GEN PHCOL II
GEN PHCOL II PHCOL 402
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This 47 page Class Notes was uploaded by Mrs. June Doyle on Wednesday September 9, 2015. The Class Notes belongs to PHCOL 402 at University of Washington taught by Staff in Fall. Since its upload, it has received 14 views. For similar materials see /class/192262/phcol-402-university-of-washington in Pharmacology at University of Washington.
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Autonomic Nervous System Slide 1 Introduction The ANS regulates the functions of the heart blood vessels GI tract various types of smooth muscle and strives to maintain the internal environment against a constantly changing external environment There are several important differences between the ANS and the neuromuscular junction that we have been talking about Slide 2 Comparison of NM and Autonomic 1 At the neuromuscular junction the actions of somatic nerves are voluntary while control of the autonomic neurons is generally involuntary You don t have to think about your heartbeat your breathing and you digestion It happens automaticallyit is autonomic autonomous 2 The target of the somatic neurons the skeletal muscle is quiescent not stimulated in the absence of neuronal stimulation while the target organs of the ANS show tonic activity In other words the autonomic nervous system has spontaneous activity which is modulated by stimulation Eg your heart is always beating and you can either slow down the rate or increase the rate through the autonomic nervous system 3 Axons for neurons innervating skeletal muscle are found in the spinal cord In the autonomic system sensory information is carried by afferent bringing to pathways to the CNS where the controlling and integrating centers for the ANS are located Efferent going away nerves of the ANS provide all innervated structures of the body with the exception of the skeletal muscle which is control by somatic neurons The most distal junctions in the ANS occur in ganglia which are totally outside the cerebrospinal axis Information from these ganglia then go to the target organs The ganglia generally have synapses which release acetylcholine which activates nicotinic receptors postsynaptically 4 Another difference between the NMJ and the ANS is the presence of presynaptic receptors in the ANS but not at the neuromuscular junction Presynaptic receptors in the ANS function to regulate the release of neurotransmitters Slide 3 parasympathetic vs sympathetic nervous system The ANS can be divided into the parasympathetic and sympathetic nervous systems The difference between the two systems is not a distinction between what neurotransmitters are used The distinction is primarily an anatomical distribution based upon where the preganglion fibers originate The parasympathetic preganglion neurons originate in the midbrain medulla and sacral portions of the spinal cord The sympathetic preganglion neurons originate from the intermediate spinal cord Many of the target organs are innervated by sympathetic and parasympathetic branches which often act in an antagonist manner Note a few examples from the slide eg the heart Slide 4 Adrenals and stress The adrenal medulla is part of the sympathetic nervous system and contains secretory cells chromaffin cells that release catecholamines eg epinephrine and norepinephrine in response to neuronal stimulation The sympathetic system is dominant during periods of stress and is responsible for the flight or fight syndrome This can lead to increased heart rate blood pressure dilation of pupils and bronchioles increased blood sugar and shifting of the blood from the skin and GI to skeletal muscle The net effect is to prepare the body for action The release of Epinephrine and Norepinephrine during this response is a major component of the adrenergic flight or fight syndrome Slide Slide 5 parasympathetic ganglia generally closer to the target organ more discrete The parasympathetic system dominates when you are sleeping and normally undergoes discharge at discrete sites Sympathetic ganglia normally innervate many targets parasympathetic ganglia are generally closer to the target and a given parasympathetic ganglia innervates one effector organ For example the parasympathetic ganglia controlling the heart are actually in the heart Slide 6 Classification of Motor fibers Preganglionic axons of the sympathetic neurons use acetylcholine as the neurotransmitter they synapse onto ganglionic neurons which normally have ganglionic nicotinic receptors The postganglionic fibers usually use norepinephrine eg with various types of smooth muscle heart muscle and glands There are exceptions The postganglionic nerves to sweat glands are generally cholinergic fibers release acetylcholine as the neurotransmitter The adrenal medulla which you can think of as a ganglion releases both NE and epinephrine The other exception is that there are some cholinergic sympathetic fibers in skeletal muscle vasculature but they are not considered physiologically important Preganglionic axons of the parasympathetic neurons use acetylcholine as the neurotransmitter and form nicotinic synapses on ganglionic neurons The postganglionic fibers of these ganglionic neurons use acetylcholine as the neurotransmitter and form cholinergic synapses on the target organ As we stated earlier motor fibers originate in the spinal axis with no intervening ganglia and at the neuromuscular junction release ACh which stimulates nicotinic receptors Slide Slide 7 Effects of Autonomic Stimulation on Organ Function This is a table which summarizes the Effect of Stimulation of the Sympathetic and Parasympathetic Systems on various organ systems that you may find usefulin other words you have to memorize this information Heart Two terms we use when talking about heart function are inotropic and chronotropic lnotropic refers to the contraction strength and chronotropic refers to the rate of heart beating The heart is a good example where