Basic Neurochemistry:Norepinephrine/ Noradrenaline, NA synthesis, Noadrenergic Pathways

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Neurological Basis of Behavior (PSY - 610)

Lesson33

Basic Neurochemistry

Objectives:

To familiarize the students with the

Various NT and their role in the modulation of behaviors

Classification of Neurotransmitters. Monoamines: Catechoalimnes

and

Indolemaine,

acetylcholine, amino acid, and Peptide

Neurotransmitters role in modulation of behaviors and Aberration

Drugs and Behavior:

Classification of Psychopharmacological substances

Behavioral correlates, Treatment:

Mechanism of synaptic transmission

Major neurotransmitter: Catecholamines

We have already discussed one of the catecholamines, Dopamine which is first in this chain of

synthesis. Dopamine is the preceding step in the synthesis of Norepinephrine NE, (also known as

Noradrenaline NA, which is the abbreviation used in this section)

Norepinephrine/ Noradrenaline

One of the major neurotransmitters of the brain this NT fall under the general category of monoamines,

further categorized as catecholamine because of its chemical composition. In this system synapses are

known as noradrenergic synapses, NA is found in various parts of the brain as well as the autonomic NS

(in the hypothalamus and the mid brain) in the Peripheral nervous system ( very important role in the

sympathetic functions and hormonal releases : readiness for fight or flight) and at the adrenal glands.

This is involved in a large number of behaviors with a wider influence as compared to DA. The

involvement in mood, emotional states, motivation (hunger, thirst, fight/ flight etc) dream, rewards

(learning), sleep alertness and wakefulness is well documented.

NA originates from a small group of neurons located in the back part of the brain and project by sending

fibers and axons to widespread region of the brain. This is why it is involved in so many behaviors.

The Noradrenergic synapses lead to Inhibitory Post Synaptic Potentials in the Central Nervous System

and Excitatory Post Synaptic Potentials in the Autonomic Nervous System (which includes the

sympathetic nervous system), and the target organs ( such as the heart).

The Noradrenergic neurons do not release NT from terminal buttons (as other NT's do) instead of it

they release NA through the axonal varicosities, which are beadlike swelling of axonal branches. The

varicosities give the axonal branches of NA neurons the appearance of beaded chains or like a necklace

of beads). NA is synthesized or manufactured in the adrenal medulla and the brain from DA. Remember

that the brain manufactures all NT's, and therefore NA also independently. Even though large amounts

of NA is manufactured and used in the body, it can not cross the blood-brain barrier to enter the brain.

NA synthesis

1. Synthesis: This is a simple one step process for transforming Dopamine into NA. Dopamine is

hydroxylated by Dopamine B-hydroxylase. This enzyme was discovered in 1960 in the adrenal medulla,

and this is the same enzyme which acts on DA in the brain. The synthesis from DA to NE takes place

within the vesicles (unlike other NT's where this is carried out in the cell body).

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2. Dopamine is hydroxylated by Dopamine B-hydroxylase, to form Noradrenaline. This hydroxylation

process can be blocked by Disulfiram. The blockade leads to a buildup of DA (since the tyrosine is

being converted to Dopamine) at the same time this reduces NE levels in the neurons, and therefore in

the brain.

3. Deactivating Norepinephrine by MAO and COMT leads to following:

The metabolite after the breakdown of NE occurs in two ways

a) It forms the Vanylmandellic Acid (VMA), a metabolited which is found mostly in the body, very

little in the brain (as it is excreted quickly).

b) The MHPG, a glycol derivativethe (abbreviation of 3 methoxy-4 hydroxy phenylglycol). This

metabolite is found that in stress there are increases in amounts of MHPG in the locus coerelleus.

Noadrenergic Pathways

There are two major pathways of NA the Dorsal bundle and the Ventral bundle with several pathways

projecting in each one of these. The pathways are known as a 1, 2,4,5,6, and 7. All these originate in the

lower brain areas and ascend to the cortex i.e. they originate in the Pons and the medulla and ascend to

the cortical areas, the limbic systems and the hypothalamus.

The A 6 comprises of the dorsal bundle which originates in one area, the locus coerelleus located on the

ventral areas of the ventricles, and sends out diffuse innervations to cerebellum-cerebral cortex and

hippocampus through the Medial Forebrain Bundle (MFB). This therefore is involved in sleep,

awakening, moods, neuro endocrinal functions and temperature regulation.

The A 1, 2, 4, 5, and 7 are the various points or locations from where the ventral bundle originates in the

pons, medulla and innervates the brain stem and the hypothalamus

The ascending fibres of A 5 and A 7 project to the cortex, hypothalamus and are part of the limbic

system (hippocampus and septum

whereas the descending fibers go down

into the spinal cord

Receptors. There are types of NA

receptors identified by their sensitivities

to various drugs: the Alpha receptors and

the Beta receptors

a) Alpha1 and Beta 1 are found mainly in

the post receptor membranes

b) Alpha 2 is primarily presynaptic

autoreceptors (these emerge out of the

presynaptic membrane area to monitor

and control the levels of the membrane

by a self inhibiting action). It is like the

one hand of the same person holding the

other hand (for support and for control)

c) Beta 2 receptors are found in the CNS

but are associated with glia cells,

muscles, and walls of blood vessels.

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Receptor

A1- these receptors are located post synaptically on blood vessels and in the spleen and peripheral

tissues: Prazosin, Indoramin selective antagonists which work near the heart. So these receptors carry

the commands of the brain directly to the organs

A2  these receptors are located on presynaptic nerve terminals in the periphery (not in the brain):

Yohimbine is a selective antagonist (stops/blocks action of NA) and clonidine is selective agonist.

These receptors are also located in the pancreas.

B1: these receptors are linked to stimulation of adenylate cyclase. These are found in greater numbers in

the heart and cerebral cortex. Epinephrine and NE potent agonists. The presence of these receptors vary

a lot in the brain region

B2: These receptors are linked to the stimulation of adenylate cyclase. This is found in high

concentration in the lungs and the cerebellum. For these receptors E is more potent than NE. The drug

salbutamol is a selective agonist

Steps in NA synthesis where drugs can modulate action:

As discussed earlier we saw that there were drugs which interacted specifically with the DA synthesis,

in the same way we will see how drugs interact and modify the working of the NA synthesis process.

Step 1. Enzyme Synthesis

a) The first step where this neurotransmitter can be modified is at the level of sysnthesis of Tyrosine.

The hydroxylation of Tyrosine by Tyrosine hydroxylase can be effectively blocked by Alpha Methyl

Para Tyrosine AMPT: This is the same process as in Dopaminergic synthesis. Since Tyrosine is the

precursor for both DA and NA therefore this is the rate limiting step for NA as well. Reducing available

Tyrosine by AMPT would reduce both DA and NA

b) The second step in the enzymatic synthesis is where Dopamine B- hydorxylase action on dopamine is

blocked by a substance known as Disulfiram, and another drug labeled as FLA-63. Both allow a buildup

of Dopamine but conversion to NA cannot take place as this is blocked by the drugs

Step 2 Storage vesicles: The two drugs which interfere with the storage vesicles are Reserpine, and

Tetrabenazine. Reserpines effects on the storage vesicles are long lasting- thereby the effect on NA is

also longlasting. Further, the storage vesicles are irreversibly damaged, and forming new one take time.

Tetrabenazien also interferes with the storage vesicles, but this is neither long lasting nor irreversible

effect.

Step 3. Release: The release of NA is affected by Amphetamine which increases the release of NA

molecules from the presynaptic area, and also blocks reuptake for enhanced and long lasting effects.

