Neurotransmitters and Neurotransmitter Dysfunction PDF

8/21/24 Ne urot ra ns m it t e rs a nd Ne urot ra ns m it t e r Dys funct ion PSYU2236 / PSYX2236 Biop s ychology & Le a rning Le c t ure r :...

8/21/24 Ne urot ra ns m it t e rs a nd Ne urot ra ns m it t e r Dys funct ion PSYU2236 / PSYX2236 Biop s ychology & Le a rning Le c t ure r : Dr Chris t ina Pe rry 1 Out line 1. Reminder of w h a t happens a t the synapse 2. Neurotransmitters (Kalal module 2.2) 1. Definition of a Neurotransmitter 2. How they are made 3. What types and where they are in the brain 4. Neurotransmitter System Dysfunction 1. Monoamines 2. Disorders of the Monoamine Systems - Schizophrenia - Depression 2 1  8/21/24 Re ca p The Synapse 3 Che m ica l Syna p s e s RECAP – EVENTS AT THE SYNAPSE Neurotransmitters Chemical synapses are typically fo rm e d between an axon term inal (b u tto n /b o u to n ) and a dendritic spine They use neurotransm itters t o convey messages Presynaptic What happens when the action potential reaches the presynaptic bouton? 1. Increase in calcium in axon terminal 2. Vesicles (containing neurotransm itters) are moved Vesicles t o th e membrane and dock 3. Once docked, vesicle co n te n t is em ptied into synapse (exocytosis) Postsynaptic What happens after release? N eurotransm itters bind t o receptors on postsynaptic Bouton dendrites Receptor Synaptic Cleft (2 0 -50nm) Active Zone exo means to leave 4 and cyto means related to the cell 4 2  8/21/24 Eve n t s a t t he Syna p s e RECAP – EVENTS AT THE SYNAPSE 5 Taking it back up into the cell is called endocytosis and it can occur via NT's (neurotransmitters) 5 Pre s yna p t ic Axon Te rm ina l RECAP – EVENTS AT THE SYNAPSE N eurotransm itter synthesis Synaptic vesicle transporters Reuptake transporters Enzymes t o metabolise neurotransmitters 6 6 3  8/21/24 Pos t s yna p t ic d e ns it y RECAP – EVENTS AT THE SYNAPSE Receptors N eurotransm itters com m unicate w i th p o st synaptic neurons via receptors Receptors can connect to: 1. Ion channels (ionotropic receptors) 2. G-proteins (G-protein coupled receptors) 3. G-protein coupled ion channels they do it the same way ionotropic receptors do but they do it slower because they have to metabolise Study o f receptors systems is called Neuropharmacology 7 There are a lot of proteins here 7 But not the vessicles? Wha t is a ne urot ra ns m it t e r? NEUROTRANSMITTERS There are 5 rules t o being a tru e “classical” chemical neurotransmitter A. The chemical m u s t exist (made and stored) in presynaptic cells (stored in terminals) B. The chemical m u s t be released fr o m presynaptic term inals on action potential C. Released chemical m u s t bind t o receptors and cause a biological effect D. There m u s t be a mechanism t o inactivate or metabolise th e chemical E. The chemical should have th e same biological e ffe c t if artificially applied t o synapse (e.g. by microinjection t o brain area - exogenously applied) So if you micro inject Glutamate (arti cially) then it should create the same e ect as the natural e ect from the neuron. 8 4  8/21/24 Ne urot ra ns m it t e r (NT) Re q uire m e nt s NEUROTRANSMITTERS Presynaptic terminal D. Inactivation D. Metabolism/Inactivation NT Unbound NT transported in to presynaptic terminal ✨✨ NT gets broken down or repackaged in vesicles (reuptake = endocytosis) A. Chemical exists presyn. NT release (exocytosis) E. Application of ✨✨ B. Release on Action Exogenous chemical produces same effect NT Binds Potential to receptor Recepto r C. Act on receptor = biological effect Post Synaptic Density (PSD) 9 Wha t a re t he ne urot ra ns m it t e rs ? NEUROTRANSMITTERS Monoamines are formed from Amino Acids Amino Acids – acids containing an amine group (NH2 ) Acetylcholine – similar to amino acids, but containing an N(CH3 )3 group Monoamines/Trace Amines – formed in a certain way from amino acids Peptides (e.g., Substance P) – chains of amino acids Lipids - (e.g. Anandamide) Purines - (e.g., adenosine) Soluble gases - (e.g., Nitric Oxide) 10 5  8/21/24 Rough ER= Rough Endoplasmic Reticulum Synt he s is of Ne urot ra ns m it t e rs NEUROTRANSMITTERS Peptides (made in the soma) Precursor peptide (small