๐ฏ Objectives
To familiarize the students with the:
- Various NT and their role in the modulation of behaviors ๐ง
- Classification of Neurotransmitters ๐: Monoamines: Catecholamines ๐งช and Indoleamine ๐, acetylcholine ๐ฏ, amino acid ๐งฌ, and Peptide ๐
- Neurotransmitter's role in modulation of behaviors and Aberration โ ๏ธ
- Drugs and Behavior ๐๐ญ
- Classification of Psychopharmacological substances ๐ฌ
- Behavioral correlates, Treatment ๐ฉบ
- Mechanism of synaptic transmission ๐ก
๐ Main Purpose
We continue our discussion on the control and involvement of 5HT in behaviors ๐.
๐ญ 5HT and Behaviors
We will now proceed to discuss the behaviors which are affected, modified changed or controlled by 5HT ๐งช.
There are some very important behaviors regulated by 5HT ranging from temperature regulation ๐ก๏ธ to sleep ๐ด, anxiety ๐ฐ and depression ๐ข.
1๏ธโฃ ๐ก๏ธ Temperature Regulation
Temperature regulation is an important motivational behavior dependent on the day and night cycles ๐๐. If 5HT is injected intraventrically ๐ it leads to increased body temperature โฌ๏ธ๐ก๏ธ.
๐ฌ Experimental Evidence
PCPA is injected to deplete brain serotonin โฌ๏ธ and after this depletion, raphe nuclei are electrically stimulated โก no rise in body temperature take place ๐ซ๐ก๏ธ. The body temperature would otherwise rise with the stimulation of raphe nuclei (increased serotonin, leads to increased body temperature) โฌ๏ธ.
2๏ธโฃ ๐๏ธ Sensory Perception
5HT involved in producing the heightened sensory and visuomotor hallucinogenic effect of LSD ๐. We have talked about LSD effects take place through the serotonergic system ๐งช.
๐งช PCPA Effects
Injections of PCPA (which depletes brain serotonin) ๐, reduced motor activity โฌ๏ธ๐, and reduced emotional reactivity โฌ๏ธ๐ข, but increased sensitivity to pain โฌ๏ธโ ๏ธ (means that in rats ๐ the electrical current given for a response is much lower - they respond at a lower current with avoidance and other behaviors ๐).
๐ Morphine Tolerance
Further, when 5HT levels are decreased โฌ๏ธ this slows down the process of tolerance to morphine ๐ (tolerance means that the effectiveness of drug dosage is lessened, so the dosage has to be increased to have the same effect of response) ๐.
3๏ธโฃ ๐ด 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 ๐ (reduced deactivation)
- 5HTP ๐ (increased enzymes)
- 5HT ๐
This treatment leads to an increase in levels of 5HT โฌ๏ธ and also increase time spent in Slow Wave Sleep (SWS) ๐ดโฌ๏ธ. If 5HT is decreased โฌ๏ธ then the time spent in SWS is also decreased โฌ๏ธ.
๐ค REM Sleep
PCPA administration (depletes/reduces 5HT drastically) ๐ also leads to reduced Rapid Eye Movement sleep (REM) โฌ๏ธ๐ค.
๐จโ๐ฌ Jouvet's Research (1973)
Jouvet (1973) ๐จโ๐ฌ was the first one to identify the relationship between 5HT and sleep ๐ด. Jouvet carried out experiments of manipulating raphe nuclei and seeing its effect in cats ๐ฑ. (Why cats are best animals for sleep research as they spend 2/3rd of their life in sleep) ๐ด.
The electrolytic lesion of the Raphe nuclei โก led to decreased 5HT โฌ๏ธ and decreased time spent in sleep โฌ๏ธ๐ด. Sleep reduced when 5HT was reduced 85% time in sleep was reduced to 20% (insomniac cats!!) ๐ผโฐ
๐งช PCPA Experiment
Further when PCPA was injected ๐, 1-2 days after injection (when complete depletion of brain 5HT has taken place) increases insomnia followed โฐโ. How was this confirmed? โ By injections of 5HTP ๐ (which increased 5HT and reverses PCPA induced lower levels of 5HT, insomnia induced by PCPA was reversed!) โ ๐ด
4๏ธโฃ ๐ญ Other Behaviors
๐ข a) Depression
5HT appears to be involved in Depression ๐ข as there is evidence of decreased 5HT and 5HIAA (5HT metabolite) in brains of suicide victims โฌ๏ธ (Bourne et al 1968) ๐ . This indicates that in depression 5HT is lower than normal levels (antidepressant such as tricyclics and MOAI also act to increase levels of 5HT) ๐โฌ๏ธ.
