Synapses, Neurotransmitters, and Neuromodulators PDF

Synapses Neurotransmitters Neuromodulators  Intended Learning Outcomes (ILOs) After reviewing the PowerPoint presentation, lecture notes and associated material, the student should be able to: ❑ Define synapses and enumerate their functions. ❑ Classify synapses and differentiate betw...

Synapses Neurotransmitters Neuromodulators  Intended Learning Outcomes (ILOs) After reviewing the PowerPoint presentation, lecture notes and associated material, the student should be able to: ❑ Define synapses and enumerate their functions. ❑ Classify synapses and differentiate between chemical and electrical synapses. ❑ Describe Synaptic transmission. ❑ Explain electrical events at synapses (EPSPs & IPSPs). ❑ Elaborate properties and patterns of synaptic transmission in neuronal pools. ❑ Differentiate between postsynaptic & presynaptic inhibition, and between temporal & spatial summation. ❑ Discuss the role of synapses in information processing and storage of information (memory). ❑ Explain what neurotransmitters are, their types and how they are released and removed. ❑ Differentiate between neurotransmitter receptors (ionotropic and metabotropic). ❑ Appreciate that effectiveness of neurotransmitters can be modified by drugs and diseases.  Intended Learning Outcomes (ILOs), Cont. After reviewing the PowerPoint presentation, lecture notes and associated material, the student should be able to: ❑ Recognize disorders associated with the cholinergic system of the brain. ❑ Explain the functions and disorders of the noradrenergic & serotonergic systems of the brain. ❑ Describe the functions and disorders of the glutamergic system of the brain. ❑ Discuss the functions and disorders of neurotransmitters of the basal ganglia (cholinergic, dopaminergic, GABAergic systems).  Recommended Readings ❑ Guyton and Hall, Textbook of Medical Physiology; 14th Edition; Chapters 46, 47 and 59.  Neuronal Signaling ❑ Communication by neurons is based on changes in the membrane’s permeability to ions → changes in membrane potential. ❑ There are types of membrane potentials, which are of major functional significance: ❑ Graded potentials, and ❑ Action potentials. Dendrites: receive information, typically neurotransmitters, then undergo graded potentials. Axons: undergo action potentials to deliver information, typically neurotransmitters, from the axon terminals. Synapses ❑ The transfer of information between neurons and between neurons and effector organs takes place at structurally and functionally specialized locations called synapses. ❑ Most synapses are chemical synapses, where the signal is transmitted from one neuron to another by neurotransmitters. COMMUNICATION: A single neuron postsynaptic to one cell can be presynaptic to another cell.  Functional Types of Synapses ❑ Chemical Synapses: ▪ Neuronal communication via secretion of neurotransmitters (NTs). ▪ The first neuron secretes a NT at the synapse that acts on receptor on the next neuron to excite it, inhibit it or modify its sensitivity. ▪ Most synapses in the CNS are chemical synapses. ❑ Electrical Synapses: ▪ Communication via current flowing through gap junctions. ▪ Membranes of the pre- and post-synaptic neurons come close together and gap junctions form → allow passage of ions and small molecules between the 2 cells. ▪ Electrical synapses are less common than chemical synapses. ▪ Electrical synapses are important in the CNS in: ✓ Arousal from sleep, ✓ Mental attention, ✓ Memory, and ✓ Emotions. ❑ Conjoint Synapses: ▪ Both electrical and chemical, e.g., neurons in lateral vestibular nucleus.  Electrical Synapses ❑ An electrical synapse consists of one or more gap-junction channels permeable to small ions and molecules. ❑ Electrical synapses have bidirectional transmission. ❑ Electrical synapses coordinate the activities of large groups of interconnected neurons. ❑ This promotes synchronous firing of a group of interconnected neurons. For example, in mental attention, emotions, memory, and arousal from sleep. ❑ Distribution: retina, hippocampal neurons, cerebellar neurons, GABA interneurons of the neocortex, thalamus. ❑ smooth muscle, and cardiac muscle.  