🎯 Objectives
To familiarize the students with the:
- Various NT and their role in the modulation of behaviors 🧠
- Classification of Neurotransmitters 📊: Monoamines: Catecholamines 🧪 and Indoleamine 💜, acetylcholine 🎯, amino acid 🧬, and Peptide 🔗
- Neurotransmitter's role in modulation of behaviors and Aberration ⚠️
- Drugs and Behavior 💊🎭
- Classification of Psychopharmacological substances 🔬
- Behavioral correlates, Treatment 🩺
- Mechanism of synaptic transmission 📡
🧪 Major Neurotransmitter: Catecholamines
We have already discussed one of the catecholamines, Dopamine 🎯 which is first in this chain of synthesis. Dopamine is the preceding step in the synthesis of Norepinephrine NE ⚡ (also known as Noradrenaline NA, which is the abbreviation used in this section).
💫 Norepinephrine/Noradrenaline
One of the major neurotransmitters of the brain 🧠 this NT fall under the general category of monoamines 🧪, further categorized as catecholamine because of its chemical composition. In this system synapses are known as noradrenergic synapses 🔗; NA is found in various parts of the brain as well as the autonomic NS (in the hypothalamus 🏥 and the mid brain) in the Peripheral nervous system (very important role in the sympathetic functions ⚡ and hormonal releases: readiness for fight or flight 🥊🏃) and at the adrenal glands 💉.
🌟 Wide Range of Behavioral Involvement
This is involved in a large number of behaviors with a wider influence as compared to DA 🎯. The involvement in:
- Mood 😊😢
- Emotional states 💭
- Motivation (hunger 🍽️, thirst 💧, fight/flight 🥊🏃 etc.)
- Dream 💤
- Rewards (learning) 🎁
- Sleep alertness and wakefulness 😴⏰
All are well documented ✅.
NA originates from a small group of neurons located in the back part of the brain 🧠 and project by sending fibers and axons to widespread region of the brain 🌐. This is why it is involved in so many behaviors 🎭.
⚡ Noradrenergic Synapses
The Noradrenergic synapses lead to:
- Inhibitory Post Synaptic Potentials (IPSP) 🛑➖ in the Central Nervous System
- Excitatory Post Synaptic Potentials (EPSP) ⚡➕ in the Autonomic Nervous System (which includes the sympathetic nervous system), and the target organs (such as the heart ❤️)
📿 Axonal Varicosities
The Noradrenergic neurons do not release NT from terminal buttons (as other NT's do) 🚫 instead of it they release NA through the axonal varicosities 📿, which are beadlike swelling of axonal branches. The varicosities give the axonal branches of NA neurons the appearance of beaded chains or like a necklace of beads 💎. NA is synthesized or manufactured in the adrenal medulla 💉 and the brain 🧠 from DA. Remember that the brain manufactures all NT's, and therefore NA also independently 🏭. Even though large amounts of NA are manufactured and used in the body, it cannot cross the blood-brain barrier to enter the brain 🚧.
⚗️ NA Synthesis
1️⃣ Synthesis Process
This is a simple one step process for transforming Dopamine into NA ✨.
Dopamine is hydroxylated by Dopamine B-hydroxylase 🧪. This enzyme was discovered in 1960 in the adrenal medulla 💉, and this is the same enzyme which acts on DA in the brain 🧠. The synthesis from DA to NE takes place within the vesicles 📦 (unlike other NT's where this is carried out in the cell body).
2️⃣ Hydroxylation
Dopamine is hydroxylated by Dopamine B-hydroxylase, to form Noradrenaline 💫. This hydroxylation process can be blocked by Disulfiram 🛑. The blockade leads to a buildup of DA (since the tyrosine is being converted to Dopamine) ⬆️ at the same time this reduces NE levels in the neurons, and therefore in the brain ⬇️.
3️⃣ Deactivating Norepinephrine
Deactivating Norepinephrine by MAO ⚗️ and COMT 🧪 leads to following:
The metabolite after the breakdown of NE occurs in two ways:
a) Vanylmandellic Acid (VMA)
A metabolited which is found mostly in the body 💪, very little in the brain (as it is excreted quickly) 🚽.
b) MHPG
The MHPG, a glycol derivative (the abbreviation of 3 – methoxy-4 hydroxy phenylglycol) 🧬. This metabolite is found that in stress 😰 there are increases in amounts of MHPG in the locus coeruleus 📈.
