Basic Neurochemistry:Neurochemicals, Neuromodulator, Synaptic cleft

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Neurological Basis of Behavior (PSY - 610)

Lesson30

Basic Neurochemistry

Objectives:

Familiarize the students with the Neurochemicals,

Definition, techniques to study Neurochemical classification Neuromodulators, neurotransmitters,

neurohormones.

Criterion for NT, The process of NT transmission.

Processes and Interaction within and outside the cellular membrane:

Main purpose:

The main purpose of this lesson is to study the

Types of Neurochemicals: including Neurotransmitter, neuromodulators, neurohormones .

Criteria of an NT, Processes of NT transmission from synthesis to degradation

Importance of neurotransmitters in modulating behaviors and Aberration

Drugs and Behavior.

Interaction of Neurotransmitters and Drugs., effect of drug at various sites in the neurons, the

NT transmission

Neurochemicals

NeuroChemicals are defined as the chemicals found within the brain, most of them are either

manufactured within the brain or are transported to the brain through the blood circulation. These

substances needed for biochemical metabolism of cells, ionic movements, enzymatic action, changes in

metabolism, neural communication and other mechanisms for support of activities within the nervous

system. All neurochemicals have three main characteristics, a) these must be substances with

demonstrated electrophysiological activity i.e. changes in electrical/ physiological potential of the

neurons and therefore can e measured as changes in the brain areas) These are found only in the CNS or

found in very high concentrations in the CNS as compared to the other areas of the system, and, c) Any

changes in their concentration levels would lead to changes in the brain and behavioural states.

We can classify the neurochemicals into four major categories based on their chemical composition,

their roles and their functions. These are the neuromodulators, neuroregulators, neurohormones and

neurotransmitters.

Neuromodulators. These act to modulate ongoing action within the neuronal systems.

Neuroregulators: These substances regulate on going action act as as 2nd messengers in neuronal

transmission. They support the ongoing transmission by acing as a gating channel (calcium gated

channels)

Neurohormones: These are secreted by the pituitary and hypothalamus, and these hormones act during

the regulation of motivational and other states (circadian rhythms, stress) to influences hormonal levels

and thereby influence behavior.

Neurotransmitter: These are substances involved in the transmission of neural messages. There are

many neurotransmitters which have been discovered so far and their influences on behaviors well

known. The neurotransmiter first to be identified was Acetylcholine, (Ach) which acts on the

neuromuscular joints.

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There were three major breakthroughs in the early 1950's/60's

The discovery of the monoamines serotonin, dopamine, epinephrine (monoamines) in the brain.

These were made by a group of European researchers (Sweden, UK, and Italy) and in the US. In

1950's, 60's brains of patients suffering from Parkinson's disease were seen in post mortem to have

degeneration of a specific area, the dopaminergic rich areas. Then those patients of Parksinon's who

were given L-Dopa (dopamine stimulant) had a remarkable reduction in Parkinson's like symptoms.

This led to the discovery that this Dopamine is important in the Parkinson's disease. See the film

The Awakening

Biochemical procedures for examination of putative NT's were developed. These were sophisticated

techniques such as spectrophotoflourescence which made the investigations into the neuronal

processes possible.

Increased interest after the manufacture and use of reserpine form rauwolfia alkaloids, and

chloropromazine for treatment (by Roche) and of Lysergic acid diethylmide (LSD), mescaline,

marijuana for recreational purposes. The last three were the drugs which beamce the drugs of choice

for the hippies and the flower children of the 60's and 70's.

These breakthroughs opened the doors for investigating neurotransmitters further and it has been

shown in the last two decades of the 20th century that a large number of brain chemicals are

candidates for neurotransmission. Further, complex chemical interactions are discovered with every

new technique which can expand the researcher's ability to search microscopically.

Putative Neurotransmitters are those which are suspected as/ possible Neurotransmitters (NT). There is

strong evidence to suggest that status, but these NeuroChemicals have yet to complete the criterion of a

NT. These are some 50 neuropeptides (such as brain opioids: endorphins) which are still waiting to be

verified. Simialrly, some aminoacids and other chemicals which are found in the brain may be NT,

depending upon how well they clear the conditions laid down for the NT status. There are several

stringent conditions which are laid down for NT status, these we will discuss in details a little later.

Psychopharmacology as a discipline emerged around the time psychotropic drugs were discovered and

manufactured late 1940's early 50's. Psychoactive substances (major tranquilizers, Chloropromazine

(CPZ) and Reserpine were found to alleviate symptoms of schizophrenia. This appears to be the first

links between drugs and behavior, eventually the discovery that this action takes place in a very minute

and specific site. Where does the action take place? In the synapse!

Synapse: The synapse is the junction between two neurons where one is communicating with the other.

The usual communication is between the axon of the messaging neuron and the dendrite of the receiving

neuron (axo-dendritic), but then there are axo-axonic, axo-somatic synapses as well. Each synapse ahs

three amin components the resynaptic ending, the synaptic cleft and the post synaptic ending. This is a

very small space (a few Angstroms) within which a large amount of chemical activity is taking place.