protein) synthesised in rough ER Cleaved in Golgi apparatus t o active neurotransm itter Secretory vesicles b u d o f f f r o m Golgi apparatus Secretory granules (large vesicles, 100 n m ) tra n sp o rte d t o te rm in a l and stored Monoamines, Amino Acids & Acetylcholine (made in the p re -synaptic terminal) Precursor m olecule (f ro m diet) synthesised t o neurotransm itter Transported t o synaptic vesicle (50 n m ) and stored They are packed into the vesicle in the pre-synaptic terminal 11 Synt he s is / St ora ge of Ne urot ra ns m it t e rs NEUROTRANSMITTERS Synaptic Peptides Precursor Vesicles Active peptide Peptide neurotransmitter Nucleus 4 1 2 3 Secretory Golgi granules Apparatus Precursor Molecules Rough Endoplasm ic 1 SE Monoamines/ Reticulum Neurotransmitter Amino Acids SE = synthetic enzyme 2 VT VT = vesicular transporter protein Synaptic Vesicle From ‘Neuroscience: exploring the brain’ Bear/Connors/Paradiso 2001, pp108 The Rough ER will create a blueprint for the precursor peptides which are synthesised in the Rough ER and then transported to the GA. In the GA they are broken down into active peptide NT's and these are the secretory vesicles that "bud o " from the GA and are transported down the axon of the neuron to the pre-synaptic terminal where they are stored and packaged as vesicles. 12 6  8/21/24 Synt he s is of Ne urot ra ns m it t e rs NEUROTRANSMITTERS Mostly synthesised fr o m amino acids ➔ Protein or other elements in diet Enzymes in th e cell break dow n these proteins t o make different neurotransmitters Neurons can be specialised t o produce certain neurotransmitters Kalat Sometimes referred to as Noradrenaline me Sometimes referred to as Adrenaline 13 13 Dis t inguis h ing b e t w e e n Ne urot ra ns m it t e rs NEUROTRANSMITTERS Peptide neurotransmitters are made in the soma and transported in secretory granules to the terminal Monoamines, amino acids and acetylcholine are made from precursor molecules in the terminal and are transported into synaptic vesicles 14 7  8/21/24 The Life of a Ne urot ra ns m it t e r NEUROTRANSMITTERS Peptides are transported Acetylcholine too! Monoamines Amino Acids Peptides made in terminals made in the soma Stored in vesicles Released Metabolised or Reuptake 15 I don't particularly like classifying the functions of NT's because NT's have di erent functions depending on where they are. E.g. when Oxytocin is described as the love hormone or when Dopamine is exclusively labelled as the reward hormone. They're heuristics because they grossly underestimate the functions of those NT's. Ma jor Role s NEUROTRANSMITTERS Dopamine is important for wanting and not liking, these are two di erent things Dopamine Glutamate Short term memory Serotonin Major Excitatory NT Strategy & planning Cognition Learning & Memory Reward Emotion Neuroplasticity Movement Reward Excitotoxicity Monoamines Amino acids Noradrenaline Attention GABA Acetylcholine Flight/Fight Major inhibitory NT Memory Perceptual Learning Sleep Modulates various processes Movement REM Sleep Ultimately NT's are signals and they bind to speci c receptors which exist on neurons that have speci c down stream connections but that depends on where they are in the brain and their function depends on which part of the brain they're released into e.g. the NaC, the VTA etc. They switch things o but in doing so they also switch other things on 16 8  8/21/24 Am ino Ac id s NEUROTRANSMITTERS Common Amino Acid Neurotransmitters Produce excitatory e ects Both GABA and Glycine are inhibitory Glutamate GABA LGlycine Aspartate (Gamma Amino Butyric Acid) Brainstem Spinal Cord 17 Am ino Ac id s : w he re a re t he ce ll b od ie s ? NEUROTRANSMITTERS Glutamate GABA GABA is also found in interneurons. Glutamate is the "on" switch GABA is the "o " switch 18 9  8/21/24 There are a lot of GABA interneurons in the Neo Cortex (25%) and are responsible for inhibitory control via activation of ionotropic GABA receptors which gate Cl (Chloride) entry into neurons. GABA In t e rne urons NEUROTRANSMITTERS Interneurons are small neurons retained in the one brain area GABA or Acetylcholine are commonly in interneurons Interneuron Projection neuron To next brain area Ventral Tegmental Area Nucleus Accumbens Parameter neurons project to other regions of the brain and they are almost always glutamatergic and excitatory and GABA neurons in the cortex are interneurons and these project from one structure within the same structure and they perform complex micro circuits which means that one structure can regulate di erent elements of the same behaviour. 