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

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Basic Neurochemistry:ACH and Behaviors, Arousal, Drinking, Sham rage and attack >>

Neurological Basis of Behavior (PSY - 610)

Lesson35

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

Main purpose:

We continue our discussion on the control and involvement of 5HT in behaviors

5HT and Behaviors:

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

5HT

There are some very important behaviors regulated by 5HT ranging from temperature regulation to

sleep, anxiety and depression

1. Temperature regulation: temperature regulation is an important motivational behavior dependent on

the day and night cycles. If 5HT is injected intraventrically it leads to increased body temperature.

PCPA is injected to deplete brain serotonin and after this depletion, raphe nuclei are electrically

stimulated no rise in body temperature take place. The body temperature would otherwise rise with the

stimulation of raphe nuclei (increased serotnonin,leads to increasedbody temperature).

2. Sensory perception: 5HT involved in producing the heightened sensory and visuomotor

hallucinogenic effect of LSD. We have talked about LSD effects take place through the serotonergic

system. Injections of PCPA(which depletes brain serotonin), reduced motor activity, and reduced

emotional reactivity, but increased sensitivity to pain (means that in rats the electrical current given for a

response is much lower-they respond at a lower current with avoidance and other behaviors). Further,

when 5HT levels are decreased this slows down the process of tolerance to morphine (tolerance means

that the effectiveness of drug dosage is lessened, so the dosage has to be increased to have the same

effect of response).

3. Serotonin and sleep

Evidence for involvement of 5HT in sleep is provided by experiments in which levels of 5HT are

increased by administration of MOAI (reduced deactivation) or 5HTP (increased enzymes) or 5HT. This

treatment leads to an increase in levels of 5HT and also increase time spent in Slow Wave Sleep (SWS).

If 5HT is decreased then the time spent in SWS is also decreased.

PCPA administration (depletes/reduces 5HT drastically) also leads to reduced Rapid Eye Movement

sleep (REM)

Jouvet (1973) was the first one to identify the relationship between 5HT and sleep. Jouvet carried out

experiments of manipulating raphe nuclei and seeing its effect in cats. (Why cats are best animals for

sleep research as they spend 2/3rd of their life in sleep). The electrolytic lesion of the Raphe nuclei led to

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decreased 5HT and decreased time spent in sleep. Sleep reduced when 5HT was reduced 85% time in

sleep was reduced to 20% (insomniac cats!!)

Further when PCPA was injected, 1-2 days after injection ( when complete depletion of brain 5HT has

taken place) increases insomnia followed. How was this confirmed? By injections of 5HTP (which

increased 5HT and reverses PCPA induced lower levels of 5HT, insomnia induced by PCPA was

reversed!

4. Other behaviours

a) 5HT appears to be involved in Depression as there is evidence of decreased 5HT and 5HIAA ( 5HT

metabolite) in brains of suicide victims ( Bourne et al 1968). This indicates that in depression 5HT is

lower than normal levels (antidepressant such as tricyclics and MOAI also act to increase levels of 5HT)

b) Decreases in 5 HT leads to a disinhibition of behaviors (reduced controls on behaviors), increased

impulsivity, increased aggressiveness, and increased suicidal tendencies.

c) Serotonin is also involved in control of sexual and reproductive behaviors. PCPA which depletes

5HT, increased sex drive in males. In females, the ovulation cycle is blocked by narcotics; this blockade

is removed by administration of 5HT

Thus, we have seen that 5HT is one of the major neurotransmitters which influences a wide range of

motivational and other behaviors.

Acetylcholine: ACH

One of the major neurotransmitters a class by itself, as there is no other like this neurotransmitter. This

NT has been well known and around since 1920's. The effects of ACH have been studied in Bioassay

and neuromuscular transmission (frog muscles contraction when Ach is applied on the muscle in the

experimental solution) demonstrated.Ach is used by neurons which terminate on the neuromuscular

junction. Since the 1960's there have been studies suing enzymatic, gas chromatography, flourometric

and other studies demonstrating the involvement of Ach in brain-behavior modulation. This is classified

as an excitatory NT. Excitatory post synaptic Potentials are released in the muscle cell. ACH has an

excitatory effect on the skeletal muscles, but it is inhibitory at heart (remember we earlier told you that

the location is as important as the classification of the NT for its actions as excitatory or inhibitory

neurotransmitter). ACH is also found to play an active role in brain areas such as hypothalamus and

cerebral cortex. It is involved in learning and memory (known as the memory molecule), and Rapid eye

Movement sleep.