Chemical Synapses ❑ In a chemical synapse, the axon of a neuron terminates on one of the following of another neuron: ▪ Dendrites (axo-dendritic), ▪ Soma (axo-somatic) or ▪ Axon (axo-axonic) ❑ Chemical synapses are characterized by one-direction transmission. The presynaptic neuron releases a chemical (NT). NT binds to a specific receptor on postsynaptic neuron enabling an electrical signal (post synaptic potential or action potential, AP) to be generated in postsynaptic neuron. This forces the signal to travel in required directions for performing specific nervous functions.  Chemical Synapses chemical signal electrical electrical electrical signal signal signal Functional Types of Synapses  Functional Types of Synapses Property Electrical Synapse Chemical Synapse Distance between the pre- 3.5 nm 30 - 50 nm and post-synaptic terminal (1 nm = 10-9 m) Cytoplasmic continuity Yes No Agent of transmission Ionic current Chemical transmitter Synaptic delay Virtually absent Significant, from 0.3 – 0.5 milliseconds to several milliseconds for transmission across one synapse Direction Usually Bi-directional Unidirectional  Examples of Synapses Outside CNS Junctions ❑ Neuromuscular junction. ❑ Contact between autonomic neurons and smooth, cardiac muscles, and glandular cells.  Mechanisms of Neurotransmitter (NT) Release ❑ Prior to the arrival of an action potential, vesicles of NT are loosely located in the presynaptic terminal by the interaction of a group of proteins that are collectively known as SNARE Proteins (soluble N-ethylmaleimide-sensitive factor protein attachment receptors). ❑ Calcium entering during depolarization binds to a separate family of proteins associated with the vesicle known as synaptotagmins → conformational change in the SNARE complex → membrane fusion and neurotransmitter release.  Activation of the Postsynaptic Cell ❑ At an excitatory synapse, NT activates receptors on the postsynaptic neuron → opening of nonselective channels that are permeable to sodium, potassium → simultaneous movement of a relatively small number of potassium ions out of the cell and a larger number of sodium ions into the cell → a slight depolarization of the postsynaptic cell. An excitatory postsynaptic potential ❑ This potential change is called an (EPSP) is a graded depolarization that excitatory postsynaptic potential moves the membrane potential closer (EPSP). to the threshold for firing an action potential (excitement).  Inhibition of the Postsynaptic Cell ❑ At an inhibitory synapse, neurotransmitter activates receptors on the postsynaptic neuron → opening of chloride channels → influx of chloride → hyperpolarization of the postsynaptic cell. ❑ This potential change is called an inhibitory postsynaptic potential (IPSP). An inhibitory postsynaptic potential (IPSP) is a graded hyperpolarization that moves the membrane potential further from the threshold for firing an action potential (inhibition).  Functional Properties of Chemical Synapses 1. One-way conduction: Synapses generally permit conduction of impulses in one direction i.e., from pre-synaptic to post-synaptic neuron: This forces the signal to travel in the required directions for performing specific nervous functions. 2. Synaptic delay: This is the minimum time required for transmission across the synapse. It is from 0.3 – 0.5 milliseconds to several milliseconds for transmission across one synapse. This time is taken for: ❑ Discharge of NT by the pre-synaptic terminal ❑ Diffusion of NT to post-synaptic membrane ❑ Action of NT on its receptor ❑ Action of NT to  membrane permeability Clinical Importance is that we can know number of synapses involved in neuronal pathways by time lag. 3. Synaptic inhibition and synaptic facilitation (synaptic strength): The strength of a given synapse is influenced by both presynaptic and postsynaptic mechanisms. These lead to either synaptic inhibition or synaptic facilitation. Types of synaptic inhibition: Direct inhibition Indirect inhibition Reciprocal inhibition Inhibitory interneuron Synaptic Delay  Synaptic Inhibition Direct inhibition (Post-synaptic inhibition): ✓ Occurs when an inhibitory neuron (releasing inhibitory NT) acts on a post synaptic neuron leading to → hyperpolarization (IPSPs) due to opening of Cl¯ and/or K+ channels. ✓ Example: Glycine at the level of the spinal cord to block pain impulses. ❑ Mechanisms of presynaptic inhibition: ❑ Neuron B is an excitatory pre-synaptic Indirect Inhibition terminal in the synapse between it and (Pre-synaptic Inhibition) neuron C. ❑ Neuron A is an inhibitory neuron. ❑ Transmission through the axoaxonic synapse between neurons A and B causes presynaptic inhibition by ↑ing the permeability of