๐ก b) Behavioral Disinhibition
Decreases in 5HT โฌ๏ธ leads to a disinhibition of behaviors (reduced controls on behaviors) ๐ซ, increased impulsivity โก, increased aggressiveness ๐ก, and increased suicidal tendencies โ ๏ธ.
โค๏ธ c) Sexual and Reproductive Behaviors
Serotonin is also involved in control of sexual and reproductive behaviors โค๏ธ. PCPA which depletes 5HT ๐, increased sex drive in males โฌ๏ธโ๏ธ. In females โ๏ธ, the ovulation cycle is blocked by narcotics; this blockade is removed by administration of 5HT ๐โ .
Thus, we have seen that 5HT is one of the major neurotransmitters ๐ which influences a wide range of motivational and other behaviors ๐ญ.
๐ฏ Acetylcholine: ACH
One of the major neurotransmitters a class by itself ๐, as there is no other like this neurotransmitter. This NT has been well known and around since 1920's ๐ . The effects of ACH have been studied in Bioassay and neuromuscular transmission ๐ช (frog muscles contraction when Ach is applied on the muscle in the experimental solution ๐ธ) demonstrated. Ach is used by neurons which terminate on the neuromuscular junction ๐.
๐ Historical Background
Since the 1960's there have been studies using enzymatic, gas chromatography, fluorometric and other studies demonstrating the involvement of Ach in brain-behavior modulation ๐งช. This is classified as an excitatory NT โก. Excitatory post synaptic Potentials are released in the muscle cell ๐ช.
โก ACH Effects
ACH has an excitatory effect on the skeletal muscles ๐ชโก, but it is inhibitory at heart โค๏ธ๐ (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 ๐).
ACH is also found to play an active role in brain areas such as hypothalamus ๐ฅ and cerebral cortex ๐ง . It is involved in learning and memory ๐ (known as the memory molecule ๐งฌ), and Rapid eye Movement sleep ๐ค.
๐ฌ Study Advantages
The study of Ach is easier than other neurotransmitters as it is easy to remove and study outside the brain in petri dish ๐งซ. The nicotinic receptors ๐ฌ was the first receptor identified (Agranoff, p205) โ .
๐บ๏ธ Distribution
Acetylcholine is found in ganglions of the autonomic nervous system ๐ง and the target organs of parasympathetic nervous system ๐.
๐ Two Types of Receptors
๐ฌ Nicotinic Receptors
The nicotinic ๐ฌ- which connects the muscle fibers and works through sodium channels ๐ก (these are ionotropic receptors). Curare ๐, a poison can block the transmission of Ach at neuromuscular joints ๐ซ. In neuromuscular joints nicotine mimics excitatory effects of ACH โก.
๐ Muscarinic Receptors
The muscarinic ๐ that are found in the CNS ๐ง and these use G proteins ๐งฌ, cyclic AMPs as second messengers ๐ฌ. These are classified as metabotropic receptors. Atropine ๐ blocks these receptors, this leads to loss of memory ๐ง โ (Pinel 2002, p. 95-102) ๐.
The ACH receptors are known as the cholinergic receptors ๐.
โ๏ธ Synthesis
Acetylcholine is synthesized in a catalytic action of cholinesterase ๐งช on the Co-enzyme A + its acetate ion and Choline ๐งฌ. It acts to detach acetate ion from co-enzyme A and attach it with choline to form acetylcholine and separate the Co Enzyme A โก. The Co Enzyme A is found in Vitamin B ๐, and choline is broken down from lipids ๐ง and Acetyl is an acetate ion.
Choline is the rate limiting factor of ach โ ๏ธ (no choline, no Ach) ๐ซ.