19 Am ino Ac id Synt he s is NEUROTRANSMITTERS Glutamate, aspartate and glycine are c o m m o n amino acids GABA is a specific amino acid present only in GABA cells Glutamate Glutamic acid decarboxylase (GAD) GABA (y-amino-butyric acid) GABA comes from Glutamate 20 10  8/21/24 Am ino Ac id Me t a b olis m NEUROTRANSMITTERS Glial cell Terminal GABA transaminase GABA transaminase breaks down GABA breaks down GABA Glutamate is recycled GABA or glutamate reuptake (transporters) Synapse Postsynaptic density/dendrite Glutamate is neurotoxic (kills neurons) in high amounts - glial cells work to reduce toxic levels 21 If they're not e ectively reduced by the glial cells then there will be too much excitation and then there will be programmed cell death (apoptosis). 21 Now we're going to focus on Acetylcholine Ma jor Role s NEUROTRANSMITTERS Dopamine Glutamate Short term memory Serotonin Major Excitatory NT Strategy & planning Cognition Learning & Memory Reward Emotion Neuroplasticity Movement Reward Excitotoxicity Monoamines Noradrenaline Amino acids Attention Flight/Fight GABA Major inhibitory NT Acetylcholine Sleep Memory Modulates various Perceptual Learning processes Movement REM Sleep Cholinergic neurotransmission is a crucial process underlying memory and cognitive function. What does it mean if a NT is Cholinergic? 22 11  8/21/24 Ac e t ylcholine : w he re a re t he ce ll b od ie s ? NEUROTRANSMITTERS 23 23 Please remember to re-number this from Acetyl to Choline to Coenzyme A to Acetylcholine Ac e t ylcholine Synt he s is NEUROTRANSMITTERS Acetylcholine (ACh) is predominantly excitatory (+) ACh is taken up by the ACh transporter into vesicles and stored 1. Acetyl coenzyme A 3 Coenzyme A (acetyl Co-A) (CoA) 2. 4 Choline Acetylcholine Choline comes from our diet Choline acetyltransferase (ChAT) This reaction is called ChAt (it's a marker for Cholinergic cells) 24 12  8/21/24 Ac e t ylcholine Me t a b olis m NEUROTRANSMITTERS Acetylcholine is broken down by Acetylcholine esterase (AChE) Acetylcholine AChE Choline Acetic Acid ACh m e ta b o lism occurs in th e synaptic c le ft Choline is th e n tra n sp o rte d in to th e presynaptic cell f o r r e - use Many insecticides or nerve gases inhibit AChE Enhances ACh transmission at muscle and heart Death usually by respiratory paralysis 25 Acetylcholine Life-Cycle NEUROTRANSMITTERS This is where ChAt is working More choline detected in the synaptic cleft = reduces ACh production Rate limiting step is choline in synapse - inversely related (negative feedback) Negative feedback explanation This means that where there's more Choline in the Synaptic cleft there's going to be less choline in the neuron so that will reduce Acetylcholine production. 26 13  8/21/24 Ma jor Role s NEUROTRANSMITTERS Dopamine Glutamate Short term memory Serotonin Major Excitatory NT Strategy & planning Cognition Learning & Memory Reward Emotion Neuroplasticity Movement Reward Excitotoxicity Monoamines Noradrenaline Amino acids Attention Flight/Fight GABA Major inhibitory NT Acetylcholine Sleep Memory Modulates various Perceptual Learning processes Movement REM Sleep 27 Serotonin is produced in response to light whereas Melatonin is inhibited in response to light. Both help us regulate our circadian rhythms. Anti-histimines make you sleepy Monoamines NEUROTRANSMITTERS 3 Catecholamines + 2 Indolamines Dopamine Serotonin (5-HT) Melatonin Noradrenaline (Norepinephrine) Circadian Rhythms Histamine Wakefulness Low levels in brain Adrenalin (Epinephrine) Posterior hypothalamus hormone from kidney (Adrenal) Forebrain 28 14  8/21/24 In this course we're more interested in (NA) (DA) and Serotonin. The SN projects dopamine towards the nigrostriatal system (NS). Whereas the VTA projects dopamine to the mesolimbic system (pathway). MSP Whe re a re t he Dop a m ine a nd Nora d re na line Ce ll Bod ie s ? NEUROTRANSMITTERS They project into the cortex and downstream into the vagal nerve and peripheral systems, including the cerebellum. Noradrenaline (NA) Dopamine (DA) There are about 14 di erent routes of dopaminergic cells that project around the brain. The ones in the ventral tegmental area (VTA) and the substancia nigra (SN). 