Chapter 5: Catecholamines

Question 1

What are the major catecholamine transmitters in the brain?

Answer 1

1. Dopamine
2. Norepinephrine
3. Epinephrine (comparatively less major)

Question 2

How are catecholamines synthesized

Answer 2

Catecholamines are synthesized from tyrosine, which is the precursor amino acid obtained from dietary protein and transported from the blood into the brain. The enzyme tyrosine hydroxylase (TH) catalyses the synthesis of tyrosine to dihydroxyphenylalanine (DOPA). Another enzyme, aromatic amino acid decarboxylase (AADC) catalyses the synthesis of DOPA to dopamine. Neurons that use dopamine as their transmitter only contain these first two enzymes. Neurons that use norepinephrine also have the enzyme dopamine B-hydroxylase (DBH) which catalyses the synthesis of dopamine into norepinephrine. Norepinephrine is converted to epinephrine by phenylethanolamine N-methyltransferase.

Question 3

What is the rate-limiting step in catecholamine synthesis?

Answer 3

The first step when the enzyme tyrosine hydroxylase (TH) catalyses the synthesis of tyrosine to dihydroxyphenylalanine (DOPA).

Question 4

How can catecholamine synthesis can be enhanced?

Answer 4

Catecholamine synthesis can be enhanced by administration of biochemical precursors such as tyrosine and l-DOPA, the latter of which is the main therapeutic agent used in the treatment of Parkinson’s disease.

Question 5

How are catecholamines stored?

Answer 5

Catecholamines are stored in and released from synaptic vesicles. Vesicle packaging protects the neurotransmitter from degradation by enzymes in the nerve terminal and provides a means of releasing predetermined amounts of neurotransmitter.

Question 6

How are catecholamines released?

Answer 6

The protein vesicular monoamine transporter (VMAT) transports neurotransmitter molecules from the cytoplasm of the cell into the vesicles. The neurotransmitters are released from the cell through exocytosis when a nerve impulse enters the terminal.

Question 7

How is catecholamine release inhibited?

Answer 7

1. The drug reserpine can block the process of neurotransmitter transport into the vesicles
2. Autoreceptors on cell bodies, terminals, and dendrites of dopaminergic and noradrenergic neurons can inhibit neurotransmitter release by: 1) inhibiting the action of voltage-gated Ca+ channels in the nerve terminal membrane, and 2) enhancing the opening of a specific type of voltage-gated K+ channel in the terminal.
3. The firing pattern of the neuron impacts catecholamine release

Question 8

How are catecholamines inactivated?

Answer 8

1. With reuptake the transporter proteins in the nerve cell membrane take the neurotransmitter back into the nerve cell. Once in the cell, some neurotransmitters are repackaged into vesicles for rerelease, while others are broken down and eliminated.
2. Metabolic breakdown by the enzymes catechol-O-methlytransferase (COMT) and monoamine oxidase (MAO).

Question 9

What are the two important dopaminergic pathways?

Answer 9

1. Mesolimbic pathway

2. Mesocortical pathway

Question 10

Describe the mesolimbic pathway.

Answer 10

The mesolimbic dopamine pathway originates in the ventral tegmental area (VTA) and innervates limbic system structures (nucleus accumbens, hippocampus, lateral septum, amygdala). It is a nerve tract in the central nervous system.

Question 11

Describe the mesocortical pathway.

Answer 11

The mesocortical dopamine pathway originates in the ventral tegmental area (VTA) and innervates the cerebral cortex, particularly the prefrontal cortex. It is a nerve tract in the central nervous system.

Question 12

What are the two major families of dopamine receptors?

Answer 12

1. D1-like receptors

2. D2-like receptors

Question 13

Describe the D1-like family of dopamine receptors.