🛤️ Noradrenergic Pathways
There are two major pathways of NA:
📊 Dorsal Bundle and Ventral Bundle
The Dorsal bundle 🔝 and the Ventral bundle 🔽 with several pathways projecting in each one of these. The pathways are known as A1, 2, 4, 5, 6, and 7 🔢. All these originate in the lower brain areas and ascend to the cortex 🧠 i.e., they originate in the Pons and the medulla and ascend to the cortical areas, the limbic systems 💚 and the hypothalamus 🏥.
🔵 A6 Pathway (Dorsal Bundle)
The A6 comprises of the dorsal bundle which originates in one area, the locus coeruleus 🎯 located on the ventral areas of the ventricles, and sends out diffuse innervations to:
- Cerebellum 🧠
- Cerebral cortex 🧠
- Hippocampus 🌊
Through the Medial Forebrain Bundle (MFB) 🔗. This therefore is involved in sleep 😴, awakening ⏰, moods 😊😢, neuro endocrinal functions 💉 and temperature regulation 🌡️.
🔴 Ventral Bundle Pathways
The A1, 2, 4, 5, and 7 are the various points or locations from where the ventral bundle originates in the pons, medulla and innervates the brain stem and the hypothalamus 🧠.
The ascending fibers of A5 and A7 ⬆️ project to the cortex 🧠, hypothalamus 🏥 and are part of the limbic system (hippocampus 🌊 and septum 🔗) whereas the descending fibers go down into the spinal cord ⬇️🦴.
🔓 Receptors
There are types of NA receptors identified by their sensitivities to various drugs: the Alpha receptors 🅰️ and the Beta receptors 🅱️
📋 Receptor Locations
a) Alpha1 and Beta1 are found mainly in the post receptor membranes 📥
b) Alpha2 is primarily presynaptic auto receptors 📤 (these emerge out of the presynaptic membrane area to monitor and control the levels of the membrane by a self-inhibiting action 🎛️). It is like the one hand of the same person holding the other hand (for support and for control) 🤝
c) Beta2 receptors are found in the CNS but are associated with glia cells 🧬, muscles 💪, and walls of blood vessels 🩸.
🔍 Detailed Receptor Functions
🅰️1 Alpha-1 Receptors
These receptors are located post synoptically on blood vessels 🩸 and in the spleen and peripheral tissues 💪: Prazosin 💊, Indoramin 💊 selective antagonists which work near the heart ❤️. So, these receptors carry the commands of the brain directly to the organs 📡.
🅰️2 Alpha-2 Receptors
These receptors are located on presynaptic nerve terminals in the periphery (not in the brain) 🔗: Yohimbine 💊 is a selective antagonist (stops/blocks action of NA) 🛑 and clonidine 💊 is selective agonist ⚡. These receptors are also located in the pancreas 🏥.
🅱️1 Beta-1 Receptors
These receptors are linked to stimulation of adenylate cyclase 🧪. These are found in greater numbers in the heart ❤️ and cerebral cortex 🧠. Epinephrine and NE potent agonists ⚡. The presence of these receptors varies a lot in the brain region 📊.
🅱️2 Beta-2 Receptors
These receptors are linked to the stimulation of adenylate cyclase 🧪. This is found in high concentration in the lungs 🫁 and the cerebellum 🧠. For these receptors E is more potent than NE ⚡. The drug salbutamol 💊 is a selective agonist.
💊 Steps in NA Synthesis Where Drugs Can Modulate Action
As discussed earlier we saw that there were drugs which interacted specifically with the DA synthesis 🧪, in the same way we will see how drugs interact and modify the working of the NA synthesis process 🔄.
Step 1️⃣: Enzyme Synthesis
a) Tyrosine Hydroxylation Blockade
The first step where this neurotransmitter can be modified is at the level of synthesis of Tyrosine 🧬. The hydroxylation of Tyrosine-by-Tyrosine hydroxylase can be effectively blocked by Alpha Methyl Para Tyrosine (AMPT) 🛑: This is the same process as in Dopaminergic synthesis. Since Tyrosine is the precursor for both DA and NA therefore this is the rate limiting step for NA as well ⚠️. Reducing available Tyrosine by AMPT would reduce both DA and NA ⬇️⬇️.
b) Dopamine B-hydroxylase Blockade
The second step in the enzymatic synthesis is where Dopamine B- hydroxylase action on dopamine is blocked by a substance known as Disulfiram 💊, and another drug labeled as FLA-63 💊. Both allow a buildup of Dopamine ⬆️ but conversion to NA cannot take place as this is blocked by the drugs 🛑.
