Basic Neurochemistry:NA and Feeding, NE and self stimulation: ICS

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Basic Neurochemistry:5HT and Behaviors, Serotonin and sleep, Other behaviours >>

Neurological Basis of Behavior (PSY - 610)

Lesson34

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

NE and Behaviors (continued)

Stress:

There are various ways in which stress can be induced in the laboratory. One of these methods is to give

continous and inescapable shocks. Rats are placed in a cage with a steel wire grid on the floor. Shock is

passed through these to the rat's feet (the paw and feet are the only part apart from their nose which

does not have fur protection). Stress induced by foot shocks (stress) lead to increased NA levels and

turnover in the hindbrain. The turnover rates increase means that more and more NA is being used and

being metabolized. This has been measured using the push pull cannulae. Various pharmacological

procedures have also shown that only NA increases after footshock.

Similarly, Electroconvulsive therapy also leads to increased NA levels in the forebrain

Trauma of all kinds also increased NA activity in the brain.

NA and Feeding

Feeding is one of the basic motivations of animals. The NA systems also are involved in the control of

feeding behaviors. If NA is administered directly in Lateral Hypothalamus leads to increased eating in

animals which have already eaten to the point of satiation (they are full and they stop eating in the

normal state). How do we know it is NA only? When we inject drugs which specifically for block NA,

the NA induced feeding is also blocked (no NA, no feeding!). This is demonstrated by injections of

Phentolamine (A-adrenergic blocker), which leads to a blockade of NA induced feeding.

Liebowitz (1971), a well known researcher has shown through her experiments that NA may be acting

to reduce the inhibition of the normal inhibition of lateral hypothalamic feeding center by the

Ventromedial hypothalamus (VMH). So, the LH starts the feeding and the VMH stops it (by telling LH

to stop sending signals for eating). When NA is injected it stops the inhibition of VMH, so that

messages of feeding can continue.

NE and self stimulation: ICS

Positive Reinforcement or "reward" is linked with NA. Learning and conditioning using positive

reinforcers or rewards are linked to intercranial self stimulation or the self stimulation. Positive ICS

areas are areas in the brain where implanted electrodes would get maximal response of self stimulation

by the animals. The animals would repeatedly press levers for electrical stimulation to these areas in the

brain. These areas closely correspond to distributions of NA and DA systems, indicating that these

neurotransmitters are modulating the reward behaviors. If we inject alpha methyl paratyrosine, we

reduce the amounts of tyrosine, DA and NA. This injection also blocks the self stimulation response in

animals which were stimulating before the injection of AMPT.

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How do we know which one of these two neurotransmitters is involved, logically following it we would

use a drug which would block only DA, or only NA, or 5 HT one by one after AMPT.

When we do so, we see that the AMPT blockade is reversed by the Alpha receptor agonists of NA, not

by B-receptor agonists or DA agonists or 5HT agonists. Thus, showing that NA is involved. Researchers

have also used the Push pull cannuleas in Ventricle to pull out the metabolites after self stimulation. It

was reported that with the self stimulation leads to an increase in the release of NA. Further it has been

shown that the NA Dorsal bundle is more than the Ventral bundle

NA and Depression

The effectiveness of Monoamine Oxidase Inhibitors in treatment of depression has provided support to

the Catecholamine hypothesis of Depression, and in particular the involvement of NA. This

involvement is indicated by the fact that long term anti depression treatment in animals leads to a

reduction in NA stimulated cyclic AMP (Beta receptors involved). This indicates that more NE stays

available (as it is not degraded) therefore less needs to be released.