๐ Breakdown
The Ach is further broken down by these enzymes Choline acetyl transferase โ๏ธ whereby Ach is broken down into choline and acetyl via a process of hydrolysis ๐ง. Half of choline in this chemical action is retrieved and recycled โป๏ธ.
๐บ๏ธ Involvement and Neuroanatomical Sites of ACH
Ach is formed in the cell bodies of the neuron ๐งฌ and transported to the neuromuscular junctions ๐. It is released by action potential โก, crosses over and activates the muscles fiber ๐ช.
๐ I. Locations
- a) Acetylcholine is found at all neuromuscular junctions ๐ช, autonomic ganglion and parasympathetic systems ๐
- b) Hippocampus ๐ receives Ach input from medial septal nucleus ๐ง
- c) Ach projects into the ascending reticular arousal system โฐ
- d) Involved in Auditory ๐ and Visual systems ๐๏ธ
- e) Found in the Caudate nucleus ๐ง
- f) Found in Ventral basal hypothalamus ๐ฅ
- g) In Supraoptic nucleus brain stem ๐ง
- h) Ach acts as a sensory transmitter in thermal receptor ๐ก๏ธ. Pain is produced by directly putting Ach on to a blister on the skin โ ๏ธ.
โ๏ธ II. Functions
Ach is involved in the:
- a) Release of catecholamines ๐งช (works to balance other NT's and has interaction with DA, NE, and 5HT in all functions) โ๏ธ
- b) Conduction of signals ๐ก: it acts in the axonal conduction by depolarizing the axon โก.
๐ Steps in ACH Synthesis Where Drugs Can Modulate Action
๐ฌ Drugs Affecting Cholinergic Synapses
Step 1๏ธโฃ: Synthesis
Ach Synthesis can be blocked by styryl pyridine ๐- a derivative ๐.
Step 2๏ธโฃ: Release
Release of Ach from the presynaptic membrane is:
- Enhanced by: ฮฒ-bungarotoxin ๐ and black widow spider venom ๐ท๏ธ โฌ๏ธ
- Blocked by: botulinus toxin ๐- deadly food poison. The latter acts to block Ach transmission leading to total paralysis โกโ๐ช
Step 3๏ธโฃ: Post Receptor Sites
Post receptor sites can be activated or blocked in both type of receptors ๐ฏ. These are activated by Ach agonists or cholinomimetic drugs โก and anticholinesterases (blocking the enzyme which breaks down Ach) ๐.
๐ฌ a) Nicotinic Receptors
Nicotinic receptors are blocked by ฮฑ-Bungarotoxin ๐ and Curare (Tubocurarine) ๐. Local anesthetics and drugs such as phencyclidine bind to these receptors to modulate action ๐.
Curare ๐, a poison used by South American Indians in arrows prevents Ach from reaching post receptor area (occupies the sites) ๐ซ, since the muscles do not get activated ๐ชโ, this lead to blockade of all muscular responses. Since there is no post synaptic response, no nerve command is processed ๐ง โ. This leads to total paralysis of muscles ๐. Poison from cobra, Alpha bungarotoxin ๐ acts through this mechanism.
๐ b) Muscarinic Receptors
Muscarinic receptors are blocked by atropine (belladonna) ๐, and scopolamine ๐ ๐.
Step 4๏ธโฃ: Presynaptic Receptor Blockade
Atropine ๐ and scopolamine ๐ block these ๐.
Step 5๏ธโฃ: Inhibition of Inactivation Activity
Inhibition of inactivation activity leads to increase in ACH in the brain by physostigmine ๐ which blocks the acetylcholinesterase breaking down of Ach ๐. This leads to increased levels of Ach in the system โฌ๏ธ, resulting in repeated stimulation of muscles ๐ชโก. This means that the muscles would be repeatedly stimulated. This results in violent muscular contractions ๐ช๐ฅ.
๐ด West Indian Tribal Custom
It is reported by (Brown and Wallace, p 40) ๐ that there is a West Indian tribal custom where Calabar bean extract ๐ซ is used to find if a person is guilty or innocent โ๏ธ. If guilty, then the person who had taken the bean extract as a test would die ๐, and if they were innocent the person would swallow and vomit ๐คฎ.