the two branches of the autonomic system antagonize each other Parasympathetic slows the heart by hyperpolarization and slowing of the diastolic depolarization in the sinoatrial node It reduces contractile force in the atria by shortening the atrial action potential Sympathetic Activity INCREASES HEART RATE BY INCREASING THE RATE OF DIASTOLIC DEPOLARIZATION AND INCREASES CONTRACTILE FORCE BY INCREASING CA2 INFLUX DURING THE ACTION POTENTIAL The sympathetic nervous system innervates all of the heart but there is very little parasympathetic innervation of the ventricles Slide 8 Vasculature Blood vessels only receive sympathetic but not parasympathetic innervation Sympathetic stimulation generally causes constriction of most blood vessels Except in the case of skeletal muscle where it can cause either constriction or relaxation of blood vessels Slide 9 Smooth Muscle General For example GI smooth muscle Parasympathetic activity Causes contraction or increased rhythmic activity of smooth muscle Sympathetic Activity Causes relaxation or decreased rhythmic activity of smooth muscle Smooth muscle in blood vessels only receives sympathetic not parasympathetic innervation Sympathetic stimulation generally causes constriction of blood vessels Exocrine glands Lachrymal Glands tear glands Parasympathetic activity normally stimulates secretion sympathetic activity either reduces or has no effect on secretion depending on the particular gland Lungs Sympathetic stimulation causes bronchial dilation relaxation of bronchial smooth muscle Parasympathetic causes bronchial constriction Sweat gland Sympathetic stimulation causes secretion it increase sweating Liver Sympathetic stimulates the breakdown of glycogen Salivary glands Sympathetic and parasympathetic stimulation causes secretion Parasympathetic stimulation is dominant Slide 10 Eye autonomic activity Pupil Cons triction Parasympathetic activity causes miosis pupillary constriction by stimulating contraction of the iris sphincter muscle Sympathetic activity causes mydriasis pupillary dilation by causing contraction of the dilator muscle Lens A ccomm oda tion Parasympathetic activity stimulates contraction of the ciliary muscle causing increased curvature of lens for near vision Sympathetic activity causes relaxation of the ciliary muscle decreasing curvature for far vision I Synaptic Transmission through Autonomic Ganglion There are a family of drugs that affect synaptic transmission in autonomic ganglia To understand the effects of these drugs we need to look at synaptic transmission in mammalian ganglia A Sympathetic Ganglia Slide 11 plot for action potentials Stimulation of preganglionic fibers causes a complex series of events in the membrane potential of the postganglionic neuron 1 An initial large depolarization EPSP due to the activation of the ganglionic nicotinic receptor of the postganglionic neuron by ACh 2 A small hyperpolarization slow IPSP due to the activity of an interneuron 3 A slow or late EPSP due to activation of mACh on the postganglionic neuron The fast EPSP is responsible for transmission through the ganglion The IPSP and the late EPSP serve to modulate synaptic transmission The late slower EPSP is due to Ach activation of muscarinic receptors Slide 12 Parasympathetic Ganglia Less is know about synaptic transmission through the parasympathetic ganglia Studies with amphibian heart suggest the presence of a fast EPSP due to activation of nAChR and a slow IPSP due to activation of mAChR Thus the main pathway for synaptic transmission through ganglia in each case uses ACh as the released neurotransmitter activating nicotinic receptors postsynaptically There are similarities between synaptic transmission through autonomic ganglia and at the NM junctions 1 The synthesis storage and release of acetylcholine in preganglionic cholinergic terminals of autonomic ganglia are similar to that described for the NM junction 2 The nerve terminal contains many synaptic vesicles which release acetylcholine upon stimulation IV Ganglionic Stimulating Drugs There are two classes of ganglionic stimulating drugs nicotinic drugs and muscarinic drugs Slide 13 nicotinic ganglionic stimulating drugs 1 Nicotinic Drugs Nicotine DMPP TMA These drugs are agonists which activate and then subsequently desensitize the nicotinic AChR in ganglionic synapses Low concentrations of the drugs stimulate nAChR in sympathetic and parasympathetic ganglia and in the adrenal medulla Higher concentrations cause blockade of both types of ganglia Their effects are very broad and unpredictable and the drugs are not used clinically However because of the widespread consumption of nicotine in tobacco it is important to understand nicotine pharmacology At low doses nicotine has sympathomimetic cardiovascular effects which include increased inotropic and chronotropic effects parasympathetic GI effects increases GI motility Nicotine is lipid soluble and can cause complex central effects including stimulation of respiration and at very high doses convulsions 10 Nicotine is a highly addicting drug and abrupt stopping of smoking can cause headaches tremor visual disorders irritability etc One solution is the availability of nicotinecontaining gum or nicotine patches to reduce withdrawal effects Nursing women or people with cardiovascular conditions should not use nicotine 2 Muscarinic Drugs These drugs stimulate muscarinic receptors and they include muscarine pilocarpine leading to stimulation of sympathetic nervous system via the late EPSP However these effects are usually masked by the direct muscarinic effects on the cardiovascular system One experimental drug McNA343 acts preferentially to stimulate mAChR in the sympathetic ganglia and in the adrenal medulla compared to heart or vascular smooth muscle This is because there are subclasses of mACh receptors and drugs which are relatively specific for these subclasses V Ganglionic Blockers Slide14 Structure of Ganglionic Blockers Pentolinium hexamethonium and