Basic Neurochemistry:Major Neurotransmitters, Mesolimbic, Metabolic degradation

<< Basic Neurochemistry:Changes in ionic gates, The direct method, Methods of Locating NT

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

Neurological Basis of Behavior (PSY - 610)

Lesson32

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 Neurotransmitters:

Catecholamines: Dopamine

Dopamine (DA) a major catecholaminergic neurtotranmitter was discovered by Udenfriend in 1964.

This is the first step in the synthesis chain of the Adrenergic ( also known as Epinephrine) and

Noradrenergic (also known as Norepinephrine) NT systems, however, this was the last to be given the

status of an NT, because DA was thought to be only an intermediatary step in the synthesis of

Norepinephrine. Dopamine has been found to have a major influence on behavior, especially motor

behavior and schizophrenia. These chemical are also found in the body, in the adrenal glands and used

in the sympathetic action in emotional states; however, whatever is produced in the body cannot cross

the blood-brain barrier to get into the brain. The brain is very well protected (as you have seen in the last

module). In order to keep the environment sterilized, the brain manufactures all the chemicals it needs

from the precursors (the first compound in the chain, which can then be acted upon by enzymes). The

precursors are taken in from the blood circulation.

The Synthesis chain of DA, NE and E begins with tyrosine (we will discuss this in detail later.

DA has two types of receptors in the brain the D1 and D2

D1.are linked to the stimulation of the adenylate cyclase. These are present in thew Corpus Straitum and

the Butrypheneones (a class of drugs known as neuroleptics, anitpsychotics) are weak antagonist for

these receptors.

D2. These are linked to the inhibition of adenylate cyclase. These are present in the pituitary and the

Corpus striatum. The Butryphenones are potent antagonists for these receptors

DA Pathways: There are three major pathways of this system

1. The Nigrostriatal DA system. This is largest and longest bundle of fibers of neurons containing DA.

This is a major tract which has 80% of brain's Dopamine It originates in the Zona Compacta of

Substantia Nigra and sends projections to the Corpus Striatum. The degeneration of this systems leads to

Parkinson's disease (a major motor disorder in which voluntary movements become increasingly

difficult and there are only some stereotypic movements seen). This is also involved in schizophrenia.

Reduced levels of DA in this system lead to Parkinson's disease and increased levels lead to

schizophrenic symtoms.

2. Mesolimbic: This is a medially located diffuse (wide spread out projections) systems. This system

sends out nerve fibers which go out to the forebrain areas such as frontal cortical area, the cingulated

cortex, the amygdale and the septum. As the names implies this is involved with the limbic system

116

Neurological Basis of Behavior (PSY - 610)

(emotional system). The anti psychotics drugs act here to reduce the apathy and lack of affect

(emotional content) which is characteristic of schizophrenia.

3. Tuberoinfundibular: This is also known as the hypothlamic hypophyseal connection. It originates

from arcuate and periventricular regions of hypothalamus, and there are very short fibres which end up

in the intermediate lobe of the pituitary. This appears to play a role in the hormonal controls and

modulations.

Dopamine is also found in other areas in the brain

Synthesis Pathway. As a rule it must be remembered that the brain manufactures its own

neurochemicals including Dopamine from the precursor taken in from the blood supply (circulatory

system).

1. Phylalanine which is taken in from food and is immediately hydroxylated (add a hydroxyl molecule)

by the enzyme phylalanine hydroxylase to convert to Tyrosine

2. Tyrosine: tyrosine is then immediately hydroxylated by tyrosine hydroxylase. This is known as the

rate limiting step (and is sensitive to pharamoclogical manipulations), we can control the amount of DA

(as well as NE, and E) manufactured in the systems. This hydroxylation leads to the formation of DOPA

3. Dopa: This is similar to a drug known as L-Dopa, effective in the treatment of Parkinson's. Dopa is

then decarboxylated (removal of the carboxyl molecule) by the enzyme dopa decarboxylase, to form

Dopamine

4. Metabolic degradation:

a) Dopamine is then metabolized by Monoamine Oxidase (MAO) which converts monoamines to

aldehydes to make them inactive. Monoamine oxidase is not specific for dopamine, but acts on all mono

amines NE, E, and serotonin. This is found in the presynaptic region.

b) COMT- catechol O methyl transferase, acts to transfer the methyl from the catechol molecule to

deactivate it. This is found in the synaptic cleft as well as the presynaptic areas

117

Neurological Basis of Behavior (PSY - 610)

http://tcw2.ppsw.rug.nl/~vdbosch/pd.html#Heading18

Pharmacological interventions: Step where DA synthesis pathway can be blocked or altered

It is clear that pharmaceutical substances/ drugs act in the central nervous systems through the

neurchemical systems.