Pre-synaptic membrane is a very busy place. It has many synaptic vesicles (storage containers made up

of membrane) containing NT, mitochondria to provide energy to the cell as metabolism generators. The

vesicles i.e. Storehouses where the transmitter is stored moves from the cell soma to the presynaptic

ending. Once the excitatory action potential stimulates the presynaptic ending to action these would fuse

with the membrane to release NT through a process known as Exocytosis. In Exocytosis the synaptic

vesicles blends with the pre synaptic membrane, opens up and ruptures to release the molecules of the

Neurotranmsitter in the cleft. The rupture eventually mends. The NT molecules spill out in the cleft and

travel across the cleft to reach the sites of the post synaptic area

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Synaptic cleft: This is a minute space between pre and postsynaptic membranes and is surrounded by

the extraCellular fluid. A synaptic web (a fine web like mesh made of glial cells) holds the pre and post

synaptic sites together in the same configuration that they exist. This is not an inactive place, there are

large numbers of chemicals floating around in the cleft to inactivate NT molecules which have not been

able to successfully cross over to the postsynaptic site and which would otherwise be harmful if they

remain in this area. After release NT, molecules travel to the post synaptic site. They cannot stay in the

cleft and cannot continue to activate the post receptor site even if the passages are open, otherwise once

released NT molecules can last a lifetime. Nature has a balance and has mechanisms of cleaning up the

debris. The NT molecules have to be inactivated and disposed of so as to leave the passage clean for

other NT molecules. The processes of inactivation or reuptake take care of these stray molecules. There

are two kinds of inactivating enzymes and we would talk about them in detail later.

Post synaptic membrane: The postsynaptic membrane can either be the cell soma (axo-somatic),

dendrites (axo-dendritic) or even axons (axo-axonic) of other cells. These are the receiving ends with

appropriate "sites" for: molecules get into these sites to lead to an excitatory post synaptic potential

(EPSP) or an inhibitory post synaptic potential (IPSP). When NT molecules get successful entry into the

postsynaptic site they change the electrical charge or permeability of the membrane leading to ionic and

electrophysiological changes in the post synaptic membrane. These changes depend on a) type of

neurtotransmitter (some are inhibitory, some are excitatory) b) the neuroanatomical sites on which they

are located some NT are excitatory at one location and inhibitory at another b) the amounts of NT

released.

The synapse is an area which will be discussed in detail for each NT and the events taking place in the

synapse would be related to the action of the NT and drugs which affect the NTsynthesis and

metabolism.

Criterion for NT

As discussed there are over 200 candidates for the candidacy of a full neurotransmitter. However, very

few have satisfied the scientific and strict criterion laid out which ahs to be fulfilled before a

Neurochemcial can be termed as an NT. The putative NT's have to fulfill the following criterion:

1. Localization: The presence of the NT molecules has to be identified in the presynaptic ending of the

neuron. This is done using the cytochemcial methods such as histoflourescence techniques,

autoradiography and later visualizing them using the light and electron microscope.

2. Storage of the NT or its precursor in the presynaptic terminal: There has to be a clear evidence of the

vesicles which contain the N in the presynaptic ending as well as the presynaptic neuron.

3. The presence of precursor (the chemical from which the NT is to be synthesized) and appropriate

enzymes for synthesis of NT should be found within the presynaptic neuron. Each neuron independently

manufactures its own NT (like a small factory).

4. With the appropriate stimulation the release of the NT should be demonstrated from the presynaptic

ending into the synaptic cleft. There should be movement of the vesicles towards the presynaptic area,

through the exocytosis, release of NT molecules should take place. This release should be measurable, in

amounts of NT released (through the push pull cannulae)

5.Synaptic mimicry: Since the NT has a particular chemical configuration, drugs with the same

chemical composition, if injected into the synapse should lead to a mimicking( copying) of the

Neurotransmitter effect (as if the neuron is stimulated). We can measure using the push pull cannulae,

the chemicals and metabolites which can be drawn from the synapse to see if the action was simiar.

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6. Recognition of and binding to sites in the postsynaptic areas. Once the NT molecules are released

they must travel across the synapse and recognize the sites to which they can bind in that area.

7.. Existence of receptors on the post receptor sites: there has to be a clear demonstration that there

are receptor proteins to bind to the NT, the shape and the form of the receptors should be in the same

chemical configurations as the NT ( so they match), then the NT can be accepted into the postsynaptic

site.

8. Effect on the post synaptic membrane: Once it is accepted in the post synaptic site, it should lead to

an action whether an EPSP or an IPSP. This would demonstrate the effect of the NT

9. Inactivating/ Deactivation mechanism: The released NT molecules have to be inactivated; there

must be demonstrated presence of the inactivating mechanisms or processes. These chemicals or

enzymes should inactivate the free NT molecules in the presynaptic membrane and the cleft. There

should also be a demonstrated reuptake mechanism.

10. Predictable pharmacological effects: Endogenous substances with known pharmacological

(synthetic) compounds, properties should have the same demonstrable and similar effects.

11. Post synaptic effects: enhanced by similar chemicals and blocked by antagonists or blocking agents

that is those drugs which are similar should stimulate the NT activity, and those which are anti agents

should block its activity.

12. Selective Electrical or chemical stimulation should lead to release of the NT from the

prejunctional endings and amount of NT released should be correlated to the amount of stimulation

Thus we see that the criterion for a NT is tough, but ongoing research shows that more and more NT's

are joining the list of active NT's. We will discuss the NT more in detail in the next lessons

(For specific references: Pinel 144, Carlson 49-53, Erulkar 1989)

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

(Additional references for the module: Iversen and Iversen, Cooper Bloom and Roth, 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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