triethyl ammonium TEA and related drugs act as competitive antagonists and block ganglionic transmission by blocking nicotinic AChR without a change in the membrane potential of the ganglionic cells 11 Hexamethonium is the sixcarbon analogue of the depolarizing neuromuscular junction blocker decamethonium 10 Hexamethonium is a weak NM junction blocker but a stronger blocker at autonomic ganglia The ganglionic blockers inhibit both parasympathetic as well as sympathetic ganglia 15 Slide predominant autonomic tone and effects of ganglionic blockers The actual pharmacological effect of the ganglionic blockers depends upon whether the predominant autonomic tone in the untreated individual is parasympathetic or sympathetic The effects on organs with predominantly sympathetic tone are 1 arterioles and veinscause ganglionic blockers cause vasodilation 2 Sweat glands Anhidrois decreased sweating Effects on organs with predominantly parasympathetic tone are 1 Heart tachycardia excessive fast heart rate 2 eye mydriasis pupillary dilation and cycloplegia paralysis of the intraocular muscle 3 Salivary gland Xerostomia dry mouth 4 GI tract relaxation of intestinal muscle constipation 5 Bladder difficulty in voiding the bladder Ganglionic blockers were used as hypotensive agents but they are not used now except in emergency treatment or to produce controlled hypotension during surgical procedures The hypotensive effects are due to the dilation of most arteries and veins in the skin and viscera causing a decrease in total systemic vascular resistance The side effects are due to their effects on other organ systems mentioned above visual problems constipation etc Drugs Acting at Muscarinic Cholinergic Receptor Sites Slide 16 differences between Muscarinic and Nicotinic Synapses There are important differences between synaptic transmission at muscarinic synapses compared to nicotinic synapses 1 At the NM junction there is a highly specialized structure with a highly differentiated nerve terminal there are discrete terminals in the ANS the muscarinic receptors are more spread out They are found at various varicosities N At the NM the synapse gap is very small 20 nm to 50 nmConsequently the time for diffusion is very short At Muscarinic synapses the distance is generally larger 20 nm to 2 pm 3 At the NM the receptors are highly localized and concentrated at the synapse At the muscarinic junctions receptors are distributed throughout the target tissue to give uniform responses 4 The response at the NM junction is very fast less than a 100 usec At muscarinic synapses the response is slow slower than 100 msec Slide 17 axons and varicosities passing through heart muscle This slide shows muscarinic synapses the varicosities in the heart You can see the axon and the varicosities points where synapses occur throughout the heart muscle ACh is released throughout the target organ You have this general wide distribution because you would not want part of the heart beating at a different rate than the other Slide 18 muscarinic synapse In contrast to the NM junction the muscarinic synapses are not concentrated or have specialized folds the synapses are spread along the target organ uniformly The distance between the nerve and target organ is much greater than at the NM junction You don39t see a highly specialized postsynaptic localized structure on the heart muscle The nicotinic receptors at the NM junction and in ganglionic synapses are ligand gated ion channels that acts fast 100 usec the muscarinic receptors act slower about 1000 times slower This is because the muscarinic receptors themselves are not ion channels but they are coupled to second messengers eg Ca2 or cAMP that in turn can regulate the activity of ion channels Parasympathominitic Drugs Agonists Slide 19 Muscarinic Agonists or Parasympathomimetic drugs These drugs mimic the effects of parasympathetic nerve stimulation mimic ACh Two classes of muscarinic agonists the first are the choline esters The second group is the cholinomimetic alkaloids The choline esters include acetylcholine carbachol methacholine and bethanecol They are all able to act as agonists at the muscarininc receptors they differ in their susceptibility to hydrolysis by choline esterases and their crossreactivity with nicotinic receptors While Ach is very susceptible to hydrolysis by choline esterase methacholine is less susceptible to hydrolysis Carbachol has high nicotinic activity methacholine has little nicotinic activity and bethanechol two spellings bethanechol bethanecol has none Because there are subclasses of muscarinic receptors with different tissue distribution the response of different systems to these drugs vary Carbachol and bethanecol are relatively effective at muscarinic receptors in the GI tract and poorer agonists for the cardiovascular system 15 Slide 20 Cardiovascular Effects of Muscarinic Agonists Some of the cardiovascular effects of these drugs are predictable and some are not If one administers acetylcholine or methacholine lV one gets Vasodilation of all vascular beds How come I told you earlier that there is no parasympathetic innervation of vascular smooth muscle mAChR in most smooth muscle causes contraction but not in vascular smooth muscle Why All the blood vessels have muscarinic receptors which cause vasodilation even though there is no parasympathetic innervation Remember blood vessels have sympathetic tone and sympathetic innervation but no parasympathetic innervation Slide 21 NO endothelial cells The mAChR are not on the vascular smooth muscle but on the endothelial cells which release quotendothelial derived relaxing factorsquot eg nitric oxide NO diffuses into the smooth muscle cells and acts on the smooth muscle to cause vasodilation M3R gt Ca2 increase gtactivation of NO Synthase gt NO Nitric oxide activates guanylyl cyclase in vascular smooth muscle to produce cGMP which relaxes vascular smooth muscle The organonitrates which would include nitroglycerin amyl nitrate are