Agonists: are drugs that copy / mimic the action of the neurotransmitter or have similar effect as the NT

or have an excitatory effect on the NT systems.

Antagonists: are drugs that block, inhibits or in any way opposes the action of the NT.

Drugs: or exogenously administered substances can affect the NT pathway at various levels

a) They can act directly on neurons containing the NT

b) They can act on various points of the synthesis pathway the pre-post receptor site

c) They can act on the inactivating enzymes in the cleft or within the presynaptic area.

Steps where drugs can interact in the synthesis pathway

Step 1. This is first step in the precursor transportation pathway within the neuron. Phenlalanine has to

be hydroxylated to form tyrosine which would then be available for the synthesis into DA. However,

this conversion can be blocked as in the case of the genetic disorder PKU (phenylketunuria) where

Phenylalanine is build up and transforms into toxics which damage the brain cell. The PKU buildup

blocks the transport of both tyrosine and tryptophan in the brain. Therefore no tyrosine, no DA!

Step 2: This is where the enzymatic synthesis of Dopamine begins. Tyrosine is the first amino acid in

the chain of metabolism of catecholamines and is the most susceptible to blockade. The hydroxylation

action can be blocked by A-Methyl Para Tyrosine (AMPT) which methylates the tyrosine (instead of

hydroxylation). This reduces the level of Tyrosine available, which then leads to reduced Dopamine,

Norepinephrine and, Epinephrine. AMPT is effective in reducing catecholamine levels in the brain.

Step 3: Conversion of DOPA into dopamine by dopa decarboxylase can be blocked by a false enzyme

A-methyl dopa. This enzyme competes for DOPA and uses it so that it cannot be converted in the

correct form in order to become dopamine

118

Neurological Basis of Behavior (PSY - 610)

Step 4: Storage vesicles: The storage vesicles are packed with Dopamine. Reserpine, a drug

manufactured from Rauwolfia Alkaloids is classified as a major and long lasting tranquilizer. Reserpine

ruptures all vesicles irreversibly and the contents get spilled out into the presynaptic area where they get

deactivated if they do not get out into the synaptic cleft. These vesicles cannot be repaired till new

vesicles are manufactured; therefore no DA molecules can store. Another drug, Tetrabenazine also

opens up the vesicles and blocks reuptake of DA into the vesicles. However, this is not irreversible as

the vesicles are not ruptured only opened up.

Step 5. This is where the release of the Nt for the presynaptic ending, and the reuptake back form the

synaptic cleft can be blocked. The drug Amphetamine (a stimulant) releases and blocks the reuptake of

DA for a prolonged agonistic action. Similarly, Cocaine (another stimulant, and street drug) and

Tricyclic group of antidepressant also block reuptake of DA, NE

Step 6. Action within the neuron, axonal ending and the synaptic cleft. The deactivation process can

be blocked by drugs which block action of MAO. The drug Pargyline, and MAOI, can increase amount

of DA available by blocking the deaminating process (blocking the blocker!).

Step 7. The post receptor site-can also be blocked or stimulated. Apomorphine is a DA receptor

stimulant at pre and post receptor sites and thereby increases the levels of DA available for action.

Haloperidol which is a potent antipsychotic drug is a DA blocking agent.

Therefore drugs can be used to modify the action of the neurochemcicals at the various sites of synthesis

pathways.

DA and Behaviors

The behaviors that are affected or modulated by the DA systems would be discussed in details

Dopamine and Motor Activities:

SN and Corpus Striatum. The Dopaminergic Nigrostrial system is atypical in the CNS format that SN

fibers do not cross over to the contralteal hemispheres i.e. they remain on the same side of the brain.

This system innervates the extrapyramidal structures (the basal ganglia) which controls motor behavior

at the sub cortical level.

A) Damage to SN leads to Parkinson's disease. This was first discovered by pathologists who reported

that the SN of Parkinson's patients was pale as compared to normal brains. The dopaminergic neurons

in Substantia Nigra have dark pigmentation; therefore the pale SN indicates damage to the DA neurons.