Answer 13

The D1-like receptor family consists of the D1 and D5 receptors. The D1 receptors stimulate the enzyme adenylyl cyclase which has the effect of increasing the rate of cyclic adenosine monophosphate (cAMP; a second-messenger) synthesis. The D1 receptors have a lower affinity for dopamine than the D2 receptors which means that more dopamine is needed to occupy a given percentage of D1 receptors that is needed to occupy the same percentage of D2 receptors. Phasic release activates the D1 receptors.

Question 14

Describe the D2-like family of dopmaine receptors.

Answer 14

The D2-like receptor family consists of the D2, D3, and D4 receptors. D2 receptors inhibit the enzyme adenylyl cyclase and decrease the rate of cAMP synthesis. Activation of D2 receptors can also enhance the opening of K+ channels in the cell membrane, which hyperpolarizes the membrane and therefore reduces cell excitability. The D2 receptors have a higher affinity for dopamine than the D1 receptors which means that less dopamine is needed to occupy a given percentage of D2 receptors that is needed to occupy the same percentage of D1 receptors. Tonic dopamine release activates the D2 receptors.

Question 15

Define tonic release.

Answer 15

Slow, consistent release of neurotransmitter that is typically associated with single-spiking mode of cell firing. It maintains low but relatively constant extracellular levels of the transmitter.

Question 16

Define phasic release.

Answer 16

Irregularly timed and larger amounts of neurotransmitter release than occurs in the case of tonic release. It is typically associated with burst mode of cell firing and produces surges in extracellular levels of the transmitter.

Question 17

What is burst mode?

Answer 17

Mode of neuronal cell firing characterized by the production of bursts of action potentials. Burst firing causes especially large amounts of the neurotransmitter to be available to postsynaptic cells, primarily because the rate of release is greater than the rate at which the neurotransmitter can be cleared and/or metabolized.

Question 18

Describe the ascending noradrenergic pathway.

Answer 18

The ascending noradrenergic pathway originates in the locus coeruleus which is a small area of the pons that has a dense collection of noradrenergic neurons. These neurons send their fibres to almost all areas of the forebrain as well as the cerebellum and the spinal cord. The locus coeruleus provides almost all of the norepinephrine in the cortex, limbic system, thalamus, and hypothalamus.

Question 19

What do adrenergic agonists do?

Answer 19

Adrenergic agonists stimulate adrenergic receptors. They work by acting directly on the adrenergic receptors or indirectly by affecting uptake of the neurotransmitter at the presynaptic nerve terminal, affecting uptake of the neurotransmitter at the postsynaptic nerve terminal, or inhibiting the enzymes responsible for enzymatic degradation of the neurotransmitter in the synapse.

Question 20

How are adrenergic drugs useful in treating medical conditions?

Answer 20

1. Yohimbine blocks A2-receptors to help with treating certain types of male sexual impotence by increasing parasympathetic activity and decreasing sympathetic activity.
2. Hypertension is treated with the A1-antagonist prazosin and the general B-adrenoceptor antagonist propranolol.
3. Prazosin works by blocking the A1-receptors responsible for constricting blood vessels, thereby causing dilation of the blood vessels.
4. Propranolol works by blocking the B-receptors on the heart which has the effect of reducing the heart’s contractile force.

Question 21

How do terminal autoreceptors function to control the release of catecholamines?

Answer 21

Terminal autoreceptors function by inhibiting voltage-gated Ca2+ channels and enhancing voltage-gated K+ channels in the terminal membrane.

Question 22

What receptor subtype are dopamine autoreceptors?

Answer 22

D2 subtype

Question 23

What receptor subtype are norepinephrine autoreceptors?

Answer 23

Alpha-2 subtype

Question 24

Which enzymes are important in catecholamine metabolism?

Answer 24

1. MAO-A
2. MAO-B
3. COMT

Question 25

What is the nigrostriatal tract?

Answer 25

Neurons in the substantia nigra send their axons to the dorsal striatum, thus forming the nigrostriatal tract. The dorsal striatum is composed of the caudate and putamen.

