2022 Neuroscience S1T4 Synaptic Transmission and Neurochemical Systems PDF

Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 c OUTLINE...

Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 c OUTLINE pathways involving several second messengers I. INTRODUCTION (neuromodulation) II. OVERVIEW III. PRINCIPLES OF NEUROCHEMICAL TRANSMISSION Termination of synaptic effects of chemical transmitters: A. Presynaptic Events 1. Presynaptic or glial uptake B. Synaptic Effects of Neurotransmitters 2. Enzymatic metabolism IV. SPECIFIC NEUROCHEMICAL SYSTEMS 3. Combination of the two A. Organization of Neurochemical Pathways in the Nervous System L-Glutamate -mediates most excitatory neurotransmission in B. Excitatory Amino Acid Systems the CNS C. Inhibitory Amino Acid Systems GABA - mediates most inhibitory effects D. Cholinergic Systems Acetylcholine, dopamine, norepinephrine, serotonin, E. Dopaminergic Systems histamine and neuropeptides - predominantly have a F. Noradrenergic, Serotonergic and neuromodulatory function Histaminergic Systems G. Neuropeptide Systems -neurochemical systems may produce long-term effects on H. Other Neurochemical Messengers neuronal activity critical for neuronal development, learning and V. CLINICAL CORRELATIONS response to injury - important for NS plasticity INTRODUCTION Communication between neurons occurs primarily at the level of synapses. Chemical Synapses - most common form of communication in the nervous systems -consist of presynaptic and postsynaptic components that are separated by a synaptic cleft 1. Presynaptic terminals - contain synaptic vesicles which are involved in the storage and release of neurotransmitters by exocytosis 2. Neurotransmitter Receptos - mediate effects of neurochemical transmitter on its target Neurochemical Systems - provide the target for pharmacologuc treatment of abnormalities in neurochemical transmission OVERVIEW Molecules involved in chemical neurotransmission include: 1. Amino acids - L-glutamate, ϒ-aminobutyric acid, and glycine 2. Acetylcholine 3. Monoamines - dopamine, serotonin and histamine 4. Neuropeptides 5. Purines - ATP 2 main classes of receptors: 1. Ligand-gated receptors -ion channels that open in response to the chemical transmitter and allow rapid influx of cations (Na+ and Ca2+) or chloride -results in fast excitatory or inhibitory postsynaptic responses, respectively PRINCIPLE OF NEUROCHEMICAL TRANSMISSION -rapid point-to-point transfer of information/ A. Presynaptic Events classic neurotransmission  include the synthesis and vesicular storage of the 2. G protein-coupled receptors neurotransmitter - mediate slower changes in neuronal 1. Trafficking, docking, and priming of the synaptic excitability through activation or inhibition of K+ or Ca2+ vesicles in the presynaptic terminal channels, either directly or through transduction 2. Ca2+-dependent NT release by exocytosis 3. Endocytotic recycling of synaptic vesicles Page 1 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 4. Presynaptic reuptake and inactivation of the  exocytosis is triggered by depolarization of the neurotransmitter presynaptic terminals, which allows a massive and transient Ca2+ influx through voltage-gated Ca2+ Synthesis of Neurotransmitters channels in response to each action potential L-glutamate, GABA and glycine  after the synaptic vesicles fuse with the synaptic  derived from the substrates of the intermediate membrane and release the NT metabolism of glucose  vesicular membrane proteins are retrieved by Acetylcholine endocytosis and recycled  indirectly related to the oxidative metabolism of glucose SYNAPSIN Dopamine, norepinephrine, serotonin and histamine  links the vesicle to the cytoskeleton and undergoes  all are derived from essential amino acid precursors phosphorylation to facilitate vesicle mobilization for provided by the diet exocytosis  synthesis involves a specific, rate-limiting enzymatic SYNAPTOBREVIN, SYNTAXIN and SNAP-25 interactions step regulated by such factors as the state of  where membrane docking, priming and fusion enzyme phosphorylation and feedback mechanisms depend Neuropeptides  target of cleavage by botulinum toxin  synthesized in the cell body as a large precursor that SYNAPTOTAGMIN undergoes cleavage and posttranslational  interaction with this protein is required by calcium- modifications as it travels through the secretory induced exocytosis granule pathway, reach the synaptic terminal by Coating by CLATHRIN and fission by action of DYNAMIN fast anterograde transport  vesicle endocytosis and recycling AMPHIPHYSIN Storage of Neurotransmitters in Synaptic Vesicles  adaptor protein that regulate these processes Glutamate, GABA, glycine and acetylcholine  stored in small clear vesicles Termination of the Action of Neurotransmitters Monoamines Synaptic effects of a neurotransmitter are terminated by:  stored in intermediate dense-core vesicles 1. Uptake by presynaptic terminals or astrocytes Neuropeptides 2. Enzymatic metabolism  stored in large dense-core vesicles (secretory 3. Diffusion out of the synaptic cleft granules) UPTAKE BY ASTROCYTES AND PRESYNAPTIC TERMINALS  sole mechanism for rapid termination of the