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Transcript
Physiology 2 Sheet #9 Dr Loai Zgoul Done By : Maher Shaheen In last lecture we talked about neurotransmitters that act as modulators, the most important modulater is Biogenic Amines such as : dopamine , norepinephrine , serotonin . The first one : Dopamine The source of dopamine in the brain: 1. substanial nigra. 2.ventral tegmental area. Then it will go to the cortex in three pathways : 1. substanial nigrastriatum (part of the basal gangliaregulates the motor system, (nigrostiatal pathway) 2. Ventral tegmental arealimbic system(mainly to the nucleus accumbens)related to the emotions especially pleasure emotion and the reinforcement because we redo things we happy to do. (mesolimbic pathway) 3. Ventral tegmental areacortex (mainly frontal), the most importantrelated to thinking, decision making and social interaction. Dysfunction in the first pathwaymotor is destroyedParkinson disease. Dysfunction in the second pathwayemotions are disrupted Cocaine has the same idea of the second pathway; when someone takes cocainethe second pathway will be activateddopamine is activated and will activate the nucleus accumbenswhich will enhance the pleasure feelingaddiction will occur for repeating it all over again. For more clarification : if we had and exam , and we studied very hard and got high mark in that exam , we would feel happy , so nucleus accumbens is activated by dopamine (which is also activated by our happiness ) and then we’ll always study hard because nucleus accumbens is activated by studying hard. Now, over activation of this pathway will lead to hallucinationwhich is one of the symptoms of schizophrenia. *Schizophrenia has positive and negative symptoms, positive like hallucination and negative like anhedonia. Anhedonia: means that nothing makes the patient happy or desire anything, and can do no social interaction. Dysfunction of the 3rd pathwaydecrease in exploring, decrease in social interaction, no enhancement of happiness or working and depressionanhedonianegative symptoms of schizophrenia. Increase in dopaminepositive schizophrenia symptomsdecreased by dopamineantagonist or D2-agonistnegative schizophrenia symptoms. So we can’t control the schizophrenia accurately. The transporter of dopamine is affected by two molecules: cocaine and amphetamine, these molecules inhibit the function of the transporterwhich will cause the accumulation of dopamine in the synaptic cleft (increase in concentration), so those are very effective drugs. Physiology 2 Sheet #9 Dr Loai Zgoul Done By : Maher Shaheen The second one : Norepinephrine The cell bodies of neurons that release nor epinephrine are located in an area in the brain stem which is called "nucleus locus coeruleus" . It is a slow neurotransmitter ( modulator ) As we said previously , dopamine are affected by cocaine and amphetamine , but here there is another state, norepinephrine are affected by amphetamine ( same as dopamine ) , but there is another drug affects norepinephrine only ( not dopamine ) , this drug is called Desipramine . How norepinephrine generates a response for any stimuli ? Stimuli (Zy lma el Dr 5b6 3la el 6awleh w 5lana ne97a ) Activation of locus coeruleus release of norepinephrine in the brain attention If locus coeruleus is sensitive to any small stimuli, it'll release more epinephrine than needed and this would keep the patient aware with extra attention causing him a stress disorder, such as: anxiety. Norepinephrine works on types of receptors : β1 receptors , α2 receptors In addition to the function of norepinephrine in enhancing attention , it will also affects mood regulation , learning and memory . Learning and memory , attention stimuli activation of posterior part of prefrontal cortex connects to α2 receptors increase releasing of norepinephrine if there was any defect ADHD ( attention deficiency hyperactivity disorder ) , anxiety may occurs Mood regulation activation of frontal cortex (area on brain are responsible for personality) connects to : β1 receptors releasing of norepinephrine if there was any defect on the receptor decreasing noreepinephrine bad mood may lead to Depression Physiology 2 Sheet #9 Dr Loai Zgoul Done By : Maher Shaheen Nor epinephrine goes to many subcorticals such as : limbic system that is related to our emotion ,so , if there is higher norepinephrine in these locations our energy level will be higher , this is called psychomotor active If there is little norepinephrine the energy level and emotions will be lower , so this is called psychomotor inactive ( retardation ) The third one : Serotonin serotonin is synthesized from the amino acid " Tryptophan" Tryptophan is an essential amino acid, we get it from diet since we can't produce it in our bodies. This means that the synthesis of serotonin depends on the presence of tryptophan so this is the rate limiting step . serotonin is releases from region in the brain stem that is called raphe nucleus ( rapha always refers to serotonin only ) serotonin as other neurotransmitter goes to all regions in the brain and it is the denser neuromodulator in the brain, and it is the most abundant. serotonin has 21 receptor and they discovered more in the last few years .these receptors are divided into families , each of them operate in a certain way . You should memorize these receptors , but you do this easily by following these steps : 5HT 3 : Works through ion channels 5HT1 inhibitory ( inhibits cAMP ) 5HT2 : Works through PLC system Other receptors rather than which are mentioned above stimulates cAMP ( excitatory ) 5HT1A , 5HT1B , 5HT2B are receptors located on presynaptic nerve cell membranes or on the serotonin neuron itself, to regulate the release of the neurotransmitter Physiology 2 Sheet #9 Dr Loai Zgoul Done By : Maher Shaheen Serotonin works through 17 receptors and controls most of the functions of the brain : mood, sleep, sexuality, impulsivity, aggression, stress, drug abuse. It's related to many diseases and disorders: Depression, Schizophrenia, OCD (obsessive compulsive disorder), Eating