๐ฉบ Myasthenia Gravis Treatment
Physostigmine ๐ is used as a therapy for Myasthenia Gravis ๐ฉบ: (neurological disorder where the muscles are extremely weak ๐ชโฌ๏ธ, and don't have normal levels of ACH- for muscles to act). The drugs given increase ACH โฌ๏ธ (cholinomimetics, or anticholinesterases). Increases in Ach using this therapy can lead to nightmares ๐ฑ, confusion ๐ค and hallucination ๐.
โก Receptor Agonists
๐ a) Muscarinic Receptor Agonists
One of them is the muscarinic extract from poison mushrooms ๐, which if taken increases ACH activity โฌ๏ธ leads to:
- Increased sweating ๐ฆ
- Increased salivation ๐ง
- Constriction of pupils ๐๏ธ
- Decreased heart rate โค๏ธโฌ๏ธ
Also, muscarine ๐, which mimics the inhibitory effects of ACH (Agranoff 1989) ๐.
๐ฌ b) Nicotinic Receptor Agonists
In neuromuscular joints, nicotine ๐ฌ mimics the excitatory effects of ACH โก.
Nicotinic agonists could be useful in the treatment of a variety of neurological disorders including Alzheimer's disease ๐ง , Parkinson's disease ๐ค and chronic pain โ ๏ธ.
๐ Receptor Antagonists
๐ a) For Muscarinic Receptors
Atropine ๐ is an antagonist for muscarinic receptors ๐. Atropine Belladonna ๐ธ- night shade poison- blocks muscarinic receptors, acts as a false transmitter ๐ซ. It occupies the post receptor sites and does not transmit message forward it cannot, it is a false molecule) ๐โ.
Atropine belladonna liquid ๐ง leads to dilation of pupils ๐๏ธ when applied directly on to the eyes. Why Belladonna (beautiful woman) ๐ฉ because women used to apply it to their eyelids for wider eye look ๐. From Grecian times, Hippocrates used it for stomach ailments and cosmetics ๐บ. In 1880's, the breakdown of atropine from the belladonna plant ๐ธโ affects the muscarinic receptor.
๐ง Memory Effects
Atropine ๐ and Scopolamine ๐ lead to decreased ACH in the brain leading to amnesia โฌ๏ธ๐ง โ (reduced ACH in Alzheimer brain related to their memory loss ๐). This also indicates that ACH is involved in learning and memory ๐.
๐ Clinical Uses
Muscarinic antagonists are used to control and prevent vomiting ๐คฎโ , are also useful for the treatment of Parkinson's disease ๐ค. In large doses however โฌ๏ธ, the muscarinic antagonists cause severe side effects such as hallucinations ๐ and memory disturbances ๐ง โ.
Step 6๏ธโฃ: Choline Uptake
ฮฒ-Bungarotoxin ๐ and black spider widow venom ๐ท๏ธ affect choline uptake.
Check table 1 taken from the website ๐, it provides a very good summary of the agonists and antagonist we have referred to above ๐.
๐ References
- Kalat, J.W. (1998). Biological Psychology. Brooks/ Cole Publishing
- Carlson, N. R. (2005). Foundations of physiological psychology. Pearson Education New Zealand.
- Pinel, J. P. (2003). Biopsychology. (5th ed). Allyn & Bacon Singapore.
- Bloom, F., Nelson., & Lazerson. (2001), Behavioral Neuroscience: Brain, Mind and Behaviors. (3rd ed). Worth Publishers New York
- Bridgeman, B. (1988). The Biology of Behavior and Mind. John Wiley & Sons, New York
- Brown, T.S. & Wallace, P.S. (1980). Physiological Psychology. Academic Press, New York
- Seigel, G. J., Agranoff, B.W, Albers W.R. & Molinoff, P.B. (1989). Basic Neurochemistry: Molecular, Cellular and Medical Aspects
- Cooper, J.R., F.E Bloom, F. E., & Roth, R. H. (1970). The Biochemical basis of neuropharmacology (5th Ed.). New York, Oxford Univ. Press.