29 The Catecholamines come from Tyrosine, which (come from our diet) Monoa m ine Synt he s is (Ca t e chola m ine s ) NEUROTRANSMITTERS Tyrosine Tyrosine is an amino acid w e get f r o m our diet We can also make Tyrosine f r o m Phenylalanine L - DOPA The enzyme that catalyses the Dopamine reaction from Tyrosine to L Dopa is called TH and it's a really common marker for dopaminergic neurons. Noradrenaline Released fr o m Kidneys Also have cell bodies in hindbrain Adrenaline 30 15  8/21/24 Whe re a re t he Se rot onin Ce ll Bod ie s ? NEUROTRANSMITTERS Dorsal raphe also contains serotonin cell bodies projecting to cortex Serotonin (5-HT) 5-HT is shorthand for Serotonin. 5-HT is produced in the raphe nuclei (all three above) they project into the cerebellum and then form the rostral raphe into the cerebral cortex and hippocampus. 5-HT is also produced in the gut but we're not going into that. 31 Monoa m ine Synt he s is (Se rot onin) NEUROTRANSMITTERS Tryptophan Which is why it's called 5-HT. 5-Hydroxytryptophan Psychedelics produce most of their e ects on the 5-HT receptors 5-Hydroxytryptamine (Serotonin, 5-HT) Tryptophan is an amino acid Found in grains, meat & dairy 32 16  8/21/24 Monoa m ine Me t a b olis m NEUROTRANSMITTERS Monoamines deactivated by Glial cell Monoamine Oxidase (MAO) or repackaged into vesicles Mitochondria MAO Terminal Monoamine reuptake by transporters Synapse Postsynaptic density/dendrite MAO inhibitors used as antidepressants They used to be used as antidepressants. 33 Monoa m ine Me t a b olis m NEUROTRANSMITTERS Dopamine is released from dopamine cells (Dopaminergic cell ➔ contains tyrosine hydroxylase) Noradrenaline is released from noradrenaline cells (Noradrenergic cell ➔ contains dopamine b hydroxylase) Serotonin is released from serotonin cells Each monoamine has its OWN transporter: Dopamine = DAT Noradrenaline = NET (due to US naming of norepinephrine) Serotonin = SERT They are each taken up into their own cell and metabolised or repackaged into vesicles Amphetamines all inhibit dopamine. Meaning that they all cause an excess (increase) of dopamine at the synaptic cleft. 34 17  8/21/24 How d o Ne urot ra ns m it t e rs Com m unica t e w it h t he Ne xt Ne uron? NEUROTRANSMITTERS Receptors! Release o f a n e u ro tra n sm itte r binds t o a receptor t o t e ll th e n e xt neuron w h a t t o do Drugs t h a t bind t o th e receptor and a ffe c t th e neuron: AGONISTS Drugs t h a t bind t o th e receptor b u t d o n ’ t a ffe c t th e neuron: ANTAGONISTS 35 Dive rs it y of Re ce p t ors µ,o,K 5-HT1A, B, D, E, F Nicotinic 5-HT2A, B, C D1, D5 5-HT3, 5-HT4, 5-HT5 Muscarinic TAR D2, D3, D4 5-HT6, 5-HT7 (M1-4) H1-3 A1, 2 NMDA sst1-5 a1A,B,C,D OT GLU1-4 V1A,B a2A,B,C GLU5-7 P1 NK1 V2 AMPA /31-3 P2X NK2 KA1, 2 P2Y NK3 CCK1 mGluR1-7 CCK2 GABA-A Y1,2 GABA-B CB1, 2 Y4-6 There are receptors found that don’t have neurotransmitters! (yet) 36 18  8/21/24 1. Sum m a ry – pa r t 1 Know th e 5 rules o f defining a chemical neurotransmitter Know your amino acids, acetylcholine and monoamines Know WHERE they are made how they are metabolised (you do n o t need to know th e chemical reaction fo r their synthesis (manufacture)) Know where their cell bodies are 37 Bre a k Bre a k Tim e 38 19  8/21/24 Ne urot ra ns m it t e r Dys funct ion 39 Ne urot ra ns m it t e r (NT) Re q uire m e nt s NEUROTRANSMITTER SYSTEM DYSFUNCTION Presynaptic terminal D. Inactivation D. Metabolism/Inactivation Unbound NT transported NT gets broken down in to presynaptic terminal or repackaged in vesicles (reuptake = endocytosis) A. Chemical exists presyn. NT release (exocytosis) E. Application of Exogenous chemical B. Release on Action produces same effect NT Binds Potential to receptor Recepto r C. Act on receptor = biological effect