🎯 Objectives
- Familiarize the students with the Neurochemicals 🧪
- Definition 📖, techniques to study Neurochemical classification: Neuromodulators 🎛️, neurotransmitters 💬, neurohormones 💉
- Criterion for NT ✅, The process of NT transmission 📡
- Processes and Interaction within and outside the cellular membrane 🔬
📚 Main Purpose
The main purpose of this lesson is to study the:
- Types of Neurochemicals: including Neurotransmitter 💬, neuromodulators 🎛️, neurohormones 💉. Criteria of an NT ✅, Processes of NT transmission from synthesis to degradation 🔄
- Importance of neurotransmitters in modulating behaviors 🧠 and Aberration ⚠️
- Drugs and Behavior 💊🎭
- Interaction of Neurotransmitters and Drugs 🧪💊, effect of drug at various sites in the neurons, the NT transmission 📡
🧪 Neurochemicals
Neurochemicals are defined as the chemicals found within the brain 🧠, most of them are either manufactured within the brain 🏭 or are transported to the brain through the blood circulation 🩸. These substances needed for biochemical metabolism of cells ⚗️, ionic movements ⚡, enzymatic action 🔬, changes in metabolism, neural communication 💬 and other mechanisms for support of activities within the nervous system.
🎯 Three Main Characteristics of Neurochemicals
All neurochemicals have three main characteristics:
- Electrophysiological Activity: These must be substances with demonstrated electrophysiological activity ⚡ i.e., changes in electrical/physiological potential of the neurons and therefore can be measured as changes in the brain areas 📊
- CNS Concentration: These are found only in the CNS 🧠 or found in very high concentrations in the CNS as compared to the other areas of the system 📈
- Behavioral Impact: Any changes in their concentration levels would lead to changes in the brain and behavioral states 🎭
📊 Classification of Neurochemicals
We can classify the neurochemicals into four major categories based on their chemical composition 🧪, their roles 🎯 and their functions ⚙️. These are the neuromodulators, neuroregulators, neurohormones and neurotransmitters.
🎛️ Neuromodulators
Neuromodulators: These act to modulate ongoing action within the neuronal systems 🎛️. They fine-tune and adjust the neural activity rather than directly transmitting signals 🔧.
⚙️ Neuroregulators
Neuroregulators: These substances regulate ongoing action, act as 2nd messengers 📬 in neuronal transmission. They support the ongoing transmission by acting as a gating channel ⛩️ (calcium gated channels 🔓).
💉 Neurohormones
Neurohormones: These are secreted by the pituitary 🏥 and hypothalamus 🧠, and these hormones act during the regulation of motivational and other states (circadian rhythms ⏰, stress 😰) to influence hormonal levels and thereby influence behavior 🎭.
💬 Neurotransmitter
Neurotransmitter: These are substances involved in the transmission of neural messages 📡. There are many neurotransmitters which have been discovered so far and their influences on behaviors well known ✅. The neurotransmitter first to be identified was Acetylcholine (Ach) 🎯, which acts on the neuromuscular joints 💪.
🔬 Major Breakthroughs (1950's/60's)
There were three major breakthroughs in the early 1950's/60's 🚀:
💡 Discovery of Monoamines
The discovery of the monoamines: serotonin 😊, dopamine 🎯, epinephrine ⚡ (monoamines) in the brain. These were made by a group of European researchers (Sweden 🇸🇪, UK 🇬🇧, and Italy 🇮🇹) and in the US 🇺🇸.
In 1950's, 60's brains of patients suffering from Parkinson's disease 🤝 were seen in post mortem to have degeneration of a specific area, the dopaminergic rich areas 🧠. Then those patients of Parkinson's who were given L-Dopa 💊 (dopamine stimulant) had a remarkable reduction in Parkinson's like symptoms ✅. This led to the discovery that this Dopamine is important in the Parkinson's disease 🎯. See the film The Awakening 🎬
🔬 Biochemical Procedures
Biochemical procedures for examination of putative NT's were developed 🧪. These were sophisticated techniques such as spectrophotoflourescence 🌟 which made the investigations into the neuronal processes possible 🔍.
💊 Psychoactive Substances
Increased interest after the manufacture and use of:
- Reserpine from rauwolfia alkaloids 🌿
- Chlorpromazine for treatment (by Roche) 💊
- Lysergic acid diethylamide (LSD) 🌀, mescaline 🌵, marijuana 🍃 for recreational purposes. The last three were the drugs which became the drugs of choice for the hippies and the flower children of the 60's and 70's ✌️
These breakthroughs opened the doors 🚪 for investigating neurotransmitters further and it has been shown in the last two decades of the 20th century that a large number of brain chemicals are candidates for neurotransmission 🧪. Further, complex chemical interactions are discovered with every new technique which can expand the researcher's ability to search microscopically 🔬.
