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

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Neurological Basis of Behavior (PSY - 610)

Lesson36

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 Neurotransmitter: Acetylcholine (continued)

ACH and Behaviors.

As we have discussed in the last lesson, Ach has a unique and important neurotransmitter role in the

brain. Without the normal levels of Ach and its receptors working effectively the brain would not be

able to command the muscles of the body.

1. Arousal: Ach has an important role as excitant of neural activity. This means that brain

electrical activity is aroused and can be monitored by the Electtroencepaholographic (EEG)

recordings. When ACH is injected intravenously or applied to cortex it leads to increased EEG

activity. Further, when anticholinergics are administered as they block and reduce Ach levels in

the brain, the EEG arousal is also blocked. Interestingly, this does not affect the behavioral

arousal). Ach is involved in sleeping and awakening via the locus coerreleus, which may

explain the involvement of Ach in brain electrical activity arousal.

Drinking: Ach is important in drinking and fluid regulation. The regulation of the water intake

takes place via the Ach mechanism. The cellular dehydration is mediated by the cholinoceptive

system of neurons in the preoptic area of the hypothalamus. They monitor the extracellular

space for volumetric changes (changes in the volume of fluid) produced after changes in

isotonic body fluids. (Whenever the intracellular membrane runs short of fluid it takes in fluids

from the extracellular membrane, as the survival of cell is more important!).This leads to the

release of Renin from kidneys which lead to increased formation of Angiotensin which then

stimulates the neurons in the preoptic area. Thus, this communication goes from the brain to the

kidneys and back leading to an increase in fluid and salt intake. The messages begin with the

Cholinoceptive receptors sending out the signals.

3. Sham rage and attack: Sham rage is the physical appearance of rage without an object of rage

in front of the animal (cats and rats). In cats rage appears in hissing and spitting, and raised hair

on the dorsal surface of the body and the tail. Sham rage is induced in cats and rats by the

cholinergic stimulation of amygdala and septum. Aggression is also produced by midbrain

ventral tegmental area. Further, the killing attack pathways in rat (of mice) and cat (of rats) are

cholinergically organized. The cholinergic stimulation of amygdala, LH, midbrain tegmental

regions leads to a quiet biting attack in rat and cats. How do we know? This attack is blocked by

atropine

Punishment: Reinforcing stimuli increases the probability of a response to it whereas

punishing stimuli decreases the probability of a response to it. The intracranial self stimulation

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is part of the reward systems and reinforcing so an animal would keep self stimulating for its

own reward. On the other hand, the periventricular area in hypothalamus part of punishment

systems. The ventromedial hypothalamus is part of this punishment system. Rats previously

trained for Variable Interval Schedule (VIS) for food are run in an experiment where every

response is followed by a shock. (Remember VIS is when the time between reinforcement

varies!). When every response is followed by a shock, a reduction in VIS response follows. If

we lesion the Ventromedial nuclei (VMN), it leads to increase in the response which had been

depressed (leads to disinhibition). Anti Ach also does the same, which is they lead to an

increase in disinhibition of the punished response. Inhibition of punished response means the

animal would stop responding, but disinhibition means that the response would return as the

inhibitor has been blocked. AntiAch are involved in removing the inhibition.

5. Alzheimers: Alzheimer's is a disease of old age where degeneration of brain takes place to a

point where the person cannot carry out any function. The important feature of this disease is

loss of memory. Recently muscarinic receptor agonists have been used in the treatment of

Alzheimer's disease. This replaces depleted Ach in the basal forebrain as the neurons in this area

degenerate. Another treatment of Alzheimer's patients is administration of acetylcholinesterase

inhibitors this increases levels of ACH in the synapse as the breakdown is blocked), thereby

increasing cholinergic activity in damaged brain areas. Physostigminewas used earlier but

results indicated strong side effects. Tetrahydroaminoacridine (THA, or tacrine), first

cholinesterase inhibitor which has been approved for Alzheimer's patients. Patients given THA

shown some reduction of Alzheimer's symptoms were able to resume normal activity.

However, not all patients can use it as it has strong side effects on increasing liver enzymes.

Ach is also involved in learning, memory, motor behaviors (it works in balance with DA for

Parkinson's and other motor disorders), in pain, in coordination with brain opioids.

Other NT's

In addition to the neurotansmitters, we have discussed so far, the Catecholamines, the Indolamine,

and Acetylcholine; there are other neurotransmitters which are active within the CNS. We will

discuss them in brief.

1. Glutamic acid: Glutamate and GABA are found in simple organisms. The first neurotransmitter

to be evolved in the brain is Glutamate. Glutamate is an excitatory neurotransmitter, its receptors

found all over the brain. Chinese food contains a large amount of Monosodium Glutamate. There

are three types of receptors: NMDA, quisquilate and the kainite receptors. The receptors are all

important in working with other NTs

2. GABA. Gamma Amino butyric acid was first synthesized in 1883 known to be a metabolite of

plant and microbial metabolism. It was discovered in the mammalian brain in the 1950's, and in

very high concentrations in the brain and the spinal cord. In the brain GABA is found in amounts

10-15 times greater than DA, NE or 5HT also a minuscule amount found in the retina. Even till now

it is not very extensively studied. It is generally classified as an inhibitory NT and accounts along

with other amino acids for a major part of the neuronal transmission. GABA works to balance the

monoamines DA, NA and 5HT wherever they are involved. GABA is implicated directly in

Huntington's chorea which is due to degeneration of GAB Aminergic neurons. GABA is indirectly

involved in Parkinson's, Epilepsy (abnormality in the biochemistry of GAB Aminergic neurons)

and Schizophrenia

GABA Synthesis; This involves only two steps: one to synthesize it and one to break it down:

1. One step synthesis from its amino acid precursor Glutamic Acid which is decarboxylased by the

enzyme Glutamic acid decarboxyalse.