Post Synaptic Density (PSD) You can mimic or block the action of that NT by producing an arti cial ligand (see chemistry) which blocks the e ect of that NT. 40 20  8/21/24 Monoamines NEUROTRANSMITTER SYSTEM DYSFUNCTION 3 Catecholamines + 2 Indolamines Dopamine Serotonin (5-HT) Melatonin Noradrenaline (Norepinephrine) Circadian Rhythms Histamine Wakefulness Low levels in brain Adrenalin (Epinephrine) Posterior hypothalamus hormone from kidney (Adrenal) Forebrain 41 Mona m ine Sys t e m Dys fu n c t ion NEUROTRANSMITTER SYSTEM DYSFUNCTION (Repeated) psychostimulant drug abuse (Mod 14.1) Depression Paranoid psychosis Similar to schizophrenia Anxiety Parkinson’s like symptoms Module 14.3 Modules 14.2, 11.2 & 7.3 Seizures If you have repeated psycho-stimulant drug abuse (amphetamines and cocaine) they inhibit the dopamine transporter. They cause an excess of dopamine signalling. The symptoms can include paranoid psychosis and depression. Furthermore, depression and anxiety involve dysfunction of the monoamine system. 42 21  8/21/24 Schizop hre nia Sym p t om s NEUROTRANSMITTER SYSTEM DYSFUNCTION 1. Psychotic ‘positive’ symptoms (episodic) Delusions, hallucinations, thought disorders 2. Deficit ‘negative’ symptoms (chronic) disturbances in: motivation, experience of pleasure social interactions, spontaneous speech, mood expression Anhedonia the lack of ability to experience pleasure. 3. Cognitive impairment (chronic) intellectual, memory, executive function, attention 43 Ps ychot ic ‘Pos it ive ’ Sym p t om s NEUROTRANSMITTER SYSTEM DYSFUNCTION Hallucinations - usually auditory (single or multiple) Delusions (paranoid) - persecution, grandiosity, external control, thoughts inserted or removed, mind read Thought disorder - tangential, loosening associations Disorganised thinking and behaviour - trouble with simple tasks 44 22  8/21/24 Monoamines (DA and 5-HT only) Ne u r o c h e m is t ry of Schizop hre n ia NEUROTRANSMITTER SYSTEM DYSFUNCTION There are 4 main neurotransmitters thought to be involved: Dopamine (DA) Serotonin (5-HT) Glutamate GABA Amino acids 45 Do p a m ine Hyp ot he s is NEUROTRANSMITTER SYSTEM DYSFUNCTION 1. Drugs which increase dopamine levels in the nucleus accumbens exacerbate or produce positive psychotic symptoms ► Amphetamine, cocaine, dopamine receptor agonists 2.Drugs which block dopamine transmission alleviate some of the symptoms of schizophrenia (dopamine antagonists) ► 1950s Chlorpromazine (developed as an antihistamine) reduced the positive symptoms of schizophrenia - blocks dopamine receptors ► Dopamine neurotransmission is involved in psychosis Dopamine receptor ANTAGONIST 46 23  8/21/24 Do p a m ine Hyp ot he s is NEUROTRANSMITTER SYSTEM DYSFUNCTION PFC Working m em ory DA Sequencing Planning Executing behaviours DA DA DA Nucleus Accumbens Motivation Movement L im b ic M o to r Interface Schizophrenics have increased dopamine (DA) in the nucleus accumbens and decreased dopamine in the prefrontal cortex (hypofrontality) Which is responsible for the cognitive de cits in negative symptoms. 47 Do p a m ine Hyp ot he s is NEUROTRANSMITTER SYSTEM DYSFUNCTION PFC Hypofrontality: DA Cognitive deficits Negative sym ptom s DA DA DA Nucleus Accumbens Increased dopamine: Positive sym p to m s (psychoses) Euphoria a t beginning Mesocorticolimbic dopamine system (A10) 48 24  8/21/24 Do p a m ine Hyp ot he s is NEUROTRANSMITTER SYSTEM DYSFUNCTION The positive psychotic symptoms are produced by increased dopamine in the nucleus accumbens (mesolimbic dopamine) The negative and cognitive symptoms are produced by decreased dopamine in the prefrontal cortex (mesocortical) ► Mesocorticolimbic dopamine system is abnormal in schizophrenia 49 What is the di erence between a D1 and D2 receptor? Me s olim b ic Dop a m ine NEUROTRANSMITTER SYSTEM DYSFUNCTION The positive psychotic symptoms are produced by increased dopamine in the nucleus accumbens (mesolimbic dopamine) The nucleus accumbens (ventral striatum) directly influences the output of the dorsal striatum (Caudate & Putamen) - weakens the ‘filter’ Increased numbers of dopamine D2 receptors in mesolimbic system with schizophrenia Generally considered that enhanced dopamine