presynaptic terminal to Cl- ions → ↓ the size of the action potentials in the presynaptic terminal → ↓ Ca2+ influx and consequently the amount of excitatory NT released from the pre-synaptic terminal. ❑ Voltage-gated K+ channels are also opened → K+ efflux → ↓ the size of the action potentials in the presynaptic terminal → decreases the Ca2+ influx. ❑ The first NT shown to produce presynaptic inhibition was GABA, which increases Cl– conductance by acting on GABAA receptors ❑ Conversely, presynaptic facilitation is produced when the action potential is prolonged in the presynaptic terminal and the Ca2+ channels are open for a longer period. Sometimes an input signal through an input fiber causes: Reciprocal Inhibition ❑ An excitatory output signal in one direction (#1), and ❑ A simultaneous inhibitory output signal going elsewhere (#3). The inhibitory output is caused by an inhibitory neuron (neuron 2), which secretes a different type of NT. This type of neuronal circuit is known as the reciprocal inhibition circuit. Such neuronal circuit controls all antagonistic pairs of muscles.  Reciprocal Inhibition ❑ Afferent fibers from stretch receptors in skeletal muscle project directly to the spinal α- motoneurons , which supply the same muscle. ❑ Impulses in this afferent fiber cause EPSPs. Summation of these EPSPs → responses in the postsynaptic spinal motor neurons supplying the same muscle. ❑ At the same time, IPSPs are produced in the motor neurons supplying the antagonistic muscles through inhibitory interneurons → inhibition of antagonistic muscles. ❑ Renshaw cells are inhibitory interneurons of the spinal cord. Renshaw cells ❑ They lie next to the α-motoneurons (anterior horn cells; AHCs) and connect to them. ❑ They receive input from: ▪ The descending tracts of supra-spinal origin. ▪ Axon collaterals of α-motoneurons (AHCs). ▪ The neurotransmitter activating Renshaw cells is acetylcholine. ❑ Renshaw cells then generate an IPSP within the α- motoneurons by glycine and GABA. ❑ α-motoneurons are multipolar neurons. So, they have many dendrites. The result of their activity is therefore determined by the sum of all EPSPs and IPSPs inputs. This means that Renshaw cells have more of a modulating than a pure inhibitory influence on the activity of motoneurons. ✓ The inhibitory effect of Renshaw cells prevents overshooting muscle contraction. ❑ Thus, α-motoneurons → a negative feedback loop by causing cholinergic activation of Renshaw cells → inhibits the same α- motoneurons that activated it. ❑ This process is called recurrent inhibition. Other Functional Properties of Chemical Synapses; 4. Summation of Post-Synaptic Potentials ❑ In most neurons, one EPSP by itself is 4. Summation of Post-Synaptic Potentials not enough to reach threshold in the postsynaptic neuron. ❑ In temporal summation, the input signals arrive the postsynaptic neuron from the same presynaptic cell at different times → greater number of open ion channels → greater flow of positive ions into the cell → greater depolarization. ❑ In spatial summation, the input signals arrive from different presynaptic cells at different locations → greater number of open Panel 1: Two distinct, non-overlapping, graded ion channels → greater flow of depolarizations from the same presynaptic cell. positive ions into the cell → greater Panel 2: Two overlapping graded depolarizations depolarization. demonstrate temporal summation. Panel 3: Distinct actions of stimulating neurons A and B ❑ The interaction of multiple EPSPs demonstrate spatial summation. through spatial and temporal Panel 4: A and B are stimulated enough to cause a summation → ↑the inward flow of suprathreshold graded depolarization, so an positive ions and bring the action potential results. postsynaptic membrane to threshold Panel 5: Neuron C causes a graded hyperpolarization; A so that action potentials are initiated. and C effects add, cancel each other out.  Other Functional Properties of Chemical Synapses; 5. Fatigue ❑ It is due to exhaustion of neurotransmitter. ❑ If the presynaptic neurons are continuously stimulated there may be an exhaustion of the NT, resulting in stoppage of synaptic transmission.  