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Glutamic acid--------------------GABA

Glutamic acid decarboxylase (GAD) and coenzyme pyroxidal phosphate, this process can be

blocked by ions such as chloride and zinc.

2. Catabolism: GABA--is trans-aminated by GABA-A-oxoglutarate transaminase. GABA is

transformed into Succinic Acid Semialdehyde to return back into the Krebs cycle

In the transaminase process- GABA conversion is reversed to Glutamic acid through alpha

ketoglutarate which acts as amine acceptor.

Distribution and pharmacological agents

From monkey to human brain 1968-1971 studies showed the highest GABAminergic concentrations

in the Substantia Nigra (SN) Globus Pallidus (GP), and the Hypothalamus (hyp)

Agonists: The post receptor GABA agonist is muscimol. This leads to increased arousal, self

mutilation, increased feeding if placed in the hypothalamus (disinhibition of inhibition)

Antagonists: Post receptor antagonist or receptor blockade by picrotoxin and bicuculine.

Benzodiazepines (Valium and Librium) stimulate a particular site of GABA Aminergic neurons.

This alleviates the anxiety symptoms/response.

Glycine: is another Inhibitory neurotransmitter like GABA however research is still ongoing to

identify its role. It is found in the mammalian spinal cord and the brain. It is found in greater

amounts in the spinal grey matter than the brain. Suggesting it may be working with the interneuron.

However, no distinct and clear glycine pathways in the brain

Strychnine (poison) blocks the action of glycine and also blocks postsynaptic inhibition.

PEPTIDES: neuroactive peptides are candidates for neurotransmitters. Some of these are like

orthodox NT's, some are performing modulatory or regulatory roles, and that these also act as

neurohormones.

BRAIN OPIOIDS, ANGIOTENSIN II, (thirst) Oxytocin and Vasopressin, Leutenizing Hormone

Releasing Hormones (LH-RH), Substance P and Adreno-Corticotropic Hormone (ACTH)

Brain Opioids: Endorphins (large molecules) and Enkephalins (smaller molecules):

Hughes and Kosterlitz (1975) in Aberdeeen discovered the existence of brain opioids in the brain.

This was a landmark finding because for the first time it was found that this chemical compound

was similar in composition to the opiates morphine, heroin etc. In later researches, Huda Akil and

her research group reported that the highest concentration in Substantia Nigra, lateral hypothalamus,

cerebral Cortex, Periaquaductal gray.

Extracts taken out from the brain, when administered to laboratory animals led to analgesia, wet dog

shakes upon application (in a manner similar to administration of opiates).Similarly, akinesia,

hypothermia, rigidity, catalepsy were also seen.

The question is whether brain opioids are natural neuroleptics or not (neuroleptics are antipsychotic

drugs).

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In some cases psychotic patients who are not responding to other treatment drugs (neuroleptics)

have responded short term endorphin treatment (Mcgreer and Mcgreer 1980).

These are also involved in emotions, growth, pleasure (acting through the mesolimbic DA

pathways), stress induced analgesia (Akil et al 1975), growth and development (Najam and

Panksepp 1980).

Opioid antagonists have also been found effective in treatment of autism and childhood disorder (

Panksepp et al's theory of brain opioids and attachment states that brain opiates are natural

conforters in the brain, it is when they are blocked that the addicts turn to morphine/heroin, and

autistic children have higher than normal brain opiate level therefore). The discovery that pain and

acupuncture pathways are similar to brain opioids pathways in the body and spinal cord provide

strong evidence for the involvement of brain opiates in the pain and acupuncture. Narcotic

analgesics such as morphine heroin are severely addictive and have a high tolerance value are potent

analgesiscs, potent anti congestion, and also for stomach and digestive problems. The interesting

aspect of opiates effect on pain is that it is only the affective component which is reduced (one does

not feel the pain) the physical component is still there. Pain is still there but the patients do not care

about it, the reaction to pain is diminished.

Psychotogenic compounds

Hallucinogens:

1. LSD is a potent drug in fact so potent that a small dose of 1/10,000 gram is effective. This has

great tolerance to the point that the same dose is not effective if taken 2nd time which means an

increased dosage needed every time for an effect to take place. The LSD "trip" depends on the

mood and personality of the user and can be controlled

2. Mescaline also hallucinogenic compound made from plants extracts in Mexico. It is used in

religious ceremonies by tribes in Mexico

Psychopharmacology

This area of specialization is the study of the effects of drugs on psychological processes. It is both a

basic and an applied science. " A recognition of the interrelationships between pharmacological

agents, neuro regulators, and behavior has become essential for those involved in helping

individuals who have psychiatric disorders" Therefore in order to develop drugs research in the

laboratory is needed before the drugs can be tested and used- especially on humans.

The evidence is provided when the symptoms of a psychiatric disorder are removed linked to

neurotransmitter, and then the normalization of behavior should occur with normalization of levels of

NT in the brain. Further, known effective exogenous substances should have similar chemical effects

as the endogenous (brain) chemicals. Pharmacological substances should be able to interact with NTs

at a given sites if they have the same chemical composition.

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 details later

5. Bridgeman,B (1988)The Biology of Behavior and Mind. John Wiley and Sons New York

6. Seigel,G.J. ( Ed. in chief) Agranoff, B.W, Albers W.R. and Molinoff, P.B. (Eds.) Basic

Neurochemistry: Molecular, Cellular and Medical Aspects

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7. Cooper, J.R... Bloom, F.E and Roth H.R. (1978): The Biochemical basis of Neuropharmacology (3rd

Edition), Oxford University Press, UK

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