Disorders, and Autism. There are lots work on serotonin receptors such as Antipsychotics ( you don't memorize the drugs in the slide , Ra7 tmor 3lena bl pharma in details ) We can notice that there is a combination between norepinephrine , dopamine, serotonin , each one affects the other , so new antidepressant drugs have more than one active site , so , they will work on these three amine system i.e they can work on dopamine and serotonin for example Most important treatment and drugs associated with serotoninselectiveserotonin reuptake inhibitor (SSRI) inhibition for the reuptake or to its transporterincrease serotonin at the synapsesrelive of the depression . Neuropeptides : those are neurotransmitters made out of proteins, proteins are made in the ribosomes in the cell body of the neuron, and the axon is very long, so making and transferring the neuropeptides to the terminals will take so much time, it’s released in the synaptic terminal. So, it’s made in the cell bodyin vesiclesbinds to the motor transport proteincytoskeletonfinally, to the terminals. This means I’ll have fewer supplements or less quantity of the protein in the terminal, so normally neuropeptides are available in small quantities. So to control that, it should work very effectively and do good amplification, so they all work through , G-protein receptors, so they are very potent (high efficiency), they are modulators Sometimes we can see that neuropeptides are available with other neurotransmitters such as : glutamate , Acetylcholine , etc . The most important family of neuropeptides is the oboid : Those are large family and very important in pharmacology because they are strong pain killers ( analgesic) But before talking about these pain killers , we must talk a little bit about pain : Pain: is one type of sensations, and it is the oldest, and is transferred to the brain through the ALS (slow), more than one level affect the pain before it reaches the cortex, and the first level is the spinal cord, and to all the sub cortical levels, that’s why pain is very associated with emotions which is the sub cortical responsibility. Physiology 2 Sheet #9 Dr Loai Zgoul Done By : Maher Shaheen There are some terminology related to the pain ( you should memorize them jay so2al 3lehom in the exam) The pathway starts from the norepinephrine, from the pain receptors (nociceptor receptors or free nerve ending), they detect pain by changing the signals from chemical to neuronal signals, and those chemicals are: tissue damage, cell death, inflammation, trauma, etc. So the pain is detected by those receptors and goes to the ALS pathway to the cortex, but also it sends many branches through all the sub cortical regions. Pain goes to the thalamus then cortex in a way that it is faster than the way which pain passes through it to reach subcortical regions After that , the pain go to region is called periaquaductal grey ( modulator to the pain) then to locus correlus (it sends ascending to the cortex and descending to the spinal cord) There are two neurotransmitter that can send signals to the spinal cord : norepinephrine , serotonin We said that the upper levels controls the lower levels, and pain awakes the upper level to pay attention, and that’s one of the reflexes job, which means that I can ignore or delete the pain reflexes Physiology 2 Sheet #9 Dr Loai Zgoul Done By : Maher Shaheen So we need pathways to control the pain even more, and that’s why we have the descending control of the pain, relive the pain, ignore the pain, or even change the mean of the pain. The first one is the cortex: usually it doesn’t go directly to the spine (sometimes it can), so it goes to the sub cortical, what goes down to the spinal cord -depending on what the cortex wants, can increase or decrease the pain. The second one is subcortex : through hypothalamus will connect to the parts beneath it in the brain stem and will affect the pain perception, usually to decrease the pain , so , that's why pain is linked with emotion to try avoiding pain as much as possible . The last two are the periaquiductul grey and the locus cerrelus, receive innervations from the pain to do an action like regulated pain, one way to regulate the pain is to descend down and affect how we feel the pain, mainly the cortex is responsible for doing that, so we can say that job of these two parts is to inhibit the pain. They are 3 types (we only going to mention 2): 1.enkephalon. 2. Endorphin. Encephalon is the smallest, the least known and least distributed in the brain, binds to an oboid receptors (sub family), its cell body is located mainly periaquaductal grey. periaquaductal grey takes the pain and descend back down to the spinal cord, so that’s how enkephalon regulates the pain. One way to ignore the pain is by blocking the pain from reaching the cortex by blocking the ALS pathway (by inhibiting the synapse) to stop it from reaching the upper level, by inhibiting the pathway. They can work alone sometimes, but usually they need a controller from above to tell them block the synapse coming from a pain , the pathway is coming from the periaquiductal grey, and encephalon neurons won’t work if they were too long, so they try to be short, so instead of going to the spinal cord they will go to the raffia nucleus to send the information to the encephalon neuron there to delete the pain. Raffia nucleusserotoninencephalon inhibition of the synapses no transmission won’t reach the cortexno pain felt. Note : we can ignore the pain, because the analysis in the state of our mind decide if there is a pain or not , so , sometimes you can forget that you have a pain and concentrate on another thing . Note : We can relieve the pain by giving blocker to pain receptor , but this way is very dangerous because the pain receptor is very important for lots of things , so, the better way to relieve the pain is give non steroidal anti inflammatory drugs to inhibit chemical signal such as : inflammation through prostaglandin , trauma, tissue damage etc . GOOD LUCK Physiology 2 Sheet #9 Dr Loai Zgoul Done By : Maher Shaheen