neurotransmission at dopamine D2 receptors produces positive symptoms of schizophrenia ► Use a dopamine D2 receptor antagonist to prevent psychoses 50 25  8/21/24 Neuroleptic, originating from Greek: νεῦρον (neuron) and λαμβάνω (take hold of)—thus meaning "which takes the nerve"—refers to both common neurological e ects and side e ects. Because they're bound to the D2 receptors, nothing happens to the D2 receptors except the fact that the D2 receptors now can't bind to anything. Firs t Ge ne ra t ion Ant ip s ychot ic s NEUROTRANSMITTER SYSTEM DYSFUNCTION Typical Antipsychotics: ‘neuroleptics’ Chlorpromazine, Haloperidol The ability f o r these drugs t o bind and b lo ck dopamine D2 receptors made t h e m m o re effective a t reducing psychotic sym p to m s B e tte r binding t o D2 receptors = b e t t e r clinical potency (Fig 14.18 Kalat) By looking at this graph you can see that Chlorpromazine is a more e ective drug or at least stronger per mg than Haloperidol 51 Typ ica l Ant ip s ychot ic s NEUROTRANSMITTER SYSTEM DYSFUNCTION The f irs t generation typical neuroleptics antagonised b o t h dopamine D1 and D2 receptors (and many o th e r receptors!!) - no effect on negative or cognitive symptoms - ineffective in 30 % patients - exacerbate s y m p to m s in some - 20 % relapse rate - 5 - 10% have intolerable side e ffe cts (due t o many receptors involved) - cardiotoxicity - Extrapyramidal Side E ffects (EPS) What are extrapyramidal side e ects? 52 26  8/21/24 Off- Ta rge t Effe c t s of Typ ic a l Ant ip s ychot ic s NEUROTRANSMITTER SYSTEM DYSFUNCTION Dopamine involved in psychosis, but DA also in reward DA D1 receptor family DADA D1,D5 D2 receptor family D2, D3, D4 Typical neuroleptics block the D1 and D2 family of receptors D2 receptors in the nucleus accumbens produce positive psychotic symptoms 53 Off- Ta rge t Effe c t s of Typ ic a l Ant ip s ychot ic s NEUROTRANSMITTER SYSTEM DYSFUNCTION Nigrostriatal DA system Important for movement Decreased DA in nigrostriatal Caudate Nucleus Substantia causes Parkinson’s Symptoms Nigra Blocking D1 and D2 receptors interrupts our ability to move Dorsal Striatum = Caudate Nucleus + Putamen Extrapyramidal side effects Major component of the BASAL GANGLIA 54 27  8/21/24 Pyra m id a l a nd Ext ra Pyra m id a l Move m e nt NEUROTRANSMITTER SYSTEM DYSFUNCTION Concerns Pyramidal neurons in the cortex Pyramidal Primary Motor Cortex M1 Motor Premotor Area Cortex Supplementary Motor Area Caudate DA Substantia Nigra Spinal cord & Muscle Voluntary Movement Extrapyramidal Nigrostriatal dopamine (A9) Substantia Nigra Caudate/Basal Ganglia Spinal cord Rythmic/Phasic movement Subconscious: eg. walking 55 Ext ra p yra m id a l Sid e Effe c t s NEUROTRANSMITTER SYSTEM DYSFUNCTION 80% of D2 receptors need to be blocked - antipsychotic ► 80% of D2 receptors blocked also effect D1 receptors ► Extrapyramidal Side Effects (EPS) Parkinson’s like symptoms (reduced dopamine transmission in Caudate Nucleus) Acute dystonias (involuntary movements) muscle spasms, protruding tongue May cause development of Tardive Dyskinesia (20-40% over years) Debilitating movement disorder - involuntary movements: jaw/lips/limbs ► Needed to develop antipsychotics that were specific for D2 subtype ► Needed to discover other neurotransmitter involvement ► Reduce EPS & reduce negative and cognitive symptoms 56 28  8/21/24 KarXT is a combination therapy meaning it combines two di erent drugs, xanomeline and trospium chloride, into one treatment. It will be the rst anti- psychotic drug that doesn't target dopamine. Ne xt Ge ne ra t ion An t ip s ychot ic s : At yp ica l NEUROTRANSMITTER SYSTEM DYSFUNCTION Drugs that were more selective for D2 receptors were made : Sulpiride Highly selective for D2 receptors Less Extrapyramidal Side Effects Still no effect on negative or cognitive symptoms…. Need to address prefrontal cortex deficits Dopamine antagonists will not help reduction of dopamine in prefrontal cortex Dopamine D2 antagonists do help to reduce the positive symptoms ► Serotonin (at 5HT2 receptors) are thought to mediate the negative and cognitive symptoms ► Glutamate antagonists produce psychosis ► Reduced function of GABA neurons in the prefrontal cortex in schizophrenia. ► Dopamine, Serotonin, Glutamate & GABA are involved in schizophrenia All target the dopamine system so there's a lot of research going into targeting novel treatments. Now, a United States-based biotech organisation called Karuna Therapeutics Inc. has developed a new combination drug called KarXT. It is the rst potential new pharmacological approach for treating schizophrenia in over 50 years and may provide an alternative option for people living with the condition. 