Termination of NT Action ❑ Neurotransmitters are removed from the synaptic cleft by the following mechanisms: ❑ Re-Uptake: The NT is actively transported back into the presynaptic axon terminal or, in some cases, into nearby glial cells; ❑ Diffusion: The NT diffuse away from the receptor site; or ❑ Enzymatic transformation into inactive substances: The NT is enzymatically transformed into inactive substances, some of which are transported back into the axon Termination of terminal for reuse. neurotransmitter action  Modification of Synaptic Transmission by Drugs Possible drug effects on synaptic effectiveness: A. Release and degradation of the NT inside the axon terminal. B. Increased NT release into the synapse. C. Prevention of NT release into the synapse. D. Inhibition of synthesis of the NT. E. Reduced reuptake of the NT from the synapse. F. Reduced degradation of the NT in the synapse. G. Agonists (evoke same response as NT) or antagonists (block response to NT) can occupy the receptors. H. Reduced biochemical response inside the dendrite.  Neuronal Pools (Neuronal Circuits) ❑ Neurons never function in isolation. They are organized into neuronal circuits/pools of varying number of neurons, which are interconnected by synapses to process specific kinds of information/function when activated. A pool may be localized, or its neurons may be distributed in several different regions of the CNS. ❑ Neural circuits/pools interconnect to one another to form large networks in the brain. ❑ Each circuit/pool receives input/signal(s), and then processes the information according to the specific characteristic of the pool. Main Types of Neuronal Pools (Neuronal Circuits) ❑Convergence means that signals Convergence from multiple inputs converge to excite or inhibit a single neuron. ❑The inputs can be: From a single neuron, or Multiple separate neurones (excitatory or inhibitory). Convergence allows information from many sources to influence a cell’s activity. ❑Convergence allows summation of information.  Divergence ❑ Divergence means that signals from a single input diverge to spread to many neurons (many outputs). ❑ Divergence can be: In the same tract/pathway (amplifying type), or In multiple tracts/pathways. Divergence allows one information source to affect multiple pathways. ❑ Divergence helps a signal to spread to a wide area. Role of Synapses in Processing Sensory Information ❑ One of the most important functions of the nervous system is to process incoming information in such a way that appropriate mental and motor responses occur. ❑ More than 99 % of all sensory information is discarded by the brain as irrelevant and unimportant. ▪ For instance, one is ordinarily unaware of the parts of the body that are in contact with clothing, as well as of the seat pressure when sitting. ❑ Synapses determine the directions that the signals will spread through the nervous system. ❑ Thus, the synapses perform a selective action: ❑ Synapses often block weak signals and allow strong signals to pass. ❑ However, at other times, synapses may select and amplify certain weak signals. Role of Synapses in Storage of Information (Memory) ❑ Only a small fraction of even the most important sensory information usually causes immediate motor response. ▪ Much of the information is stored for future control of motor activities and for use in the thinking processes. ❑ This is also a function of the synapses: Each time certain types of sensory signals pass through sequences of synapses, these synapses become more capable of transmitting the same type of signal the next time, a process called FACILITATION. After the sensory signals have passed through the synapses a large number of times, the synapses become so facilitated that signals generated within the brain itself can also cause transmission of impulses through the same sequences of synapses, even when the sensory input is not excited. This gives the person a perception of experiencing the original sensations, although the perceptions are only memories of the sensations.  Factors Affecting Synaptic Transmission ❑ Alkalosis: ❑ Increases neuronal excitability. ❑ Causes cerebral epileptic seizures (increased excitability cerebral neurons), e.g., over-breathing in person with epilepsy. This blows off carbon dioxide and therefore elevates the pH of the blood momentarily. ❑ Acidosis: ❑ Depresses neuronal activity; pH around 7.0 usually causes coma, e.g., severe diabetic ketoacidosis. ❑ Drugs: ❑ Caffeine found in coffee and tea increases neuronal excitability by reducing the threshold for excitation of neurons. ❑ Hypoxia: Depression of neurons. ❑ Neurotransmitter (NT) is a Neurotransmitters (NTs) and chemical that: ▪ is released by the neuromodulators presynaptic neuron into the cleft of chemical synapse by an action potential. ▪ binds to receptors on the post-synaptic neuron. ▪ generates either an excitatory or inhibitory post-synaptic potential. ❑ NTs can either be excitatory, inhibitory. ❑ NTs are chemically diverse – ranging from amino acids to peptides to biogenic amines to gases.  