Antidepressant also increases the synaptic availability of NE (more NA becomes available). Reserpine

(which has been used for treating mental illness in the Indian subcontinent since ages) when injected

inot the brain leads to depression like syndrome (remember, it destroys the storage vesicles and depletes

NE, DA and 5HTfrom the presyanptic membrane). Iproniazid (which is an MAOI and an effective

antidepressant-) when administered increased brain concentrations of NE and 5HT. Thus showing that

NA is involved in depression, as decreases in NA lead to depression, and reward behaviors as depletion

of NE reduced self stimulation

Major Neurotransmitters: Monoamines: Indolamines

Serotonin: Indolamine (also known as 5 hydroxytrytamine or 5 HT)

Serotonin is one of the major neurotransmitters of the brain with an important role in several behaviors

(ranging from sleep to depression). The neurons are known as serotonergic neurons and the pathways as

sertonergic pathways. Scientists had known since the mid 19th century that there is a substance involved

in powerful contraction of the smooth muscles. Later, this was also found in the Ohio research labs to be

the possible cause of high blood pressure, in American labs, this was called serotonin around the same

time Italian scientists were trying to identify the substance in the intestinal mucosa, and also of the gut

which led to powerful contractions of smooth muscle of the intestinal tract. This substance was called

Enteramine by the Italian scientists. This substance is also found in clotted blood. These two groups of

scientists eventually found that this substance was identical to 5 hydroxytryptamine (5HT). This has a

strong resemblance to Lysergic acid diethylmide (LSD) molecule

In the brain 5HT is synthesized in the same way as NE and DA from the precursor which is taken from

the circulating blood. The precursor for 5HT is Trytophan, which varies according to the daily intake of

the tyrtophan rich foods (milk, red meat, fruits such as bananas pineapples etc.). The body and the brain

both have a high concentration of 5HT, where it is synthesized independently. About 90% of 5HT is

found in the gastrointestinal area (in the enterochromaffin cells of the intestine) and only about 1-2 % in

the brain. The highest concentration of 5HT in the brain is found in the pineal gland. The Pineal gland is

a very small organ lying on the dorsal surface of the thalamus. The pineal contains all the enzymes for

the use of serotoninin addition to two other enzymes for transformation of serotonin. The pineal

contains about 50% more serotonin per gram of the brain that the rest of the brain areas. (Wonder

why?). The extension of pineal serotonin is Melatonin. In the pineal, Tryptophan is transformed into N-

Acetyl Serotonin, which is then transformed into Melatonin. Melatonin is the substance which you see

when your skin gets darkened by the sun (more melatonin, more pigmentatiom). Melotonin secretion is

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enhanced by light and suppressed by darkness. Thus, Melatonin content is affected by the Light Dark

(L/D cycles) and this bring daily and seasonal changes in the 5HT content in the pineal and the brain.

We will talk more about serotonin's involvement in day night cycles (sleep), in the later part of this

lesson.

Serotonin Synthesis:

We will discuss the synthesis of serotnonin and where it begins and the enzymatic actions which occur.

We must be again very clear that the brain synthesizes its own serotonin from the amino acid

1. Trptophan: This is the first step in the synthesis pathway. Tryptophan enters the cells but in

competition with phenlalanine ( daily variation depends upon the consumption of tryptophan

rich foods)

2. Hydroxylation of Tryptophan: This is the rate limiting step. The hydroxylation of tyrptophan

takes place immediately at the 5th position of the molecule to form 5- Hydroxytryptophan or

5HTP. The enzyme involved in this action is Tryptophan hydoxylase. This step can be blocked

by a drug called Parachlorophenylalanine (PCPA). PCPA competes with tryptophan for this

enzyme and binds irreversibly with this enzyme. In rats one injection of PCPA of 200 mg/kg

depletes brain 5HT drastically (to about 20%) and recovery to normal levels can take weeks.

3. Decarboxylation: 5HTP is immediately decarboxylated to form 5HT. The decarboxylating

agent is the one similar to Dopa (he same protein is used in the Catecholamines and Serotonin

neurons for decarboxylation). The enzyme L- Amino Acid Decarboxylase is involved in this

action.

4. Deactivation: Serotnin is deactivated or deaminated by Monoamine Oxidase (MAO) as in the

other monoamines. The metabolite of this action is 5-Hydroxy Indole Acetic Acid (5-HIAA)

Serotonergic Anatomical location and Pathways

Though attempts had been made to identify the pathways of 5HT, it became possible only after

Falck and Hillarp's formaldehyde induced fluorescence histochemcial procedures became well

known, and through the immunocytochemcial methods ( through retrograde transport), and

procedures using radiolabelled amino acids taken up by the orthograde axoplasmic system when

injected into the neurons. Dahlstrom and Fuxe ( 1964) and other researchers identified about nine

clusters of 5HT neurons in the nuclei of the raphe system located in the midline of the pons and

upper brain stem. These are spread out like islands (or a bunch of grapes).