antianginal drugs that release NO which in turn lowers blood pressure by causing vasodliation The discovery of NO led to a Nobel prize in medicine Slide 22 BP changes when treat with Ach 1 Decrease in BPvasodilation through NO in vascular smooth muscle which causes vasodilation 2 More ACh even lower BP 3 This is blocked by a muscarinic antagonistatropine 4 If atropine is present go to really higher Ach instead of a decrease in BP we get a pressor response Why When you block the muscarinic receptors ACh acting in the adrenal medulla it stimulates nicotinic ganglionic receptors and causes release of catecholamines vasoconstriction and an increase in BP Slide 23 Effects of acetylcholine on the heart Ach causes decreased blood pressure as just described This leads to an autonomic reflex causing an increase in sympathetic tone and reflex tachycardia The heart tries to accommodate for the large decrease in peripheral resistance One needs very high doses of Ach to overcome this reflex sympathetic tone So the effects are dose dependent At very high concentrations of AcH you start to see a reduction in heart rate Why The heart does have cholinergic innervation which deceases the beating rate negative chronotropic effect activation of mAChR in the pacemaker region of the SA node increases K permeability decreases the rate of diastolic depolarization delaying the onset of an action potential and causes a longer interval between beats Slide 24 Pharmacology of Choline Esters GI Effects All of the choline esterases cause increases in tone contractile force and peristalsis and secretory activity of the GI system Carbachol and bethanechol can give GI effects with minimal cardiovascular effects Other Effects Bethanecholamine also stimulate the urinary tract The choline esters increase secretion from all exocrine glands cause bronchial constriction and produces constriction of the pupils Because these drugs do not cross the bloodbrain barrier they do not have significant CNS effects Slide 25 Therapeutic Uses of the Choline Esters 1 Methacholine was used in the past to control tachycardia but not now because of side effects 2 Bethanechol is used as a GI tract stimulant to relieve a variety of conditions and to relieve urinary tract retention when there is no physical obstruction so that catherization can be avoided 3 ACh is used to produce brief periods of miosis during extraction of cataracts Methacholine bethanecol and carbachol are used in treatment of glaucoma to cause miosis which enhances drainage of aqueous humor 4 Methacholine is also used for diagnosis of belladonna a muscarinic antagonist poisoning and for diagnosis of bronchial hyperactivity ie Supersensitivity to broncoconstriction in patients with asthma B Cholineromimetic Alkaloids the alkaloids Slide 26 Structure of the alkaloids Muscarine arecoline are co line pilocarpine pe lo car pine are natural alkaloids Oxotremorine and aceclidine a cec li dine are synthetic Pilocarpine muscarine and Oxotremorine are relatively specific for mAChR while arecoline can activate nicotinic receptors 19 Pharmacological activities mimic those of the choline esters Unlike the choline esters these drugs are not charged and can have effects in the CNS Eg Oxotremorine can cause Parkinson like tremors Therapeutic Uses The sole therapeutic use of these drugs only pilocarpine is for the treatment of glaucoma 27 Mushrooms Toxicology Somme toxic mushrooms eg of the Amanita class contain muscarine lngestion produces a number of symptoms due to over stimulation of autonomic organs salivation diarrhea bradycardia and CNS effects Atropine is used as an antidote for muscarine poisoning Antimuscarinc Drugs Slide 28 Structure of the Belladonna Alkaloids A The Belladonna Alkaloids Belladonna poison night shade is mixture of atropine and scopolamine These are very specific competitive drugs for reversible inhibition of mACHR They block the parasympathetic stimulation of target organs These drugs are rapidly absorbed through he GI tract and slowly absorbed through the eyes or skin 20 Slide 29 atropine biphasic effect on heart rate M Low doses cause a slight reduction in heart rate This due to blockade of presynaptic inhibitory muscarinic receptors on the postganglionic parasympathetic nerve terminals In other words the presynaptic terminal of parasympathetic ganglia have muscarinic receptors which are coupled to inhibition of adenylyl cyclase through Gi Since they depress signaling through parasympathetic innervation to the heart when activated these presynaptic muscarinic receptors actually increase heart rate The low concentrations of atropine by blocking these receptors decrease heart rate Slide 30 Pharmacology of the Anticholinergics High doses give the expected result which is tachycardia Circulation Anticholinergics block vasodilation due to cholinergic agonists eg vasodliation caused by administration of carbachol However Anticholinergics have little effect in untreated individuals Why Because blood vessels have primarily sympathetic tone with no cholinergic innervation Eye Anticholinergics cause mydriasis excessive dilation of the pupil and cycloplegia paralysis of the intraocular muscles which can last for l to 2 wks GI Tract Anticholinergics inhibit tone and motility of the stomach and intestine and also inhibit gastric secretion 21 Salivary and Sweat GlandsAnticholinergics inhibit secretion by these glands Toxicity Atropine and scopolamine are lipid soluble and cross the bloodbrain barrier At clinical doses atropine acts as a mild CNS stimulant Higher doses cause hallucinations and delirium followed by depression Therapeutic doses of scopolamine cause drowsiness tachycardia hallucination delirium and urinary retention Anticholinesterases eg physostigmine can be used as an antidote Slide 31 Quaternary Derivatives of Antimuscarinic Alkaloids These drugs which are quaternary ammonium derivatives of the antimuscarinic alkaloids have different properties from their corresponding tertiary amine derivatives 