Note ❑ A note on terminology: ✓ Neurons are often referred to as –ergic; ✓ The missing prefix is the type of neurotransmitter the neuron releases. ❑ For example, dopaminergic applies to neurons that release the neurotransmitter dopamine. Neurotransmitters Receptors ❑ There are two types of neurotransmitter receptors located on post-synaptic membranes: Ionotropic receptors Metabotropic receptors  Ionotropic Receptors They are characterized by the following: ❑ Neurotransmitter receptors and ion channels are linked. ❑ Receptor activation alters channel conductance. ❑ Synaptic transmission is rapid. ❑ Examples are: ✓ Nicotinic acetylcholine Ionotropic receptor receptors, ✓ Some glutamate receptors and ✓ GABAA and C receptors.  They are characterized by the following: ❑ Synaptic transmission is slow. Metabotropic Receptors ❑ Neurotransmitter receptors and ion channels are separate ❑ Receptor activation alters intermediate proteins, i.e., G-protein-linked receptors. ❑ Thus, the receptor molecule interacts with specific regulatory proteins (G proteins) in the cell membrane. ▪ G protein directly opens ion channel e.g., muscarinic cholinergic receptors in heart → open K+ channel → hyperpolarize ▪ G protein activates enzyme to produce a second messenger, e.g., IP3 (inisitol triphosphate), DAG, cAMP. Examples are: ✓ Muscarinic acetylcholine receptors, Metabotropic receptor ✓ Some glutamate receptors, and ✓ GABA B receptors. Cholinergic Acetylcholine (ACh) System ❑ Acetylcholine (Ach) is the 1st neurotransmitter to be identified (about 90 years ago). Otto Loewi (1873 – 1961) ❑ German Pharmacologist ❑ Discovered acetylcholine ❑ Received Noble Prize in Physiology (1936) ❑ Neurons that release ACh are called cholinergic neurons 1. Nerve terminals of all fibers Sites of Release of arising from CNS including: Acetylcholine A. Motor nerves to skeletal (Cholinergic Fibers) muscles (motor end plate). B. All preganglionic fibers of ANS (at all autonomic ganglia), and 2. Nerve terminals of all parasympathetic postganglionic fibers 3. Nerve terminals of some sympathetic postganglionic fibers like: A. Fibers to sweat glands B. Vasodilator fibers of some blood vessels 4. Suprarenal medulla (modified ganglia). 5. Some fibers inside CNS ❑ ACh is the major Cholinergic System neurotransmitter in the peripheral nervous system. ❑ In the brain, cholinergic neurons are present mainly in 2 areas : 1. Basal Forebrain; namely Nucleus Basalis of Myenert, and Septal nuclei. 1. Ponto-Mesencephalic Cholinergic Complex. Degeneration in Alzheimer's disease ❑ ACh influences mental processes such as: ▪ Learning & Memory Cholinergic System ▪ Sleeping, Dreaming and Wakefulness Function and ▪ Sexuality & Thirst Disorders ❑ Alzheimer’s Disease, which is the most common form of dementia is associated with acetylcholine loss in the brain. ✓ Thus, inhibitors of acetylcholinesterase in the brain are the main drugs used to treat Alzheimer’s disease. ❑ Damage to Ach producing cells in the basal forebrain → ▪ Bipolar disorder ▪ Mood swings ▪ Depression  Acetylcholine (Cholinergic) Receptors ❑ There are two types of cholinergic receptors: ❑ Muscarinic receptors, and ❑ Nicotinic receptors. Acetylcholine (Cholinergic) Receptors Nicotinic Acetylcholine (Cholinergic) Receptors ❑ Nicotinic cholinergic receptors are so called because they can be activated by the alkaloid Nicotine. ❑ Nicotinic receptors are blocked by curare. ❑ Nicotinic receptors are present in the synapses between preganglionic and postganglionic neurons of both sympathetic and parasympathetic systems (NN receptors). ❑ Nicotinic receptors are also present in the neuromuscular junction on the plasma membrane of skeletal muscle (NM receptors). ❑ Nicotinic receptors are ionotropic receptors.  Nicotinic Acetylcholine Receptors ❑ The nicotinic acetylcholine (ACh) receptor is a ligand-gated ion channel. ❑ The receptor molecule composed of five subunits (two α , one β ,one γ, and one δ). ❑ The receptor opens a central transmembrane ion channel when ACh binds to sites on the extracellular domain of its subunits.  