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

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Basic Neurochemistry:Major Neurotransmitters, Mesolimbic, Metabolic degradation >>

Neurological Basis of Behavior (PSY - 610)

Lesson31

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

Neurotransmitters: synaptic transmission

Synaptic transmission can be divided into several clear cut and major steps these are relatively

independent, however each one step has to occur before the next one can take place

1. Synthesis of the NT and storage in the synaptic vesicles. As we have learnt earlier that the

synaptic vesicles are storage containers where NT is protected from the deactivating enzymes, thus

the synaptic vesicles protect NT from degradation by enzymes in cytoplasm. These vesicles are also

the safe transporters of the NT. Where do they come from? The synaptic vesicles are manufactured

from proteins in the cytoplasm of the cell body by the Golgi apparatus. These then travel down

towards the axonal endings to the synaptic buttons. The packaging for Peptides group of NTs

(which are short chains of amino acids) takes place in the Cisternas in the synaptic buttons (button

or bead like bulbous ends). For the Non-Peptide class of NTs, the packaging into vesicles is carried

out within the cytoplasm, before they are transported down to the axonal synaptic buttons. The

material can be transported in two different directions by the axonal transport system, the

anterograde transport and the retrograde transport.

The Anterograde (forward) axonal transport is a fast track transport mechanism which

moves materials out from the cell body, through the microtubules towards synaptic ending.

The synaptic vesicles go through this rapid system traveling very fast speed of 400

millimiteres per day. (It is like driving in the fast lane). This is known as the fast

anterograde transport.

When materials and synaptic vesicles ooze along the axon in the cytoplasm at a very slow

speed of less than 10 millimeters per day, they use the slow anterograde transport

2. Release of the Neurotransmitter: When the action potential reaches the presynaptic ending it is

translated into a chemical message (remember the neuronsa can communicate in both systems). The

arrival of the action potentials translated using the calcium gated channels. The process is as

follows: The action potential arrives at the terminal button; it leads to the opening of the Calcium

channels. This allows the calcium to get into the button and to trigger the release of the

neurotransmitter. If calcium is reduced in the extracellular space then the amount of NT is also

reduced, and it the extracellular Calcium is increased the amount of NT released is also increased.

Release is identified to occur through a process called exocytosis.

a) The NT vesicles move out towards the terminal to empty contents into the synaptic cleft,

b) The NT vesicles fuse with presynaptic membrane, at contact the membrane opens up and NT

molecules are released into the cleft.

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c) The vesicle merges as part of the pre synaptic membrane, and the ruptureor the break in the

membrane eventually mends

Generation of the post synaptic potential: this means action at the receiving end at the post

synaptic potential after the NT molecule is received. When the NT molecule crosses over the

synaptic cleft (it is like crossing over a river full of alligators!) and gets transferred to post

synaptic membrane for action. There are several processes which would now take plce at the post

receptor sites

a) Binding of NT molecules to post receptor site. All molecules released would rush to reach

and enter the postreceptor sites, the entry requires that they must connect or "bind" chemically

with the membrane site (a receptor protein). The membrane is very specialized with a particular

configuration therefore only those which resemble that shape and chemical composition would

bind these sites. This means the gates would open to allow only specific molecules to enter

b) Changes in ionic gates: The NT molecule leads to changes in the chemically gated ionic

channels in the receptor membrane for further action either through the direct or the indirect

method,

i) The direct method: The binding of the NT to a receptor can directly open or close the

chemically gated channels in the areas surrounding the membrane (to make it more permeable) or

ii) a series of chemical changes can take place in the molecules in the cytoplasm which can bring

about a change in the status of the of the chemically gated ions channels of the postreceptor site.

These changes take place in chemicals/molecules (2nd messenger, Cyclic Adenosine

MonoPhosphate which is involved in conversion of Adenosine triphosphate to CAMP through

enzymes. Note: the Cycic AMP is needed for the energy in the cell for action). The second method

uses classof molecules which are called the 2nd messenger (because they are the ones which

intervenes the messages and translate further action). The effect of CAMP is brief...

Action in the Post Receptor membrane: In the post synaptic membrane, there are two kinds of

actions that can take place, either an excitatory post synaptic potential (EPSP) or an Inhibitory

post synaptic potential (IPSP'). The EPSP's generate an action potential in the post synaptic

membrane,and the IPSP's inhibit ongoing activity in the cell membrane. Both of these actions

depend on a) the type of NT involved, i.e. some NT's are classified as excitatory NT's and some

are classified as inhibitory ( such as GABA), and , b) the site at which the action is taking place.

The NT action may be excitatory at some sites and inhibitory at other sites, as some NT is

excitatory at one site and inhibitory at another.

Inactivation of the NT: What happens to an NT if it is released from the vesicles

a) It cannot stay in the neuron, or in the cleft,

b) It cannot keep activating the post synaptic membrane (otherwise one single dose of amphetamine

stimulant can last a life time!!!),

c) It cannot continue to stay in the cleft and keep the site full of molecules. This would clutter the cleft

and the sites. The NT has to be removed or degraded so that the systems remain efficient and

clean.