1 They do not cross the blood brain barrier Therefore they exhibit no CNS side effects 2 They have substantial nicotinic blocking activity and can have side effects due to ganglionic and neuromuscular blockade They are more slowly absorbed through the GI and have more prolonged activity there C Therapeutic Uses of the AntiMuscarinics 1 Preanesthtic medication Atropine and scopolamine reduce excessive salivation and bronchial secretion and dilate bronchial passages Scopolamine has an additional effect it is a tranquilizer 22 Slide 32 Antimuscarinics use to induce mydriasis and cycloplegia 2 OphthalmologyGo through slide Note that the drugs differ in duration of action and the recovery time is significant It can take days 3 GI Antimuscarinic have been used to relieve symptoms of peptic ulcer by decreasing motility and gastric secretion They also inhibit intestinal tone or motility in mild dysentery or conditions of the irritated lower bowl 4 Cardiovascular System Atropine is used to relieve bradycardia caused by excessive stimulation of vagal tone following myocardial infarction 5Respiratory Tract Belladonna alkaloids and other antagonists decrease secretion in the upper and lower respiratory tract They are used in cold and hay fever medications lpratropium a quaternary ammonium antagonist is used for asthma Inhalation of ipratropium produces bronchodilation but does not inhibit bronchial secretions nor does it show anticholinergic actions 5 CNS The antimuscarinics are used to prevent motion sickness and the relieve symptoms of Parkinson39s disease IV Slide 33 Muscarinic Receptor Subtypes There are at least five distinct mAChR designated Ml M5 These receptors show different tissue distribution and therefore offer the opportunity for more specific drug effects 23 1 McNA343 activates mAChR in the sympathetic ganglia and in the adrenal medulla but has little effect on mAChR in heart and the vasculature 2 Pirenzepine is a muscarinic antagonist used in Europe to reduce gastric secretion it has little effect on heart rate or pupillary constriction 3 Subtype Distribution a M1 is main mAChR in sympathetic ganglia and it is preferentially activated by McNA343 b M2 is the main subtype in heart it is coupled to inhibition of cAMP levels Ml Ca2 mobilization and PKC activation M2lnhibition of adenylyl cyclases through Gi M3 M4lnhibition of AC M5 Slide 34 Anticholineesterases in the Autonomic Nervous System AChE terminates the action of acetylcholine at autonomic junctions in the same way it does so at the NMJ Thus inhibitors AChE have cholinometric effects at both nicotinic and muscarinic synapses Physostigmine and the organophosphate drugs are absorbed from the GI whereas the quaternary ammonium compounds eg neostigmine and echothiophate are not readily absorbed 24 Uses Ophthalmology AChE inhibitors are used in the treatment of primary and congenital glaucoma to cause miosis and increase drainage Gl AntiAChE increase GI and urinary tract motility Neostigmine is used for treatment of ileum and atony of the urinary bladder Atropine intoxication The peripheral and central effects of atropine poisoning or atropinelike side effects of the tricyclic antidepressants are reversed by physostigmine 25 Introduction to the Nervous System January 5 2009 Course Organization Slide 1 Instructors and Contact Email Pharm 402 Web site For each lecture you should receive Xerox of PowerPoint presentations These PowerPoint presentations will also be posted on the Web sites after lectures Some instructors may also post other material For example I will post the text for all of my lectures along with the PowerPoint presentations Slide 2 Class meets Slide 3 Grading Midterm 13 vs 14 lectures therefore each exam 100 points Slide 4 TAs and Quiz assignments Slide 5 Lecture Content Today a simple overview of the nervous system which is one of the main topics covered this quarter We will return to specific details as the pharmacology of each class of drug is covered in detail during subsequent lectures Organization of the nervous system Slide 6 The human nervous system is divided into two major parts the peripheral and central nervous systems This division is based on functional considerations Peripheral Nervous System Slide 7 The peripheral nervous system is made up of two major components the somatic and autonomic nervous system Somaticmeans of the body pertaining to the walls of the body as distinguished from the inner organs The receptors for somatic sensory neurons are distributed throughout the body whereas those for other sensory systems are restricted to small specialized organs eg the eye or olfactory epithelium Somatic senses are sometimes called the skin senses or body senses There are four distinct somatic modalities touch pain thermal and proprioceptive elicited by mechanical movements of muscles and joints The other major components of the somatic nervous system are the motor neurons which originate in the spinal cord and innervate skeletal muscle The Autonomic nervous systems is comprised of ganglia that receive information from the CNS and innervate organs We will talk about the distinctions between the parasympathetic and sympathetic autonomic nervous systems in upcoming lectures Slide 8 Central Nervous System CNS The CNS consists of the spinal cord brain stem and brain By way of brief overview The Spinal cord carries information to and from the periphery and plays a major role in autonomic physiology It is that part of the CNS that functions at the lowest level It contains both sensory and motor neurons Damage to the spinal cord can cause loss of sensation or paralysis Slide 9 The brain stem is made up of the upper spinal cord pons and medulla t controls vegetative responses The medulla control respiration and blood pressure The pons relays information between the cerebral cortex and the cerebellum Slide 10 CerebellumControls motor coordination control of movement and motor learning Slide 11 Midbrain midlevel processing of visual and auditory information Slide 12 Diencephalon Thalamus integrates information between subcortical and cortical structures a relay organ Hypothalamus regulates body temperature feeding and reproductive behaviors Slide 13 Limbic System Structures not shown on the diagram Hippocampal formation spatial contextual object recognition memory and emotion Amygdala Fear responses emotion and some control of the autonomic system Limbic lobe memory and emotion Slide 14 Cerebral Cortex Different lobes for specific functions Frontal lobe planning and judgment Occipital lobevision Slide 15 Neurons and Glia Slide 16 Glia Glia are support cells Some glia wrap around axons thereby enhancing electrical signals Others contribute to the bloodbrain barrier Some types of glia take up and release ions and neurotransmitters For example excess glutamate released at synapses that is not degraded or transported back into the presynaptic terminal is taken up by astrocytes Oligodendrites form myelin sheaths around axons in the CNS Schwann cells found in the peripheral nervous system form myelin sheaths around neurons at regular intervals AstrocytesThey make contact with blood capillaries and neurons and thereby are part of the bloodbrain barrier Astrocytes may have a nutritive role Also take up excess neurotransmitters released from neurons Slide 17 Neurons There are many types of neurons which can be distinguished on the basis of morphology location and neurotransmitters released For example the cell body of spinal motor neurons are in the spinal cord and send axonal projections long distances throughout the body to skeletal muscle The pyramidal neurons in the hippocampus are thought to play a major role in the formation of hippocampusdependent memory A pyramidal neuron can have up to a thousand synapses Purkinjee neurons in the cerebellum are distinguished by having elaborate dendritic trees Slide 18 19 Neurons are polarized cells Neurons are signaling cells that receive and send messages Usually signals received at one end of the neuron dendrites and sent from the opposing end the axon and axonal terminal There are three parts to a neuron cell body axons and dendrites Where axons meet dendrites of another neuron or the cell body of another neuron is called a synapse Slide 20A neuron This is a more detailed view of a neuron showing intracellular organelles Slide 21 Signaling within neurons is electrical The neuronal plasma membrane contains pumps and exchange proteins that produce ionic gradients across the membrane These ion gradients result in an electrical potential across the membrane Transient changes in membrane potential are used to signal within the neuron You will hear more about the electrical properties of excitable cells and ion channels in subsequent lectures These changes are generally initiated by the opening of neurotransmitter gated ion channels which allow ions to flow down their concentration gradient thus disrupting the resting membrane potential It the membrane potential reaches a threshold value voltagegated channels in the membrane open generating an action potential a large rapid self correcting flux in membrane potential Action potentials propagate toward the axon terminal where they cause voltagegated calcium channels to open Influx of calcium into the axon terminal triggers the release of chemical messengers called neurotransmitters Slide 22 Signaling between neurons neurotransmission is chemicaLand is mediated by the tightly regulated secretion of neurotransmitters Neurotransmitters are secreted at synapses sites where an axon terminal comes in close apposition to the dendrite of another neuron Chemical signaling between neurons is referred to as neurotransmission or synaptic transmission Drugs that affect neurotransmission constitute the majority of psychotropic reagents It is therefore important to know the molecular events that produce and regulate neurotransmission The tightly regulated membrane trafficking cycle that mediates the secretion of transmitter the diffusion of neurotransmitter across the synaptic cleft the space between axon and dendrite and the interaction of neurotransmitter with specific receptors on the postsynaptic membrane are illustrated below Each is a potential site of drug action Slide 23 Stages of neurotransmission 1 synthesis of transmitter occurs in the presynaptic terminal ie the enzymes required for transmitter synthesis are present in the synapse 2 transport of transmitter into synaptic vesicles is accomplished by specific transporter proteins in the vesicle membrane Synaptic vesicles are assembled in endosomal structures 3 targeting of vesicles to a specialized region of the presynaptic membrane that is directly opposite the postsynaptic receptors priming of the vesicles for fusion Targeting and priming are mediated by the formation and disassemny of protein complexes depolarization of the presynaptic membrane by an action potential induces the opening of voltagegated calcium channels calciumdependent fusion of the vesicles Diffusion of transmitter across the synaptic cleft Transmitter binds to and activates postsynaptic receptors Neurotransmitter receptors can be classified by their mechanism of action Transmittergated ion channel mediate fast neurotransmission Gprotein coupled receptors initiate the production of secondary chemical messengers second messengers Gproteincoupled receptors mediate slower neurotransmission also called neuromodulation Clearance of transmitter from the synapse This is accomplished by two mechanisms i degradation of transmitter in the synapse by metabolic enzymes ii reuptake of transmitter by transporter proteins on the plasma membrane All of these stages are potential sites of drug action Slide 24 Neurotransmitter Classes Amino Acids Acetyl choline biogenic amines and neuropeptides Slide 25 Amino acid neurotransmitters Amino acid neurotransmitters mediate the majority of fast neurotransmission in the nervous system are used by the majority of the neurons in the nervous system mediate most fast local neurotransmission can also mediate slow neurotransmission Slide 26 Amino acid neurotransmitters can be classified on the basis of their action excitatory increase the excitability of target neurons ie activate receptors that depolarize the postsynaptic membrane inhibitory decrease the excitability of target neurons ie activate receptors that hyperpolarize the postsynaptic membrane GABA and glycine Slide 27 Glutamate and Aspartate are excitatory neurotransmitters The amino acid glutamate is the major excitatory neurotransmitter in the CNS Aspartate is also an excitatory amino acid transmitter However it is less common than glutamate Glutamatesecreting neurons are distributed throughout the brain and generally synapse onto neurons within the same structure ie they mediate local neurotransmission Glutamate is the product of general metabolism Its synthesis is not regulated at the synapse Glutamate is transported into synaptic vesicles by a specific glutamate transporter protein in the synaptic vesicle membrane A unique class of reuptake transporters removes glutamate from the synapse 10 Slide 28 Glutamate Receptors include both transmittergated ion channels ionotropic and Gproteincoupled metabotropic receptors There are two major classes of glutamategated ion channel NMDA and nonNMDA channels Kainate nonNMDA channels pass sodium fast and common Slide 29 AMPA Receptors nonNM DA channels pass sodium display fast kinetics opening closing desensitization found at the majority of excitatory synapses where they mediate the majority of fast neurotransmission rapid desensitized Slide 30 NMDAactivated channels pass sodium and calcium display complex regulation NMDA sensitive channels are activated by a combination of glutamate and membrane depolarization At normal membrane potentials magnesium sits in the pore of the channel blocking it Membrane depolarization for example resulting from the opening of AMPA channels dislodges the magnesium allowing sodium and calcium ions to pass Therefore the NMDA receptor must both bind 11 glutamate and be in a depolarized membrane to pass ions These properties mean that NMDA receptors function as coincidence detectors they detect the coincidence of glutamate and depolarization NMDA receptors in the hippocampus are activated during memory formation and initiate a chain of events that generate memory traces in the hippocampus In contrast to AMPA receptors which are activated during normal signaling during neurotransmission NMDA receptors are only activated under very strong rapid signaling when the membrane depolarization through AMPA receptors is coincident with glutamate binding to NMDA receptors SLIDE 31 metabotropic receptors There is one pharmacological class of glutamate receptor that acts through second messengers These channels are sensitive to the drug guisgualate Quisqualatesensitive glutamate receptors are referred to as metabotropic glutamate receptors They act through G coupling proteins Slide 32 Inhibitory amino acids GAMMA AMINO BUTRYIC ACID GABA GABA a simple amino acid is the major inhibitory transmitter in the CNS GABA is derived from the decarboxylation of the amino acid 12 glutamate This reaction is catalyzed by the enzyme glutamic acid decarboxylase GAD There is cellspecific expression of GAD Slide 33 GABA is transported into synaptic vesicles by a specific vesicular GABA transporter GABA is removed from the synapse by a high affinity reuptake transporter GABA Receptors two major classes GABAdated chloride channels that mediate fast inhibitory neurotransmission Opening of these chloride channels hyperpolarizes the post synaptic membrane making it lg likely to produce an action pote nti al metabotropic GABA receptors Gprotein coupled receptors that regulate potassium channels via changes in levels of the second messenger cA M P Slide 34 Acetylcholine ACh Like the amino acid neurotransmitters acetylcholine mediates both fast and slow neurotransmission ACh is involved in a variety of CNS functions ranging from autonomic regulation of the peripheral nervous system neuroendocrine activity learning and memory affect 13 and motor functions Loss of cholinergic neurons is a hallmark Alzheimer39s disease suggesting that cholinergic neurotransmission has a central role in higher brain functioning We will discuss the synthesis and degradation of Acetylcholine when we consider the NM junction Slide 35 Anatomy of cholinergic neurons While there are many cholinergic neurons in the brain they are considerably fewer in number than neurons that secrete glutamate and GABA Cholinergic neurons also have broader projections than do glutamate and GABA neurons The major pathways are illustrated in this figure They include 1 Neurons from the nucleus basalis project to cerebral cortex 2Neurons from those from medial septal and diagonal band project to hippocampus pathways important for learning and memory which degernate in Alzheimer s diseaseAcetylcholione esterase inhibitors are used to treat Alzheimers Slide 36 Biogenic amines The biogenic amines include the catecholamines dopamine norepinephrine and epinephrine 14 the indolamine serotonin histamine Biogenic amine transmitters mediate slow neurotransmission ie act on Gproteinlinked receptors Drugs that act on amine neurotransmission are common in psychiatric medicine We will cover the biosynthesis of the catecholamines under autonomic pharmacology Slide 37 Dopamine DA Dopamine neurotransmission plays a role in motor control deficiencies in dopamine neurotransmission are associated with Parkinson39s disease Huntington39s chorea and Gilles de la Tourette syndrome sexual behavior increases in central dopamine activity produce increased sexual behavior DA agonists such as apomorphine enhance and antagonists such as haloperidol decrease the frequency of mounting behavior in rats suggesting that DA is also involved in regulating sexual function 15 the action of antipsychotic drugs This suggests that dopamine plays a role in normal mentation Slide 38 Dopaminergic pathways Neurons synthesizing DA in two regions the midbrain containing the substantia nigra and the adjacent ventral tegmental area and the hypothalamus Nigrostriatal projections go to the striatum and control posture and movement they degenerate in Parkinson s Ventral tegmental extend to the cortex and limbic system important for targeted oriented behaviors including psychotic behavior Those projecting form the ventral tegmental to the nucleus accumbens are believed to be involved in addiction DA synthesized in the arcuate extend to the pituitary Slide 39 Dopamine synapse The Dopamine reuptake transporter is a member of a family of transporters that includes the GABA norepinephrine and serotonin reuptake transporters These transporters are the site of action of many psychoactive drugs and are discussed in more detail in the lecture on stimulants 16 Dopamine receptors are divided into several classes based on their sensitivity to pharmacological agents Slide 40 D1 post synaptic receptors work through Gprotein activated second messenger generation D2 both post synaptic and presynaptic receptors D2a D2b the site of action of classical antipsychotic drugs D4 The site of action of atypical antipsychotic drugs The expression of D4 receptors has been reported to be increased in schizophrenics Slide 41 Norepinephrine NE Neurotransmission mediated by norepinephrine plays a role in Affect an expressed or observed emotional response tricyclic anti depressants alter NE neurotransmission 17 attention drugs that increase NE neurotransmission increase attention and focus Slide 42 Norepinephrine secreting neurons are present in two structures the locus ceruleus in pons with projections to the cortex thalamus and olfactory bulb the lateral tegmental system in brain stem with projections to the amygdala cerebellum and spinal cord Slide 43 Serotonin 5HydroxyTryptamine Serotonergic neurotransmission is important in the control of affect The most common antidepressants alter serotonergic neurotransmission sleep Blockade of serotonin biosynthesis causes marked insomnia in experimental animals For a number of years the amino acid tryptophan the precursor of serotonin was used as a mild sedative agent While tryptophan is no longer available for this purpose in the USA a tryptophan contaminant caused serious side effects in some people another serotonin derivative melatonin is now being used as a sedative agent 18 appetite Increased serotonin levels decrease appetite sexual behavior Decreasing brain serotonin increases sexual behavior in rats both heterosexual and homosexual while increasing brain serotonin levels decrease it Slide 44 Serotonin Metabolism The pathway of serotonin synthesis is shown here The initial step in the biosynthesis of serotonin involves the ring hydroxylation of tryptophan This is the ratelimiting step in the pathway Serotonin is degraded by monoamine oxidase MAO Serotonin is also the precursor of melatonin a hormone synthesized in the pineal gland which is thought to regulate entrainment of your circadian rhythm Slide 45 Anatomy of serotonergic pro39ections Serotonergic neurons are found in the raphe ra phe nuclei in both midbrain rostral raphe and brain stem caudal raphe These neurons have very broad projections to thalamic limbic and cortical regions Note the projections to the spinal cord from the caudal raphe nucleus This projection may be involved in the increased pain perception observed in depressed low serotonergic individuals 19 Slide 46 the Serotonin Synapse Serotonin receptors fall into seven classes which will be discussed in subsequent lectures Most of the 5HT receptors are Gprotein coupled receptors and so mediate slow neurotransmission through second messenger generation Serotonin receptors are differentially localized in the brain Different serotonin receptors are the site of action of different drugs Slide 47 Histamine neurotransmission is involved in arousal increased histamine increases wakefulness decreased histamine increases slow wave sleep motor behavior eatingdrinking sexual behavior these actions may be indirect and may reflect histamine effects on catecholaminergic neurons metabolism histamine is synthesized from histidine an amino acid present in all cells by the enzyme histidine decarboxylase Slide 48 Anatomy of histamine neurons Amine secreting neurons are found in the TM tuberomammillary nucleus of the hypothalamus These neurons have very broad 20 projections suggesting that histamine is a primary neurotransmitter in hypothalamic regulation of brain function Histamine receptors are found throughout the brain and are also present on gia and blood vessels H1 coupled to Gq which activates phospholipase C H2 activate Gs which increases cAMP production Slide 49 Neuropeptides In addition to classical neurotransmitters neurons also communicate by releasing peptide transmitters Many neuroactive peptides have been characterized Peptides are thought to act in concert with other transmitters ie neurons that release neuropeptides often release a classical neurotransmitter in addition to a peptide The action of peptides is generally modulatory Neuropeptides regulate many complex functions and behaviors including reproduction eating and mood Neuropeptides are small proteins that are often synthesized as larger precursor peptides which are proteolyzed to produce shorter biologically active peptides 21 Neuropeptides are secreted via a different mechanism than standard neurotransmitters Rather than being secreted from small vesicles assembled and filled at the synapse peptides are released from large Golgiderived vesicles that do not cluster over active zones in presynaptic terminals Much less is known about the regulation of peptide release than the release of standard neurotransmitters Most neuropeptide receptors of which the opiate receptors are the best characterized are Gprotein coupled receptors 22
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