Muscarinic Acetylcholine (Cholinergic) Receptors ❑ Muscranic acetylcholine receptors are so called because they can be activated by the alkaloid muscarine. ❑ Muscarinic action are blocked by atropine. ❑ There are five subtypes (M1-M5): all are found in the brain but M1 is abundant. ❑ Muscarinic receptors are also present in all organs innervated by the postganglionic fibers of the parasympathetic system and by the sympathetic cholinergic nerves. ❑ Glutamate (glutamic acid) is the most found NT in the Glutaminergic System brain (king of NTs, ~50% neurons). ❑ It is the major excitatory neurotransmitter of the brain and spinal cord. ❑ Glutamate is widespread, but high levels in hippocampus; Hypo function of NMDA receptors of glutamate (N-methyl-D-aspartate) in this area and prefrontal cortex is associated with schizophrenia. Glutamate receptors are widely distributed in the brain. They are of two major types: Glutamate Receptors 1. Ionotropic receptors (ligand-gated ion channels): There are 3 types, which are named after the agonists that activate them : ▪ NMDA receptors (N-methyl D-aspartate): These receptors play a role in long-term potentiation in the hippocampus (LTP is a persistent increase in synaptic strength following high-frequency stimulation of a chemical synapse). ✓ So, they are involved in learning and memory. ▪ AMPA receptors (α-amino-3-hydroxy-5- methylisoxazole- 4-propionate). ▪ Kainate receptors. 2. Metabotropic receptors (G protein- coupled receptors): mGluR1-mGluR11: ▪ They are found in hippocampus, cerebellum and the cerebral cortex ▪ They act through second messengers, which activate biochemical cascades, leading to modification of other proteins such as ion channels. NMDA Receptors permit passage of Na+ and large amounts of Ca2+. NMDA Receptors They are unique since: ❑ Glycine is essential for their normal response to glutamate. The channel opens only when both glycine and glutamate bind to the receptor. ❑ The channel is blocked by Mg2+ ion at normal membrane potentials. This blockade is removed by depolarization (caused by e.g., AMPA).  Functions & Disorders of Glutaminergic System Functions: ❑ Glutamic acid (and aspartic acid): are the major excitatory NTs in CNS. ❑ Cooperative activity of NMDA and AMPA receptors has been implicated in long-term potentiation (LTP). LTP is a persistent increase in synaptic strength following high- frequency stimulation of a chemical synapse. This mechanism is thus thought to be a cellular process underlying learning and memory (hippocampus). ❑ Motor coordination in the cerebellum. Long-term potentiation at glutamatergic synapses  Functions & Disorders of Glutaminergic System Disorders: ❑ Excess glutamate activity is implicated in some types of epileptic seizures. ❑ Hypo function of NMDA receptors in the hippocampus and prefrontal cortex is associated with schizophrenia. ❑ Reduced levels of glutamic acid are seen in cases of stroke and autism. ❑ Disorders of glutaminergic system are also associated with Alzheimer's disease. ❑ NMDA receptors have also been implicated in mediating excitotoxicity. This is a pathological phenomenon in which the injury or death of some brain cells (due, for example, to blocked or ruptured blood vessels) rapidly spreads to adjacent regions. When glutamate-containing cells die and their membranes rupture → flooding of glutamate → excessive stimulation of AMPA and NMDA receptors on nearby neurons → accumulation of toxic levels of intracellular calcium, which in turn kills those neurons and causes them to rupture, and the wave of damage progressively spreads. Recent experiments and clinical trials suggest that administering NMDA receptor antagonists may help minimize the spread of cell death following injuries to the brain. ❑ Gamma Aminobutyric Acid (GABA) is the main inhibitory GABAergic System neurotransmitter in the CNS. ❑ GABA interneurons are abundant in the brain, with 50% of the inhibitory synapses in the brain being GABA mediated. ❑ GABAergic inhibition is seen at all levels of the CNS: ✓ Cerebral cortex ✓ Cerebellar cortex ✓ Hippocampus ✓ Hypothalamus ❑ There are 3 types of GABA receptors: GABAA B & C. GABA Receptors ❑ GABA A & B receptors are widely distributed in CNS. ❑ GABAC are found in retina only. ❑ GABA B are metabotropic (G-protein-coupled receptors). ❑ GABA A & C receptors (ionotropic) have multiple binding sides (for benzodiazepine and barbiturates). ❑ The channel is a Cl- channel (not Na). Functions: ❑ GABA is involved in presynaptic inhibition. Functions & Disorders of ❑ GABAA receptors are GABAergic System chronically stimulated in the CNS to regulate neuronal excitability. Disorders: ❑ Under activity of GABA leads to seizures. Depressant drugs (alcohol, barbiturates) work by increasing GABA activity.  Catecholamines Noradrenergic System  Catecholamines Noradrenergic System ❑ Catecholamines are formed in the adrenergic fibers and the adrenal medulla (suprarenal medulla) from the amino acid phenylalanine through the following steps: ❑ Phenylalanine is transformed to tyrosine by phenylalanine hydroxylase then:  Catecholamines Sites of release in the PNS: 1. Noradrenaline; NA (norepinephrine; NE) is the chemical transmitter of all sympathetic postganglionic fibers EXCEPT at: ▪ Sweat glands ▪ Skeletal muscle blood vessels 2. Catecholamines (80% adrenaline & 20% noradrenaline) are secreted by the adrenal medulla in emergency conditions. Noradrenaline Adrenaline (norepinephrine) (Epinephrine) Secretion Sympathetic fibers Suprarenal medulla Effects on blood +++ + vessels Heart + +++ Metabolic effects + +++  Adrenergic Receptors (Adrenoceptors) There are 2 major types of adrenergic receptors: 1. Alpha (α) adrenergic receptors: subdivided into: ▪ α1: present on membranes of postsynaptic cells (smooth muscle cells). ▪ α2: present on membranes of both presynaptic and postsynaptic cells. 2. Beta (β) adrenergic receptors: subdivided into: ▪ β1: on cardiac muscles cells ▪ β2: on smooth muscle cells including smooth muscles cells of blood vessels, bronchial smooth muscle, uterine smooth muscle, urinary bladder smooth muscle. ▪ β3: on fat cells  Noradrenergic (NA) System in the PNS ❑ Norepinephrine (NE) is released from: Sympathetic nerves, and the adrenal medulla in the PNS. ❑ It acts on both α- and β- adrenergic receptors (G- protein-coupled receptors).  Noradrenergic (NA) System of the Brain ❑ The Noradrenergic system has a very wide-spread projection system. ❑ Noradrenergic neurons are located in locus coeruleus (LC) which projects to: ✓ Spinal cord, ✓ Cerebellum, ✓ Thalamus, ✓ Hypothalamus, ✓ Amygdala, ✓ Cerebral cortex, and ✓ Autonomic brainstem centers ❑ In the brain, the Noradrenergic system The LC is activated by similar stimuli to constitutes part of the Reticualr those that activate ANS. Activating System (RAS) → alertness.  Noradrenergic (NA) System of the Brain ❑ The firing of LC neurons of action potentials is a function of vigilance and arousal. Vigilance is defined as the action or state of keeping careful watch for possible danger or difficulties. ❑ The neurons of the LC demonstrate irregular firing during quiet wakefulness. ❑ The firing decreases markedly during slow-wave sleep & virtually disappears during REM sleep. ❑ Stress causes very high levels of LC activity. ❑ Drugs that suppress LC have a powerful sedating effect because LC controls arousal level. Functions and Disorders of NA System of the Brain Functions: ❑ It constitutes part of the RAS (Reticular Activating System); Attention/Vigilance, and alertness, ❑ Learning, ❑ Fight or flight response. Disorders: NA is implicated in Stress-Related Disorders: ❑ Depression. ❑ Withdrawal from some drugs of abuse. ❑ Other stress-related disorders such as panic disorder.  Dopaminergic System of the Brain ❑ Dopamine is a catecholamine that is synthesized from tyrosine. ❑ There are 5 dopaminergic receptors (D1 - D5). Overstimulation of D2 receptors is thought to be related to schizophrenia.  Dopaminergic Pathways in the Brain Dopamine is transmitted via three major pathways (circuits) in the brain: ❶ Nigrostriatal ❷ Mesolimbic & Mesocortical ❸ Tuberoinfundibular  Dopaminergic Pathways in the Brain ❶ The Nigrostriatal circuit: This circuit/pathway extends from the substantia nigra to the striatum (caudate nucleus and putamen). ▪ This circuit is concerned with motor control. ▪ Death of neurons in this pathway is linked to Parkinson's disease.  Dopaminergic Pathways in the Brain ❷ The Mesolimbic & Mesocortical system: This system projects to the mesolimbic forebrain and prefrontal cortex. ▪ It is involved with memory, motivation, emotion, reward, and desire. ▪ Dysfunction of this dopaminergic system is associated with hallucinations and schizophrenia.  Dopaminergic Pathways in the Brain ❸ Tuberoinfundibular System: This system extends from the infundibular region (median eminence of hypothalamus) to the pituitary gland. It is concerned with: ▪ Regulation of hormones, ▪ Maternal behavior, and ▪ Pregnancy.  