The study of Ach is easier than other neurotransmitters as it is easy to remove and study outside the

brain in petri dish. The nicotinic receptors was the first receptor identified (Agranoff, p205)..

Acetylcholine is found in ganglions of the autonomic nervous system and the target organs of

parasympathetic nervous system.

This has two distinctive types of receptors the nicotinic- which connects the muscle fibers and works

through sodium channels (these are ionotropic receptors). Curare, a poison can block the transmission of

Ach at neuromuscular joints. In neuromuscular joints nicotine mimics excitatory effects of ACH

The muscarinic that are found in the CNS and these use G proteins, cyclic AMPs as second messengers.

These are classified as metabotropic receptors. Atropine blocks these receptors, this leads to loss of

memory (Pinel 2002, p. 95-102)

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The ACH receptors are known as the cholinergic receptors

Synthesis

Acetylcholine is synthesized in a catalytic action of cholinesterase on the Co-enzyme A + its acetate ion

and Choline. It acts to detach acetate ion from co-enzyme A and attach it with choline to form

acetylcholine and separate the Co Enzyme A. The Co Enzyme A is found in Vitamin B, and choline is

broken down from lipids and Acetyl is an acetate ion. Choline is the rate limiting factor of ach (no

choline, no Ach)

The Ach is further broken down by these enzymes Choline acetyl transferase whereby. Ach is broken

down into choline and acetyl via a process of hydrolysis

Half of choline in this chemical action is retrieved and recycled

Involvement and neuroanatomical sites of ACH

Ach is formed in the cell bodies of the neuron and transported to the neuromuscular junctions. It is

released by action potential, crosses over and activates the muscles fiber.

I a) Acetylcholine is found at all neuromuscular junctions, autonomic ganglion and parasympathetic

systems

b) Hippocampus receives Ach input from medial septal nucleus

c) Ach projects into the ascending reticular arousal system

d) Involved in Auditory and Visual systems

e) Found in the Caudate nucleus

f) Found in Ventral basal hypothalamus

g) In Suproptic nucleus brain stem

h) Ach acts as a sensory transmitter in thermal receptor. Pain is produced by directly putting Ach on to a

blister on the skin.

II Ach is involved in the:

a) Release of catecholamines (works to balance other NT's and has interaction with DA, NE, and 5HT

in all functions)

b) Conduction of signals: it acts in the axonal conduction by depolarizing the axon.

Steps in ACH synthesis where drugs can modulate action

Drugs affecting cholinergic synapses

Step 1. Synthesis: Ach Synthesis can be blocked by styryl pyridine- a derivative

Step 2. Release of Ach from the presynaptic membrane is enhanced by B-bungarotoxin and black

widow spider venom and blocked by butolinus toxin-deadly food poison. The latter acts to block Ach

transmission leading to total paralysis

Step 3. Post receptor sites can be activated or blocked in both type of receptors

These are activated by Ach agonists or cholinometic drugs and anticholinesterases (blocking the enzyme

which breaks down Ach)

a) Nicotinic receptors are blocked by A- Bungarotoxin and Curare (Tubocurarine). Local anesthetics

and drugs such as phencyclidine bind to these receptors to modulate action.

Curare, a poison used by South American Indians in arrows prevents Ach from reaching post receptor

area (occupies the sites), since the muscles do not get activated, this lead to blockade of all muscular

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responses. Since there is no post synaptic response, no nerve command is processed. This leads to total

paralysis of muscles. Poison from cobra, Alpha bungarotoxin acts through this mechanism

b) Muscarinic receptors are blocked by atropine (belladona), and scopolamine

Step 4. Presynaptic receptor blockade: Atropine and scopolamine block these

Step 5. Inhibition of inactivation activity leads to increase in ACH in the brain by physostigmine which

blocks the acteylcholinesterase breaking down of Ach. This leads to increased levels of Ach in the

system, resulting in repeated stimulation of muscles. This means that the muscles would be repeatedly

stimulated. This results in violent muscular contractions.