synaptic  Storage of amino acids, ACh and monoamines in action of glutamate, GABA, and glycine synaptic vesicles depends on specific vesicular  initial mechanism of inactivation of catecholamines transporters and serotonin  involves Na+ /ATP-dependent uptake transporters 3 core families of vesicular transporters:  determined by a concentration gradient, which is 1. Vesicular acetylcholine and vesicular monoamine maintained by Na, K-ATPase transpoters  decrease ATP- impaired NT reuptake 2. GABA and glycine transporter ENZYMATIC DEGRADATION TO INACTIVE METABOLITES 3. Glutamate vesicular transporter  dopamine, norepinephrine and serotonin -storage of NT is driven by an electrochemical gradient of  by action of monoamine oxidases H+ across the vesicle membrane  catecholamines are also metabolized by catechol- -generated by vacuolar ATP-dependent proton pump O-methyltransferase -within the vesicle, NT is costored with ATP, synthetic  sole mechanism for termination of the action of enzymes or ions (Zn2+) acetylcholine (by AChE) and neuropeptides (peptidases) Calcium-Triggered Exocytosis  after synaptic vesicle loading with neurotransmitter, it undergoes mobilization and docking at a presynaptic zone, followed by priming for Ca2+ - triggered exocytosis  synaptic vesicles ready for release dock near the presynaptic active zones which contain clusters of voltage-gated Ca2+ channels Page 2 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 but also on the soma as axosomatic synapses, and even at the beginning and at the end of axons (axoaxonic synapses).  Asymmetric- since communication is structurally designed to be in one direction; anterograde from the axon of the first neuron to the dendrite, soma, or axon of the second neuron.  There are presynaptic elements that differ from postsynaptic elements. Specifically, neurotransmitter is packaged in the presynaptic nerve terminal like ammunition in a loaded gun, and then fired at the postsynaptic neuron to target its receptors. Classic Neurotransmission  In classic synaptic neurotransmission, stimulation of a presynaptic neuron (e.g., by neurotransmitters, light, drugs, hormones, nerve impulses) causes electrical impulses to be sent to its axon terminal. These electrical impulses are then converted into chemical messengers and released to stimulate the receptors of a postsynaptic neuron. Thus, although communication within a neuron can be electrical, communication between neurons is chemical.  Begins with an electrical process by which neurons send electrical impulses from one part of the cell to another part of the same cell via their axons. These electrical impulses do not jump directly to other neurons.  Involves one neuron hurling a chemical messenger, or neurotransmitter, at the receptors of a second neuron (see the synapse between neuron A and neuron B. This happens frequently but not exclusively at the sites of synaptic connections. Neuromodulation  It is the alteration—or modulation—of nerve activity by delivering electrical or pharmaceutical agents directly to a target area.  Neuromodulation devices and treatments are life changing. They affect every area of the body and treat nearly every disease or symptom from headaches to tremors to spinal cord damage to urinary incontinence.  Most frequently, people think of neuromodulation Synaptic Effects of Neurotransmitters in the context of chronic pain relief, the most Neurotransmission common indication. However, there are a plethora of neuromodulation applications, such  The anatomical basis of neurotransmission is as deep brain stimulation (DBS) treatment for neurons and the connections between them, Parkinson's disease, sacral nerve stimulation for called synapses. pelvic disorders and incontinence, and spinal  Synapses can form on many parts of a neuron, cord stimulation for ischemic disorders (angina, not just the dendrites as axodendritic synapses, peripheral vascular disease). Page 3 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 Neuromodulation devices can stimulate a Neurotransmitters can also be categorized into one of six response where there was previously none, as in types: the case of a cochlear implant restoring hearing in a deaf patient. Amino Acids  Neuromodulation implantable devices are either neural stimulators or microinfusion pumps. These  Gamma-aminobutyric acid (GABA) acts as the body's main inhibitory chemical messenger. devices are being utilized for the management GABA contributes to vision, motor control, and of chronic pain, movement disorders, psychiatric plays a role in the regulation of anxiety. disorders, epilepsy, dismotility disorders, disorders Benzodiazepines, which are used to help treat of pacing, spasticity, and others. anxiety, function by increasing the efficiency of  Neuroprostheses such as cochlear implants and GABA neurotransmitters, which can increase sacral root stimulators are also commonly feelings of relaxation and calm. included within the definition of neuromodulation.  