Step 2️⃣: Storage Vesicles
The two drugs which interfere with the storage vesicles are Reserpine 💊, and Tetrabenazine 💊.
- Reserpine effects on the storage vesicles are long lasting ⏳ thereby the effect on NA is also long-lasting. Further, the storage vesicles are irreversibly damaged 💥, and forming new one take time ⏰
- Tetrabenazine also interferes with the storage vesicles 📦, but this is neither long lasting nor irreversible effect ✅
Step 3️⃣: Release
The release of NA is affected by Amphetamine 💊 which increases the release of NA molecules from the presynaptic area ⬆️📤, and also blocks reuptake for enhanced and long-lasting effects ⚡.
Step 4️⃣: Post Receptor Site Interaction
This involves interaction at the post receptor sites 🎯. This could be agonistic ⚡- meaning that they stimulate these sites, or antagonistic 🛑 when they block these sites.
- The drug Clonidine 💊 is very potent receptor stimulant (agonist) ⚡
- Phentolamine 💊 is an A-blocking agent 🛑
- Sotalol 💊 a B-blocking agent 🛑
Step 5️⃣: Reuptake
The action of NA molecules can be stopped by their reuptake into the presynaptic area ♻️ (and back into the vesicles 📦). The drug Desipramine 💊 belonging to the tricyclic antidepressant group, acts through blocking reuptake of the NA molecules (thereby enhancing NA levels in the synaptic cleft) ⬆️.
Step 6️⃣: MAO Degradation
The NA or DA molecules floating in the presynaptic area are degraded or broken down into inactivated forms by MAO ⚗️. This degradation by MAO blocked by the MAO inhibitors 💊 (which inhibit the action of inhibitor) leads to an increase in its levels ⬆️. The antidepressant drug Pargyline 💊 is a potent MAO inhibitor it acts to block MAO action 🛑.
Step 7️⃣: COMT Inactivation
Norepinephrine can be inactivated by the enzyme COMT 🧪 in the synaptic cleft. The drug Tropolamine 💊 blocks COMT action 🛑.
(From Cooper Bloom and Roth pages 180-182) 📚
🎭 NE and Behaviors
We will now proceed to discuss the behaviors which are affected, modified changed or controlled by Norepinephrine/Noradrenaline 🧪.
⚡ Arousal
The behavioral arousal and arousal of electrical activity in the brain is correlated with Increases in NE by MAOI 💊. Thus, Monoamine oxidase inhibition leads to an increase in available NA ⬆️ which leads to increases in arousal as seen in behavioral excitation 🎭 and EEG activity 📊.
Furthermore, in states of stress 😰 NA levels are also increased ⬆️. In states of stress where a person cannot go to sleep (stays awake for long periods because of stress) 😴❌, the NA levels are also increased in the brain 📈.
It is clearly only NA involvement (No DA involvement 🚫- complete depletion of striatal DA still leads to waking and sleeplessness) ⏰.
If NA is injected intravitreally (directly into the brain) 💉 also leads to behavioral excitation 🎭. This means that increases in NA leads to a state of arousal ⚡, excitation 🎪, and increased activity 🏃.
🏃 NA: Conditioned Avoidance
There is evidence that NA is involved in conditioned avoidance in the learning and conditioning paradigms 🧠.
If we inject Reserpine 💊 (which ruptures the vesicles to spill out the NA molecules) 💥 and also Alpha Mehtyl paratyrosine 💊 to block any further synthesis of tyrosine (and DA and NA) 🛑 we find complete abolishment of a learned conditioned avoidance of electric shock ⚡❌. (The animal had earlier learned to avoid shock 🐀, but with no NA the response is gone 🚫). Thus, this shows that NA plays an important role in avoidance behavior 🏃. How? Through either the reward and punishment mechanisms 🎁🛑 or through the learning and memory centers being affected 🧠📚.
🔬 Confirming NA's Role
How do we make sure that it is only decreases in NA which leads to this response? ❓
If we give Disulfiram 💊 or FLA-63 💊 which will increase DA ⬆️ but decrease NE ⬇️ by blocking the synthesis of NE, we also abolish the learnt avoidance response 🚫.
Thus, we have seen that NA is an important NT 🌟 and is involved in a wide range of behaviors 🎭.
📚 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.