🤔 Putative Neurotransmitters
Putative Neurotransmitters are those which are suspected as/possible Neurotransmitters (NT) 🤔. There is strong evidence to suggest that status, but these Neurochemicals have yet to complete the criterion of a NT ⏳. These are some 50 neuropeptides 🧬 (such as brain opioids: endorphins 😌) which are still waiting to be verified ✅. Similarly, some amino acids and other chemicals which are found in the brain may be NT, depending upon how well they clear the conditions laid down for the NT status 📋.
💊 Psychopharmacology
Psychopharmacology as a discipline emerged around the time psychotropic drugs were discovered and manufactured late 1940's early 50's 🕐. Psychoactive substances (major tranquilizers 😌, Chlorpromazine (CPZ) 💊 and Reserpine 💉 were found to alleviate symptoms of schizophrenia 🧠. This appears to be the first links between drugs and behavior 🔗, eventually the discovery that this action takes place in a very minute and specific site. Where does the action take place? In the synapse! 🎯
🔌 Synapse
Synapse: The synapse is the junction between two neurons where one is communicating with the other 💬. The usual communication is between the axon of the messaging neuron and the dendrite of the receiving neuron (axo-dendritic) 🔗, but then there are axo-axonic 🔗, axo-somatic 🔗 synapses as well. Each synapse has three main components: the presynaptic ending 📤, the synaptic cleft 〰️ and the post synaptic ending 📥. This is a very small space (a few Angstroms) ⚛️ within which a large amount of chemical activity is taking place 🧪.
📤 Pre-Synaptic Membrane
Pre-Synaptic Membrane is a very busy place 🏃. It has many:
- Synaptic vesicles 📦 (storage containers made up of membrane) containing NT
- Mitochondria ⚡ to provide energy to the cell as metabolism generators
The vesicles i.e., Storehouses where the transmitter is stored moves from the cell soma to the presynaptic ending 🚚. Once the excitatory action potential stimulates the presynaptic ending to action these would fuse with the membrane to release NT through a process known as Exocytosis 💥.
💥 Exocytosis Process
In Exocytosis the synaptic vesicles blend with the pre synaptic membrane 🔗, opens up and ruptures to release the molecules of the Neurotransmitter in the cleft 💨. The rupture eventually mends 🩹. The NT molecules spill out in the cleft and travel across the cleft to reach the sites of the post synaptic area 🎯.
〰️ Synaptic Cleft
Synaptic Cleft: This is a minute space between pre and postsynaptic membranes 〰️ and is surrounded by the extra cellular fluid 💧. A synaptic web 🕸️ (a fine web like mesh made of glial cells) holds the pre and post synaptic sites together in the same configuration that they exist.
This is not an inactive place ⚠️, there are large numbers of chemicals floating around in the cleft to inactivate NT molecules which have not been able to successfully cross over to the postsynaptic site and which would otherwise be harmful if they remain in this area 🧹. After release NT, molecules travel to the post synaptic site 🎯. They cannot stay in the cleft and cannot continue to activate the post receptor site even if the passages are open 🚫, otherwise once released NT molecules can last a lifetime ♾️.
Nature's Balance: Nature has a balance and has mechanisms of cleaning up the debris 🧹. The NT molecules have to be inactivated and disposed of so as to leave the passage clean for other NT molecules 🔄. The processes of inactivation 🛑 or reuptake ♻️ take care of these stray molecules. There are two kinds of inactivating enzymes ⚗️ and we would talk about them in detail later.
📥 Post Synaptic Membrane
Post Synaptic Membrane: The postsynaptic membrane can either be the cell soma (axo-somatic) 🔘, dendrites (axo-dendritic) 🌿 or even axons (axo-axonic) 🔗 of other cells. These are the receiving ends with appropriate "sites" 🎯 for molecules to get into these sites to lead to an excitatory post synaptic potential (EPSP) ⚡➕ or an inhibitory post synaptic potential (IPSP) 🛑➖.