Electrical neuromodulation- electrical stimulation  Glutamate is the most plentiful neurotransmitter of the brain, spinal cord, peripheral nerves, found in the nervous system where it plays a role plexuses of nerves, the autonomic system, and in cognitive functions such functional electrical stimulation of the muscles as memory and learning. Excessive amounts of  Chemical neuromodulation uses direct glutamate can cause excitotoxicity resulting in placement of chemical agents to neural tissues cellular death. This excitotoxicity caused by through utilization of technology of implantation glutamate build-up is associated with some such as epidural or intrathecal delivery systems. diseases and brain injuries including Alzheimer's disease4 , stroke, and epileptic seizures. Multiple Effects of Neurochemical Transmitters Peptides Neurotransmitters can be classified by their function:  Oxytocin is both a hormone and a neurotransmitter. It is produced by the Excitatory neurotransmitters: These types of hypothalamus and plays a role in social neurotransmitters have excitatory effects on the neuron, recognition, bonding, and sexual reproduction. meaning they increase the likelihood that the neuron will Synthetic oxytocin such as Pitocin is often used as fire an action potential. Some of the major excitatory an aid in labor and delivery. Both oxytocin and neurotransmitters include epinephrine and Pitocin cause the uterus to contract during labor. norepinephrine.  Endorphins are neurotransmitters than inhibit the transmission of pain signals and promote feelings Inhibitory neurotransmitters: These types of of euphoria. These chemical messengers are neurotransmitters have inhibitory effects on the neuron; produced naturally by the body in response to they decrease the likelihood that the neuron will fire an pain, but they can also be triggered by other action potential. Some of the major inhibitory activities such as aerobic exercise. For example, neurotransmitters include serotonin and gamma- experiencing a "runner's high" is an example of aminobutyric acid (GABA). pleasurable feelings generated by the production of endorphins. Acetylcholine and dopamine - create both excitatory and inhibitory effects depending upon the type of Monoamines receptors that are present.  Epinephrine is considered both a hormone and a Modulatory neurotransmitters neurotransmitter. Generally, epinephrine (adrenaline) is a stress hormone that is released  often referred to as neuromodulators, are capable by the adrenal system. However, it functions as a of affecting a larger number of neurons at the same neurotransmitter in the brain. time.  Norepinephrine is a neurotransmitter that plays  influence the effects of other chemical messengers. an important role in alertness is involved in the Where synaptic neurotransmitters are released by body's fight or flight response. Its role is to help axon terminals to have a fast-acting impact on other mobilize the body and brain to take action in receptor neurons, neuromodulators diffuse across a times of danger or stress. Levels of this larger area and are more slow-acting. neurotransmitter are typically lowest during sleep and highest during times of stress.  Histamine acts as a neurotransmitter in the brain and spinal cord. It plays a role in allergic Page 4 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 reactions and is produced as part of the immune Long term potentiation (LTP) and long term depression system's response to pathogens. (LTD) of synaptic transmission are now widely recognized  Dopamine plays an important role in the as representing cellular mechanisms used by a variety of coordination of body movements. Dopamine is neuronal networks to store certain types of information. also involved in reward, motivation, and The molecular and cellular events underlying these forms additions. Several types of addictive drugs of activity-dependent synaptic plasticity are also being increase dopamine levels in the brain. Parkinson's elucidated. Like learning and memory processes, LTP and disease, which is a degenerative disease that LTD undergo age-related alterations. results in tremors and motor movement impairments, is caused by the loss of dopamine- Long Term Potentiation of Synaptic Transmission generating neurons in the brain.  Serotonin plays an important role in regulating The phenomenon of long-term potentiation (LTP) of and modulating mood, sleep, anxiety, sexuality, synaptic transmission is an activity-dependent, long- and appetite. Selective serotonin reuptake lasting increase in synaptic strength that is hypothesized inhibitors, usually referred to as SSRIs, are a type to play critical roles in cognitive processing and the of antidepressant medication commonly encoding of long-term memories. prescribed to treat depression, anxiety, panic disorder, and panic attacks. Properties are that persistent increases in synaptic strength should Purines 1) require a minimum threshold for neuronal activity,  Adenosine acts as a neuromodulator in the brain 2) require temporally coincident presynaptic and and is involved in suppressing arousing and postsynaptic activation, and improving sleep.  