There are two well documented processes by which neurotransmitters are deactivated:

Reuptake: By this mechanism the NT can return to the presynaptic areas and be taken in for

recycling and use. The reuptake processes allows the presynaptic area to reuptake and absorb

the molecules back. These are then repackaged into the vesicles and used

Deactivating: The active chemical state or composition of the NT is deactivated by chemicals/

enzymes which are specialized to do this job. These enzymes locate free floating unprotected

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NT molecules in the synaptic cleft (and also in the presynaptic areas) to degrade them and then

so that they are excreted out of the cleft. Imagine that these are like the little Pac men running

after the little molecules.

6. Recycling of the vesicular membrane: The vesicles which had ruptured are recycled. When many

synaptic vesicles release molecules after fusing with the presynaptic membrane and the process of

exocytosis, the terminal button gets swollen with so many left over vesicles. Then the pieces of excess

are broken off and returned to cytoplasm. There these may be used again as packaging material in one

of the following forms;

a) They may be filled with non-peptide NT by the cisternas.

b) They may be sent back to the cell body by the retrograde transport (traveling at the rate of 200

millimeters per day.

c) They may be refilled with NT by the golgi bodies in the cell soma

d) They may be broken down and molecules recycled.

Methods of Locating NT:

Apart from the many given techniques of neuroanatomical tracing the following techniques are

especially used for the NT localization identifying their sites and their projections.

1. Histoflouresence Technique: This was developed by Falck and Hillarp around the early

1960's. In this technique the monoamine group of NT's when exposed to formalin fixative

glow when exposed under a flourecent light. This technique was useful in locating the various

monoamines, their sites, their systems. However, this is none specialized as it does not

differentiate between various NT within the class of monoamines.

2. .Receptor Binding Autoradiography: The NT are radiolabelled with a radio active isotope

(Hydrogen3 or carbon3) Then the neural tissue is exposed to the labeled ligand (molecule that

binds to a target). We can also inject this directly into the brain and expose the slices for a

longer period after decapitating the animal head and slicing the brain tissues. The slices are

exposed to a photographic plate which reacts to radioactivity and high radio active areas show

up in the plates.

3. Monoclonal Antibodies: These involve immunocytochemistry procedures. Just as the

lymphocytes secrete antibodies, and hybrid lymphocytes and bone marrow cells secrete

antibodies and subdivide. We can use this same process to identify antibodies for particular

proteins (remember all NTs are chains of amino acids). Specific monoclonal antibodies are

developed and injected and they identify specific regions and target proteins.

4. Microiontophoresis (push pull cannulae). This procedure analyzes the chemicals being

released within the synapse. The response of the postsynaptic sites is monitored using a double

barreled pipette. The tip of the inner pipette (contains saline) is inserted into the postsynaptic

membrane to record intracellular voltage. Weak current when passed to stimulate the neuronal

ending leads to a discharge which is then pulled out for analysis, and also checked at the

oscilloscope for EPSP's or IPSP's

Major Neurotransmitters:

There are a large number of neurochemicals which have been classified as neurotransmitters; there are

six (6) major groups, and within each group there are several independent neurotransmitters which have

specific actions. These major groups are as follows:

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Neurological Basis of Behavior (PSY - 610)

1. Amino acids: These are neurotransmitters which are formed from chains of amino acids, the

basis of proteins. In this group the major NT's are Glutamate, Gamma aminobutyric acid

(GABA), Glycine (gly), and aspirate. This is the largest group with relatively quick acting

synaptic connections. Glutamate is excitatory, while GABA is known as the inhibitory

neurotransmitter.

2. Monoamines I: Catecholamines: This group of neurotransmitters is synthesized from a single

amino acid; therefore this is called mono (single) amine. The monoamines modulate a wide

range of behaviors. The neurons of monoamines have little bulbous bead-like knobs throughout

the length of the axons, through which the NT appear to seep out. This particular group of

Monoaminesis called catecholamines because they have one catechol group. The

catecholamines are Dopamine, Norepinephrine (also known as Noradrenaline) and Epinephrine

also known as Adrenaline.

3. Monoamines: Indoleamine: This also belongs to the monoamine group, but has a different

structure attached to the amine group, the indoleacetic acid. The Indoleamine NT is known as

Serotonin

4. Soluble gases: These are small molecule NT. These follow a different mechanism of

transmission. Since they are lipid soluble they diffuse through the cell membrane into the

extracellular space to pass into the other cells. They work through 2nd messengers and break

down immediately after action. Nitric acid and Carbon dioxide are two which have been

discovered so far.

5. Acetylcholine: a small molecule transmitter,one of its kind--there are no other NT's in this

group. This is the only NT which works on the neuromuscular joints

6. Neuropeptides: a large number of peptides (chain of 5 molecules) floating around in the

brain- and are possible candidates for NT status. Among the well known are the brain opioids,

the Endorphins ( large molecules) and enkaphalins ( small molecules), the pituitary peptides,

Substance P and many others

www.chemistryexplained.com.NE-NA.Neurotranmitters

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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 Biochemcial basis of neuropharmacology 5th Edition, OUP

Pharmacology, Biochemcistray 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.

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