Thus, reduced levels of DA in SN leads to Parkinson's symptoms.

Logically it can be assumed that if we inject dopamine in these patients we should see a reduction in

Parkinson's symptoms. This is exactly what happens if we increase levels of Dopamine by injecting

Dopa (or L-Dopa) in SN.

B) Evidence that rats injected with 6-OHDA a toxic agent which selectively damages only the DA

pathways and neurons by retrograde transmission, exhibit the same symptoms as in Parkinson's

(rigidity, tremor, etc). This also indicates that DA is involved in Parkinson' as well as motor behavior

C) If DA levels are increased in animals or humans by injections of L-Dopa, it leads to stereotypic

(repetitive) motor behavior. The stereotypic behavior is a symptom of higher than normal levels of DA

in the brain. In rats we see repeated running back and forth, or grooming their faces with their paws or

any other motor activity. Stereotypic behavior is also seen in human Parkinson's patients who are

treated with high doses of L-Dopa. Furthermore, apomorphine and amphetamine (both strong agonists

of DA) at high enough doses lead to stereotypic behaviors.

119

Neurological Basis of Behavior (PSY - 610)

D) Injections of Haloperidol& Chloropromazine (anti psychotic drugs which block DA activity) block

the stereotypy induced by the amphetamine injections. This means the following:

Increase DA by amphetamine-> Stereotypy,

Block DA.by Haloperidol-> Reduce Amphetamine induced stereotypy

E) Unilateral lesions of 6-OHDA lesions lead to a symmetry in body postures that is the body becomes

lopsided. The body turns from the side with high DA to the side with low DA. This lopsided body

posture is exaggerated by amphetamine and apomorphine (Ungerstedt et al, Najam 1980). So if we

lesion the right side, the body turns from left to right (right side has lost its DA) On the other hand,

unilateral electrical stimulation in the intact brain also lead to same kind of body asymmetry. If we

stimulate the right side, then the posture would be lopsided from right to left. The body Postural

asymmetry is from side with more DA to the side with lesser DA

F) Bilateral Lesions with 6-OHDA lead to a compelte reduction of DA in the brain. Animals with

bilateral lesions do not eat, (aphagia) drink (adipsia), and cannot survive. They recover feeding only is

forcefed.

Dopamine and Depression

It is very well researched that Antidepressants such as Monoamine oxidase inhibitors (MAOI)

and the Tricyclics both increase the levels of DA

Alpha methyl para tyrosine (AMPT) if injected reduces both the NA, DA levels in the brain. If

we then inject MOAI, there is reduced effectiveness of the anti depressives effect of MAOI.

This indicates that some levels of DA is needed in the brain (However, evidence indicates that

these have greater interaction with NA than DA (Desipramine an antidepressant has no effect on

DA neurons, and Tricyclics also greater interaction with NA).

Dopamine and hyperactivity

Hyperactivity is due to increased levels of dopamine in the brain. This is also seen with injections of

Amphetamine and apomorphine.

The market drug "speed" is actually amphetamine, which users take to feel tireless and increased

energy and euphoria (I can conquer the world feeling!)

Dopamine and Schizophrenia

There is strong evidence that DA is involved in Schizophrenia.

a) Drugs which are effective in treatment of schizophrenic symptoms are strong DA blockers. The more

effective the drug is as a DA blocker, the greater would be its anti psychotic potency/efficacy in

treating the symptoms.

b) The greater the efficacy of treatment (reducing DA) the greater the side effect of extrapyramidal

symptoms (Parkinson's like tremor, rigidity). The extrapyramidal symptoms such as body tremors

appear because DA is decreased postsynaptically. The DA synapses are blocked by these

antipsychotic drugs such as Phenothiazines (largectil and haloperidol: haldol)

c) The patients of Parkinsons when treated with L-Dopa start exhibiting symptoms of schizophrenia- as

a side effect of the treatment

e) Chronic users of amphetamine end up with symptoms of paranoid schizophrenia

120

Neurological Basis of Behavior (PSY - 610)

Therefore DA is important in a wide range of behaviors, from motor activity to schizophrenia

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

8. Cooper,J.R, F.E Bloom,and R.H Roth (1996) Biochemcial 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 2, 3, 4, 7 more closely followed in addition to the references cited in text.

121

Table of Contents: