by increasing precursors such as tyrosine and L-DOPA.
What is Tyrosine administration used for?
Enhancing cognitive functions e.g. memory
What is L-DOPA the primary therapeutic agent for?
treating Parkinsons
What does a typical dopaminergic neuron’s membrane possess?
Autoreceptors. When these receptors are stimulated, they inhibit sub¬sequent DA release by the cell.
What are some psychostimulants and what do they do?
Psychostimulants amphetamine and methamphetamine cause release of catecholamines without nerve firing. Lab animals show increased activity.
What type of behaviors occur with high doses of psychostimulants and what are they?
Stereotyped behaviors include intense sniffing, repetitive head and limb movements, and licking and biting.
What are human side effects of psychostimulants?
In humans, drug effects include increased alertness, high energy levels, euphoria, insomnia
What release is impacted by autoreceptors and how?
DA release is inhibited by autoreceptors
What also influences DA release?
Neuron firing pattern
What is the first way neuron firing impacts DA release?
Single-spiking mode: action potentials appear at irregular intervals (tonic release)
What is the second way neuron firing impacts DA release?
Burst mode: trains of 2–20 spikes at higher frequency (phasic release); transmitter release occurring faster than it can be cleared and/or metabolized.