It is reported by (Brown and Wallace, p 40) that there is a West Indian tribal custom where Calabar bean

extract is used to find if a person is guilty or innocent. If guilty, then the person who had taken the bean

extract as a test would die, and if they were innocent the person would swallow and vomit.

Physostigmine is used as a therapy for Myasthenia Gravis: (neurological disorder where the muscles

are extremely weak, and don't have normal levels of ACH- for muscles to act). The drugs given

increase ACH (cholinometics, or anticholinesterases). Increases in Ach using this therapy can lead to

nightmares, confusion and hallucination.

Receptor Agonists: a) muscarinic receptors are affected by muscarinic agonists. One of them is the

muscarinic extract from poison mushrooms, which if taken increases ACH activity leads to increased

sweating, increased salivation, constriction of pupils and decreased heart rate. Also muscarine, which

mimics the inhibitory effects of ACH (Agranoff 1989), b) Nicotinic receptor agonists, in neuromuscular

joints, nicotine mimics the excitatory effects of ACH

Nicotinic agonists could be useful in the treatment of a variety of neurological disorders including

Alzheimer's disease, Parkinson's disease and chronic pain.

Receptor Antagonists:

a) For Muscarinic receptors: Atropine is an antagonist for muscarinic receptors. Atropine Belladonna-

night shade poison- blocks muscarinic receptors, acts as a false transmitter. It occupies the post receptor

sites and does not transmit message forward it cannot, it is a false molecule). Atropine belladonna liquid

leads to dilation of pupils when applied directly on to the eyes. Why Belladonna (beautiful woman)

because women used to apply it to their eyelids for wider eye look. From Grecian times, Hippocretes

used it for stomach ailments and cosmetics. In 1880's, the breakdown of atropine from the belladonna

plant affects the muscarinic receptor

Atropine and Scopolamine lead to decreased ACH in the brain leading to amnesia (reduced ACH in

Alzheimer brain related to their memory loss). This also indicates that ACH is involved in learning and

memory.

Muscarinic antagonists are used to control and prevent vomiting, are also useful for the treatment of

Parkinson's disease. In large doses however, the muscarinic antagonists cause severe side effects such as

hallucinations and memory disturbances.

Step 6. Choline uptake. B-Bungarotoxin and black spider widow venom

Check table 1 taken from the website, it provides a very good summary of the agonists and antagonist

we have referred to above

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Neurological Basis of Behavior (PSY - 610)

Table1: Natural Cholinergic Agonist and Antagonists

Agonists

Source of Compound

Mode of Action

Activates nicotinic class

Alkaloid prevalent in the

Nicotine

of ACh receptors, locks

tobacco plant

the channel open

Alkaloid produced by

Activates

muscarinic

Muscarine

Amanita

muscaria

class of ACh receptors

mushrooms

Induces massive ACh

Protein produced by the

release,

possibly

a-Latrotoxin

Ca2+

black widow spider

acting

ionophore

Antagonists

Atropine (and related

Alkaloid produced by the

Blocks ACh actions only

compound

deadly

nightshade,

at muscarinic receptors

Scopolamine)

Atropa belladonna

Eight proteins produced

Inhibits the release of

Botulinus Toxin

Clostridium

ACh

botulinum

Protein produced

Prevents ACh receptor

a-Bungarotoxin

Bungarus

genus

channel opening

snakes

Prevents ACh receptor

Active

ingredient

d-Tubocurarine

channel opening at motor

curare

end-plate

Source: http://web.indstate.edu/thcme/mwking/nerves.html#ach

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 Behavior and Mind. John Wiley and Sons New York

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

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Neurological Basis of Behavior (PSY - 610)

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) 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 more closely followed in addition to the references cited in text.

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