Ascending 5HT bundles travel through the Medial Forebrain Bundle with terminals in the reticular

formation (You will find out later why this connection is important), hypothalmus, lateral geniculate

nuclei, preoptic area, hippocampus and the cortex (crucial role in sleeping and awakening). These

also project into the telencephalon and the deincephalon, and descend into the spinal cord (Cooper,

Bloom and Roth, 7th edition)

Pathways:

There are several serotonergic pathways each with their own connection and receptors. Nuclei

Raphe comprise of several different groups. The Dorsalis, Superior and Magnus nuclei pass through

the MFB.

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Nuclei Raphe Dorsalis: The serotonergic receptors here are B7. It sends projections to the

Neocortex, Olfactory bulb, Thalamus, Amygdala, Hippocampus, Substantia Nigra and the

Locus Cerelleus

Nuclei Centralis Superior: The serotonergic receptors are known as B 8. They project to the

cerebral cortex, hippocampus, superchiasmatic nuceli (SCN) anterior hypothalamus, medial

preoptic area, and the raphe dorsalis.

Nuclei Raphe Magnus: The serotonergic receptors here are B3. They extend to medulla and

the anterior hypothalamic area

Nuclei Raphe Obscurus: This is an interesting pathway as the powerful hallucinogen LSD acts

here. The receptors here are known as B2

Raphe Pallidus has B1 receptors, it contains substance P ( a peptide) involved in Pain, goes

down into spinal cord

Steps in 5HT synthesis where drugs can modulate action

Step 1. Synthesis by enzyme: Tryptophan is converted into 5 hydoryxytryptophan by tryptophan

hydroxylase in the serotnergic neuron. This process can be blocked by the action of PCPA which

uses up the hydroxylating enzyme

Step2. Storage: Reserpine, a major tranquilizing agent affects DA,NE and 5HT storage vesicles by

irreversibly damaging the storage vesicles. It is not clear whether DA, NE and 5HT responsible for

behavioural depression.

However, researchers have found that when Reserpine is administered along with 5HTP or DOPA,

there are increases in sedation (induced by reserpine). Injections of PCPA (removed 90% of the

brain serotonin) before reserpine, no behavioral effects of reserpine were seen.

Step 3. Release. There are no drugs which are specific serotonin blocking agents, but a major

hallucinogenic drug Lysergic Acid Diethylmide LSD potentiates serotonin effects in low doses.

LSD inhibits the release of serotonin by blocking the firing of serotonergic neurons (indirect

blocking)

LSD in high doses- led to an increase in 5HT levels by reducing break down of serotonin (measured

through reduced metabolites i.e. 5HIAA)

Increase LSD dosages reduced 5HT turnover rates, how?

1) Serotonin receptor sites occupied

2) Inhibit serotonin production by blocking action of 5HT

3) LSD appears to decrease the release of 5HT

Step 4. Receptor Interaction: LSD acts as a partial agonist at the receptor sites of postrecpetor

membrane

Step 5: Reuptake: serotonin action can be terminated by reuptake in the presynaptic area.

Tricyclics such as Imipramine also increase 5HT levels by inhibiting reuptake. The Selective

serotonin Reuptake inhibitors (SSRI's) are effective for treatment of anxiety.

Step 6: degradation by MAO can be inhibited by MAOI. Iproniazid blocks MAO action in the

epresynaptic area

Thus we have seen that in a manner to other neurotransmitters, drugs interact with 5HT at various

sites and can modulate levels of 5HT, and these drugs are also effective in treating

psychopathology.

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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 (1996) Biochemcial basis of neuropharmacology 7th Edition,

OUP

9. Pharmacology, Biochemcistray and behavior

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

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

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