⚡ Postsynaptic Changes
When NT molecules get successful entry into the postsynaptic site they change the electrical charge ⚡ or permeability of the membrane leading to ionic and electrophysiological changes in the post synaptic membrane 🔄. These changes depend on:
- a) Type of neurotransmitter 🧪 (some are inhibitory 🛑, some are excitatory ⚡)
- b) The neuroanatomical sites 📍 on which they are located (some NT are excitatory at one location and inhibitory at another 🔄)
- c) The amounts of NT released 📊
The synapse is an area which will be discussed in detail for each NT 📚 and the events taking place in the synapse would be related to the action of the NT and drugs 💊 which affect the NT synthesis and metabolism 🧪.
✅ Criterion for NT
As discussed, there are over 200 candidates for the candidacy of a full neurotransmitter 🧪. However, very few have satisfied the scientific and strict criterion laid out which has to be fulfilled before a Neurochemical can be termed as an NT ✅. The putative NT's have to fulfill the following criterion 📋:
📋 The 12 Criteria for Neurotransmitter Status
1️⃣ Localization
The presence of the NT molecules has to be identified in the presynaptic ending of the neuron 📍. This is done using the cytochemical methods such as histoflourescence techniques 🌟, autoradiography 📷 and later visualizing them using the light 💡 and electron microscope 🔬.
2️⃣ Storage
Storage of the NT or its precursor in the presynaptic terminal 📦: There has to be clear evidence of the vesicles which contain the NT in the presynaptic ending as well as the presynaptic neuron 🧪.
3️⃣ Presence of Precursor
The Presence of Precursor (the chemical from which the NT is to be synthesized) 🧬 and appropriate enzymes for synthesis of NT should be found within the presynaptic neuron ⚗️. Each neuron independently manufactures its own NT (like a small factory 🏭).
4️⃣ Release Mechanism
With the appropriate stimulation the release of the NT should be demonstrated from the presynaptic ending into the synaptic cleft 💨. There should be movement of the vesicles towards the presynaptic area 🚚, through the exocytosis, release of NT molecules should take place 💥. This release should be measurable 📊, in amounts of NT released (through the push pull cannulae 💉).
5️⃣ Synaptic Mimicry
Synaptic Mimicry: Since the NT has a particular chemical configuration 🧪, drugs with the same chemical composition, if injected into the synapse should lead to a mimicking (copying) 🔄 of the Neurotransmitter effect (as if the neuron is stimulated) ⚡. We can measure using the push pull cannulae, the chemicals and metabolites which can be drawn from the synapse to see if the action was similar 📊.
6️⃣ Recognition and Binding
Recognition of and binding to sites in the postsynaptic areas 🔗. Once the NT molecules are released, they must travel across the synapse and recognize the sites to which they can bind in that area 🎯.
7️⃣ Existence of Receptors
Existence of Receptors on The Post Receptor Sites 🔓: there has to be a clear demonstration that there are receptor proteins to bind to the NT 🧬, the shape and the form of the receptors should be in the same chemical configurations as the NT (so they match 🔐), then the NT can be accepted into the postsynaptic site ✅.
8️⃣ Effect On Post Synaptic Membrane
Effect On the Post Synaptic Membrane ⚡: Once it is accepted in the post synaptic site, it should lead to an action whether an EPSP ➕ or an IPSP ➖. This would demonstrate the effect of the NT 📊.
9️⃣ Inactivating/Deactivation Mechanism
Inactivating/Deactivation Mechanism 🛑: The released NT molecules have to be inactivated; there must be demonstrated presence of the inactivating mechanisms or processes 🧹. These chemicals or enzymes should inactivate the free NT molecules in the presynaptic membrane and the cleft ⚗️. There should also be a demonstrated reuptake mechanism ♻️.
🔟 Predictable Pharmacological Effects
Predictable Pharmacological Effects 💊: Endogenous substances with known pharmacological (synthetic) compounds, properties should have the same demonstrable and similar effects 🔄.
1️⃣1️⃣ Post Synaptic Effects
Post Synaptic Effects: enhanced by similar chemicals ⚡ and blocked by antagonists 🛑 or blocking agents that is those drugs which are similar should stimulate the NT activity ➕, and those which are anti agents should block its activity ➖.
1️⃣2️⃣ Selective Stimulation
Selective Electrical or chemical stimulation should lead to release of the NT from the prejunctional endings ⚡ and amount of NT released should be correlated to the amount of stimulation 📈.
Thus, we see that the criterion for a NT is tough ⚠️, but ongoing research shows that more and more NT's are joining the list of active NT's 📈. We will discuss the NT more in detail in the next lessons 📚.
📚 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