57 Depression is also though to be a ected by your monoamine system. De p re s s ion NEUROTRANSMITTER SYSTEM DYSFUNCTION Major affective disorder: Depression Depressed mood Reduced interest in pleasure Sleep disorders (insomnia or hypersomnia) Loss of energy Feelings of guilt or worthlessness Decreased attention Altered eating patterns Recurrent thoughts of death 15 % suicide rate if left untreated 58 29  8/21/24 Monoa m ine Hyp ot he s is NEUROTRANSMITTER SYSTEM DYSFUNCTION Monoamines deactivated by Monoamine Oxidase (MAO) or repackaged into vesicles 1950s Iproniazid (Monoamine Oxidase Inhibitor) Mitochondria Elevated mood in tuberculosis patients MAO Given that it was quite e ective at increasing mood it was thought perhaps the decreased mood in depression was Terminal because there was not enough monoamines in the system. Monoamines Postsynaptic density/dendrite 59 Monoa m ine Hyp ot he s is NEUROTRANSMITTER SYSTEM DYSFUNCTION Blocking metabolism of the monoamines increases the amount to be repackaged and released 1950s Iproniazid (Monoamine Mitochondria Oxidase Inhibitor) X Elevated mood in tuberculosis MAO patients Terminal Increased Monoamines in synapse Postsynaptic density/dendrite If you block MAO there will be more available to be repackaged and re-used. (I.e. greater bio availability) 60 30  8/21/24 Monoa m ine Hyp ot he s is NEUROTRANSMITTER SYSTEM DYSFUNCTION The effectiveness of a monoamine oxidase inhibitor to elevate mood in depressed patients indicated that the depletion of monoamines contributed to the pathology of depression Monoamines: Serotonin Noradrenaline (norepinephrine) Dopamine Depletion of dietary tryptophan produces symptoms of depression 61 Ne urop a t hology of De p re s s ion NEUROTRANSMITTER SYSTEM DYSFUNCTION hippocampus Depleted monoamines in brain regions produce symptoms of depression How can we increase monoamines? amygdala U ncontrolled activation 62 31  8/21/24 Enha ncing Monoa m ine Ne urot ra ns m is s ion NEUROTRANSMITTER SYSTEM DYSFUNCTION First Generation anti-depressants Tricyclic Antidepressants (TCAs) Block re-uptake of all monoamines Monoamine Oxidase Inhibitors Block the metabolism of active monoamines 63 Norm a l Monoa m ine Ne urot ra ns m is s ion NEUROTRANSMITTER SYSTEM DYSFUNCTION Noradrenaline Dopamine Serotonin Presynaptic action ⚡⚡ ⚡⚡ ⚡⚡ MAO potential MAO MAO NET DAT SERT Synaptic cleft Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 64 32  8/21/24 Ac t ion Pot e n t ia l: Re le a s e of Monoa m ine NEUROTRANSMITTER SYSTEM DYSFUNCTION Noradrenaline Dopamine Serotonin Presynaptic MAO MAO MAO NET DAT SERT Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 65 Monoa m ine s Bind t o t he ir Re ce p t ors NEUROTRANSMITTER SYSTEM DYSFUNCTION Noradrenaline Dopamine Serotonin Presynaptic MAO MAO MAO NET DAT SERT Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 66 33  8/21/24 Re ce p t ors “C oup le ” to G- Prot e ins NEUROTRANSMITTER SYSTEM DYSFUNCTION Noradrenaline Dopamine Serotonin Presynaptic MAO MAO MAO NET DAT SERT Gs GsGs Gs Gs Gs Gs Gs Gs Gs Gi Gi Gi Gi Gi Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 67 Se cond Me s s e nge r Sys t e m s Act iva t e d … …or Not ! Noradrenaline Dopamine Serotonin Presynaptic MAO MAO MAO NET DAT SERT Gs GsGs Gs Gs Gs Gs Gs Gs Gs Gi Gi Gi Gi Gi Second Second Second messengers messengers messengers activated activated inhibited Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 68 34  8/21/24 Pos t s yna p t ic Pot e n t ia ls Are Ge ne ra t e d NEUROTRANSMITTER SYSTEM DYSFUNCTION Noradrenaline Dopamine Serotonin Presynaptic MAO MAO MAO NET DAT SERT Gs GsGs Gs Gs Gs Gs Gs Gs Gs Gi Gi Gi Gi Gi EPSP EPSP