Serotonin System The Serotonin System ❑ Serotonin or 5-hydroxytryptamine (5-HT) is synthesized from the amino acid tryptophan. ❑ Tryptophan deprivation alters brain chemistry and mood. ❑ There are 14 classes of serotonin receptors in different parts of CNS (most are metabotropic, except 5-HT3).  The Serotonin System (Pathways) in the Brain ❑ The principal centers for serotonergic neurons are the caudal and rostral raphe nuclei. ❑ Neurons in caudal raphe nuclei project to: ▪ Cerebellum ▪ Medulla ▪ Spinal cord ❑ Neurons in rostral raphe nuclei project to: ▪ Thalamus ▪ Basal ganglia ▪ Limbic system ▪ Cerebral cortex Serotonin innervates the entire CNS Functions and Disorders of The Serotonin System Drugs (e.g., Prozac) that prolong serotonin’s actions relieve symptoms of depression & obsessive disorders  Clinical Significance of Neurotransmitters The pathophysiology of many neurological disorders has been attributed to changes in neurotransmitters. Just a few of many…. examples: ❑ Parkinson’s Disease is associated with dopamine deficiency in the basal nuclei (in the Nigrostriatal pathway). ❑ Treatment: Levodopa (L-dopa). This drug is a precursor of dopamine. It crosses the blood-brain barrier (unlike dopamine). Once inside the brain, it is converted to dopamine & relieves the symptoms of disease.  Clinical Significance of Neurotransmitters ❑ Schizophrenia is associated with dopamine excess in the mesolimbic pathway, and Hypo function of NMDA receptors of glutamate in the hippocampus and in the prefrontal cortex. ❑ Depression is associated with decreased release of serotonin or norepinephrine. ❑ Epilepsy is associated with increased excitatory or decreased inhibitory neurotransmitters. ❑ Alzheimer’s disease is associated with acetylcholine deficiency and disorders of glutaminergic system.  Clinical Significance of Neurotransmitters ❑ Myasthenia gravis: this is an autoimmune disease that targets nicotinic Ach receptors on the membrane of skeletal muscle fibers (antibodies are directed against these receptors). ✓ The hallmark of this disorder is muscle weakness, particularly during sustained activity. ✓ Treatment: Myasthenia gravis can be improved by treatment with inhibitors of acetylcholinesterase; the enzyme that normally degrades Ach at the neuromuscular junction. Pharmacological Significance of Neurotransmitters Neurotransmitters have been the target of many drugs for treatment of neurological disorders. Just a few of many…. examples: ❑ Prozac is an example of a Selective Serotonin Reuptake Inhibitor (SSRIs). ✓ Serotonin is involved in neural pathways regulating mood & behavior. ✓ Prozac is used for treating depression, which is characterized by deficiency of serotonin. ❑ Alzheimer’s Disease is treated with cholinesterase inhibitors. ❑ Schizophrenia is treated with dopamine SSRIs (selective serotonin reuptake blockers. inhibitors – e.g., Prozac) prolong the PSP by inhibiting reuptake of serotonin.  Intended Learning Outcomes (ILOs) After reviewing the PowerPoint presentation, lecture notes and associated material, the student should be able to: ❑ Define synapses and enumerate their functions. ❑ Classify synapses and differentiate between chemical and electrical synapses. ❑ Describe Synaptic transmission. ❑ Explain electrical events at synapses (EPSPs & IPSPs). ❑ Elaborate properties and patterns of synaptic transmission in neuronal pools. ❑ Differentiate between postsynaptic & presynaptic inhibition, and between temporal & spatial summation. ❑ Discuss the role of synapses in information processing and storage of information (memory). ❑ Explain what neurotransmitters are, their types and how they are released and removed. ❑ Differentiate between neurotransmitter receptors (ionotropic and metabotropic). ❑ Appreciate that effectiveness of neurotransmitters can be modified by drugs and diseases.  Intended Learning Outcomes (ILOs), Cont. After reviewing the PowerPoint presentation, lecture notes and associated material, the student should be able to: ❑ Recognize disorders associated with the cholinergic system of the brain. ❑ Explain the functions and disorders of the noradrenergic & serotonergic systems of the brain. ❑ Describe the functions and disorders of the glutamergic system of the brain. ❑ Discuss the functions and disorders of neurotransmitters of the basal ganglia (cholinergic, dopaminergic, GABAergic systems).