Question 26

Describe the dopamine receptor types.

Answer 26

Researchers have identified five main DA receptor subtypes, designated D1 to D5, all of which are metabotropic receptors. The most common subtypes are D1 and D2, both of which are found in large numbers in the striatum and the nucleus accumbens.

Question 27

In general, how does dopaminergic function affect behaviour?

Answer 27

Enhancement of dopaminergic function has an activating effect on behavior, whereas interference with DA causes suppression of normal behaviors, ranging from temporary sedation and catalepsy to the profound deficits observed after treatment with a DA neurotoxin such as 6-OHDA.

Question 28

Where in the brain is the most important cluster of noradrenergic neurons?

Answer 28

The most important cluster of noradrenergic neurons is the A6 cell group, which is located in a region known as the locus coeruleus. These neurons innervate almost all areas of the forebrain and mediate many of the important behavioral functions of NE.

Question 29

What do norepinephrine and epinephrine do to the body?

Answer 29

NE and EPI released into the bloodstream as hormones work together with NE released from sympathetic neurons to mediate the physiological reactions that make up the “fight-or-flight” response. These reactions include:

1. vascular changes that direct more blood flow to skeletal muscles, heart, and brain
2. increases in blood pressure, heart rate, and cardiac muscle contractile force
3. respiratory changes that produce increased oxygen intake
4. reduced digestive activity
5. pupil dilation
6. increased availability of metabolic fuels due to liberation of sugar from the liver and fats from adipose tissue
7. decreased secretion of gastric juices and saliva

Question 30

What receptors do norepinephrine and epinephrine work through?

Answer 30

NE and EPI activate a group of metabotropic receptors called adrenoceptors. They are divided into two broad families, α and β, which are further subdivided into α1, α2, β1, and β2. Both β-receptor subtypes enhance the synthesis of cAMP, whereas α2-receptors inhibit cAMP formation.

Question 31

What do β adrenoceptors do?

Answer 31

Both β-receptor subtypes enhance the synthesis of cAMP.

Question 32

What do α2 adrenoceptors do?

Answer 32

1. α2-receptors inhibit cAMP formation

2. stimulate K+ channel opening and hyperpolarize the cell

Question 33

What do α1 adrenoceptors do?

Answer 33

α1-receptors increase the intracellular concentration of Ca2+ ions by means of the phosphoinositide second-messenger system

Question 34

What behavioural functions is the noradrenergic system involved in?

Answer 34

1. arousal
2. cognition
3. consolidation of emotional memories (e.g., related to fear-inducing situations).

Question 35

Explain how norepinephrine affects arousal.

Answer 35

The effect is primarily mediated by pathways from the locus coeruleus (LC) to the medial septal, medial preoptic, and lateral hypothalamic areas. Both α1- and β-receptors are involved in these effects.

Question 36

Explain how norepinephrine affects cognition.

Answer 36

Activation of high-affinity α2-adrenoceptors in the prefrontal cortex (PFC).

Activation of lower-affinity α1-receptors causes a decrease in cognitive function.

Consequently, the relationship between NE release in the PFC and cognition can be described as an inverted U-shaped function: optimum cognitive function occurs at moderate amounts of NE release, whereas either too little or too much release can cause cognitive impairment.

Question 37

Explain how norepinephrine affects memory consolidation.

Answer 37

There are 2 theories:

1. activation of β-receptors on the vagus nerve
2. EPI-mediated elevations in plasma glucose

Question 38

How are adrenergic agonists used therapeutically?

Answer 38

Adrenergic agonists are used therapeutically for various physiological and psychological disorders. These include:

1. the α1-agonist phenylephrine, which helps relieve nasal congestion
2. the α2-agonist clonidine, which is used in the treatment of hypertension and drug withdrawal symptoms
3. β2-agonists such as albuterol, which is an important medication for relieving bronchial congestion in people suffering from asthma.