IPSP Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 69 Monoa m ine s Le a ve Re ce p t or Bind ing Sit e s , G- prot e ins uncoup le Noradrenaline Dopamine Serotonin Presynaptic MAO MAO MAO NET DAT SERT GsGs Gs Gs Gs Gs Gs Gs Gs Gi Gi Gi Gi Gi Gs EPSP EPSP IPSP Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 70 35  8/21/24 Monoa m ine s Are Tra ns p ort e d Ba ck t o Pre s yna p t ic Te rm ina l (‘Re - up t a ke ’) Noradrenaline Dopamine Serotonin TCA stop the Presynaptic re-uptake of all monoamines MAO MAO MAO XNET XDAT XSERT TCA TCA TCA GsGs Gs Gs Gs Gs Gs Gs Gs Gi Gi Gi Gi Gi Gs Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 71 Monoa m ine s a re Broke n Dow n b y Mona m ine Oxid a s e (MAO) or Re p a cka ge d in Ve s ic le s Noradrenaline Dopamine Serotonin Presynaptic MAO MAO MAO NET DAT SERT GsGs Gs Gs Gs Gs Gs Gs Gs Gi Gi Gi Gi Gi Gs Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 72 36  8/21/24 Monoa m ine s a re Broke n Dow n t o Monoa m ine Me t a b olit e s (ina c t ive che m ic a ls ) Noradrenaline Dopamine Serotonin MAOI stop the Presynaptic metabolism of all MAOI MAOI MAOI monoamines X MAO X MAO X MAO Metabolites Metabolites NET Metabolites DAT SERT GsGs Gs Gs Gs Gs Gs Gs Gs Gi Gi Gi Gi Gi Gs Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic 73 Tricyclic Ant id e p re s s a nt s NEUROTRANSMITTER SYSTEM DYSFUNCTION Imipramine (1960s), Amitryptyline Side Effects: Tricyclic drugs Sympathetic/antimuscarinic Dry mouth, impaired vision, increased heart rate, difficult to pee Memory and learning impairments antihistamine Sedation blocks alpha 1 adrenoceptors - periphery Postural hypotension (low blood pressure on standing) They also increase suicide rates CARDIOTOXIC (blocks ability for heart to pump) 15 % depressed patients suicide - 25% by TCA overdose The more non-speci c your drug is the more it's going to produce side- e ects that you don't want. The di erent NT's have di erent functions. 74 37  8/21/24 Monoa m ine Oxid a s e Inhib it ors NEUROTRANSMITTER SYSTEM DYSFUNCTION Phenelzine, Pargyline, Isocarboxazid, Tranylcypromine These drugs block the breakdown of all monoamines Side Effects: Tremors, excitement, insomnia (CNS overstimulation:convulsions) Food & drug interactions Cheese/Concentrated yeast p r o d u c ts /r e d w in e t h a t c o n ta in Tyramine Hypertension - headaches or intracranial haemorrhage Cardiotoxic (less than TCA’s) ► 40% non-compliance ► Needed to develop better pharmacotherapies 75 Se le c t ive Re - up t a ke Inhib it ors NEUROTRANSMITTER SYSTEM DYSFUNCTION Second Generation Antidepressants These focus on th e r e - uptake o f serotonin or noradrenaline or both (Reduced Dopamine is n o t a major problem in depression) Selective Serotonin Reuptake Inhibitors (SSRIs) Noradrenaline Reuptake Inhibitors (NRIs) Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) More selective = less side effects 76 38  8/21/24 This is what SSRI's do (they selectively block the Serotonin re-uptake inhibitors) but they don't a ect Noradrenaline or Dopamine re-uptake inhibitors. Se le c t ive Se rot onin Re - up t a ke Inhib it ors (SSRI’s) NEUROTRANSMITTER SYSTEM DYSFUNCTION Noradrenaline Dopamine Serotonin Presynaptic ⚡⚡ ⚡⚡ ⚡⚡ MAO MAO MAO NET DAT X SERT SSRI Alpha or beta D1 or D5 5-HT1A adrenoceptors receptor receptor Postsynaptic ✅ ✅ 🚫 77 2. Sum m a ry – pa r t 2 1. Schizophrenia is caused by abnormal regulation o f dopamine, serotonin, glutam ate & GABA - th e positive psychotic sym ptom s can be treated w ith dopamine D2 receptor antagonists. 2. Parkinson-like sym ptom s are due t o th e neurodegeneration o f nigrostriatal dopamine neurons (not enough dopamine in th e basal ganglia). Treatments aim t o increase dopamine levels (e.g. L - DOPA: a precursor t o dopamine) 3. Depression is caused by reduced monoamine levels (particularly in the amygdala) - i t can be treated w i th MAOIs, TCAs and SSRIs. Reductions in serotonin and noradrenaline are th e main cause. 78 39  8/21/24 Ne xt Tim e The lecture topic next week is “Neurobiology o f Learning and Memory” Reading: Kalat Chapter 12 Remember t o post questions in team s if you don’t understand anything! Ha ve a good d a y! 79 40