Step 4. Post receptor site interaction: This involves interaction at the post receptor sites. This could be

agonistic- meaning that they stimulate these sites, or antagonistic when they block these sites. The drug

Clonidine is very potent receptor stimulant (agonist), and Phentolamine is an A- blocking agent, and

Sotalol a B-blocking agent

Step 5: Reuptake: The action of NA molecules can be stopped by their reuptake into the presynaptic

area (and back into the vesicles). The drug Desipramine belonging to the tricyclic antidepressant group,

acts through blocking reuptake of the NA molecules (thereby enhancing NA levels in the synaptic cleft)

Step 6. The NA or DA molecules floating in the presynaptic area are degraded or broken down into

inactivated forms by MAO. This degradation by MAO blocked by the MAO inhibitors (which inhibit

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the action of inhibitor) leads to an increase in its levels. The antidepressant drug Pargylin is a potent

MAO inhibitor it acts to block MAO action.

Step 7: Norepinephrine can be inactivated by the enzyme COMT in the synaptic cleft. The drug

Tropolamine blocks COMT action.

(From Cooper Bloom and Roth pages 180-182).

Thus we have seen the steps in the synthesis of NA which can be modified by drug action. These drugs

are mainly psychotropic drugs (act on the psychological states).N

NE and Behaviors:

We will now proceed to discuss the behaviors which are affected, modified changed or controlled by

Norepinephrine /Noradrenaline

Arousal:

The behavioral arousal and arousal of electrical activity in the brain is correlated with Increases in NE

by MAOI. Thus Momonamine oxidase inhibition leads to an increase in available NA which leads to

increases in arousal as seen in behavioral excitation and EEG activity. Furthermore, in states of stress

NA levels are also increased. In states of stress where a person cannot go to sleep (stays awake for long

periods because of stress), the NA levels are also increased in the brain. It is clearly only NA

involvement (No DA involvement- complete depletion of striatal DA still leads to waking and

sleeplessness)

If NA is injected intraventrically (directly into the brain) also leads to behavioral excitation. This means

that increases in NA leads to a state of arousal, excitation, and increased activity.

NA: Conditioned Avoidance

There is evidence that NA is involved in conditioned avoidance in the learning and conditioning

paradigms. If we inject Reserpine (which ruptures the vesicles to spill out the NA molecules) and also

Alpha Mehtyl paratyrosine to block any further synthesis of tyrosine (and DA and NA) we find

complete abolishment of a learned conditioned avoidance of electric shock. (The animal had earlier

learned to avoid shock, but with no NA the response is gone). Thus this shows that NA plays an

important role in avoidance behavior. How? Through either the reward and punishment mechanisms or

through the learning and memory centers being affected.

How do we make sure that it is only decreases in NA which leads to this response? If we give

Disulfiram or FLA-63 which will increase DA but decrease NE by blocking the synthesis of NE. we

also abolish the learnt avoidance response.

Thus we have seen that NA is an important NT and is involved in a wide range of behaviors.

References:

1. Kalat J.W (1998) Biological Psychology Brooks/ Cole Publishing

2. Carlson N.R. (2005) Foundations of Physiological Psychology Allyn and Bacon, Boston

3. Pinel, John P.J. (2003) Biopsychology (5th edition) Allyn and Bacon Singapore

4 Bloom F, Nelson and Lazerson (2001), Behavioral Neuroscience: Brain, Mind and Behaviors (3rd

edition) Worth Publishers New York

5. Bridgeman, B (1988) The Biology of Behaviour and Mind. John Wiley and Sons New York

6. Brown,T.S. and Wallace.(1980) P.M Physiological Psychology

Academic Press New York

7. Seigel, G.J. (Ed. in chief) Agranoff, B.W, Albers W.R. and Molinoff, P.B. (Eds) (1989) Basic

Neurochemistry: Molecular, Cellular and Medical Aspects

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8. Cooper,J.R, F.E Bloom,and R.H Roth (1996) Biochemical basis of neuropharmacology 7th Edition,

OUP

9. Pharmacology, Biochemistry and behavior

(Additional references for the module: Iversen and Iversen, Gazzaniga, Bloom, and handouts)

Note: References, 3, 8, 9 are more closely followed in addition to the references cited in text.

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