🎯 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: 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 💪.
1️⃣ ⚡ 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 Electroencephalographic (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 coeruleus 🧠, which may explain the involvement of Ach in brain electrical activity arousal ⚡.
2️⃣ 💧 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 📡.
3️⃣ 😾 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 lead to a quiet biting attack in rat and cats 😼🦷. How do we know? ❓ This attack is blocked by atropine 💊🛑.
4️⃣ 🛑 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 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 🏥.
🔬 Experimental Setup
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 ⬇️.
🧪 Lesion Effects
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 🚫🛑.
5️⃣ 🧠 Alzheimer
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 ⬇️.
💊 Treatment Approaches
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 ⬆️🧠.
Physostigmine 💊 was 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 reductions 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 ⚠️🩺.
🔗 Other Involvements
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 neurotransmitters, 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 📋.
1️⃣ ⚡ 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 🔗.
2️⃣ 🛑 GABA
Gamma Amino butyric acid (GABA) 🛑 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 ⚖️.
🩺 Clinical Involvement
GABA is implicated:
- Directly in Huntington's chorea 💃 which is due to degeneration of GABAminergic neurons 🧠⬇️
- Indirectly involved in Parkinson's 🤝
- Epilepsy ⚡ (abnormality in the biochemistry of GABAminergic neurons 🧠)
- Schizophrenia 🧠
⚗️ GABA Synthesis
This involves only two steps: one to synthesize it and one to break it down:
1️⃣ One Step Synthesis
One step synthesis from its amino acid precursor Glutamic Acid 🧬 which is decarboxylase by the enzyme Glutamic acid decarboxylase (GAD) ⚗️ and coenzyme pyroxidal phosphate 🧪, this process can be blocked by ions such as chloride and zinc 🛑.
Glutamic acid → GABA ✨
2️⃣ 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) 🧠
- 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
Benzodiazepines 💊 (Valium and Librium) stimulate a particular site of GABAminergic neurons ⚡. This alleviates the anxiety symptoms/response 😰✅.
3️⃣ 🔄 Glycine
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 🚫.
4️⃣ 🔗 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 💉.
Include: BRAIN OPIOIDS 😌, ANGIOTENSIN II 💧 (thirst), Oxytocin and Vasopressin ❤️, Luteinizing 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 Aberdeen 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 opiate's morphine, heroin etc 💉.
In later researches, Huda Akil 👩🔬 and her research group reported that the highest concentration in Substantia Nigra 🖤, lateral hypothalamus 🏥, cerebral Cortex 🧠, Periaqueductal gray 🧠.
🧪 Effects of Brain Opioids
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)
- Akinesia 🛑
- Hypothermia 🥶
- Rigidity 💪
- Catalepsy 🧊
❓ Natural Neuroleptics?
The question is whether brain opioids are natural neuroleptics or not (neuroleptics are antipsychotic drugs) 💊? 🤔
In some cases, psychotic patients who are not responding to other treatment drugs (neuroleptics) 🩺 have responded short term endorphin treatment 😌✅ (Mcgreer and Mcgreer 1980) 📅.
🎭 Behavioral Involvement
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) 📅
🩺 Clinical Applications
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 comforters 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
Narcotic analgesics such as morphine 💉 heroin 💉 are:
- Severely addictive 🔗 and have a high tolerance value ⚠️
- Potent analgesics ⚠️❌
- Potent anti congestion 🫁
- 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
1️⃣ LSD
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 🎭.
2️⃣ Mescaline
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 👨🔬.
📊 Evidence Requirements
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
- 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
- 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.