Adenosine triphosphate (ATP) acts as a neurotransmitter in the central and peripheral 3) be confined only to the synapses that are so activated. nervous systems. It plays a role in autonomic control, sensory transduction, and Long Term Depression of Synaptic Transmission communication with glial cells. Research suggests it may also have a part in some While LTP has long been thought to be a key mechanism neurological problems including pain, trauma, of storage of long-term memories, it has recently become and neurodegenerative disorders. clear that some mechanism is necessary for long-term depression (LTD) of synaptic transmission for a number of reasons. Gasotransmitters One is to avoid saturation of synaptic strength at  Nitric oxide plays a role in affecting smooth maximum levels. Another is that bi-directional synaptic muscles, relaxing them to allow blood vessels to plasticity that follows some type of covariance rule, i.e., dilate and increase blood flow to certain areas senses the amount of presynaptic input that is temporally of the body. coincident with postsynaptic firing versus the amount that  Carbon monoxide is usually known as being a is not, maximizes the pattern of strengthened and colorless, odorless gas that can have toxic and weakened synapses in a way the optimizes both the potentially fatal effects when people are development of synaptic networks and the storage of exposed to high levels of the substance. However, information it is also produced naturally by the body where it acts as a neurotransmitter that helps modulate II. SPECIFIC NEUROCHEMICAL SYSTEMS the body's inflammatory response. Organization of Neurochemical Pathways in the Nervous Acetylcholine System Neurons never function in isolation; they are organized  Acetylcholine is the only neurotransmitter in its into ensembles or circuits that process specific kinds of class. Found in both the central and peripheral information. Although the arrangement of neural circuits nervous systems, it is the primary neurotransmitter varies greatly according to the intended function, some associated with motor neurons. It plays a role in features are characteristic of all such ensembles. muscle movements as well as memory and learning. The direction of information flow in any particular circuit is essential to understanding its function. Nerve cells that Long-Term Effects of Neurochemical Transmitters and carry information toward the central nervous system (or Synaptic Plasticity farther centrally within the spinal cord and brain) are Page 5 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 called afferent neurons; nerve cells that carry information  Synaptic effects are terminated by its uptake by the away from the brain or spinal cord (or away from the astrocytes via several specific excitatory amino acid circuit in question) are called efferent neurons. Nerve cells transporters that only participate in the local aspects of a circuit are o Glutamate uptake is associated with the uptake called interneurons or local circuit neurons. These three of Na+ and depends on the maintenance of a classes—afferent neurons, efferent neurons, and Na+ gradient by action of the Na+, K+ ATPase interneurons—are the basic constituents of all neural In cases of energy failure (ATP depletion), Na+ gradient circuits. cannot be maintained and glutamate transport may be decreased or reversed. This leads to the release of Interneurons can be further broken down into two groups: glutamate from astrocytes and excessive accumulation local interneurons and relay interneurons. Local of glutamate in the synaptic space interneurons have short axons and form circuits with nearby neurons to analyze small pieces of Receptor Mechanisms information. Relay interneurons have long axons and Two main families of receptors connect circuits of neurons in one region of the brain with  Ionotropic receptors those in other regions. The interaction between o Cation channels that mediate fast excitatory interneurons allow the brain to perform complex functions transmission such as learning, and decision-making. o Includes AMPA (a-amino-3-hydroxy-5-methly-4-isoxazole Relay neurons are found between sensory input and propionate) receptor- permeable only to Na+ motor output/response. Relay neurons are found in the and present in all excitatory glutamatergic brain and spinal cord and allow sensory and synapse motor neurons to communicate.  Kainate receptors NMDA (N-methyl-D-aspartate)- ligand gated Local Interneurons are nerve cells that only participate in Ca2+-channels that are blocked by Mg2+ ions the local aspects of a circuit are called interneurons at normal resting (influx of Ca2+ through an or local circuit neurons. NMDA receptor requires removal of Mg2+ blockade by membrane depolarization which Diffuse Projection Systems is generally triggered by Na+ influx via the a set of thalamic nuclei that project numerous fibers to all AMPA receptors; activation requires binding parts of the cerebral cortex. It is the projection system for of glycine to an allosteric site of the receptor the reticular formation and sets the tone of the cerebral molecule) cortex.  Metabotropic receptors o G-protein coupled receptors that are involved in What are the four diffuse projection systems (activating the modulation of excitatory and inhibitory systems) in the CNS? synapses o An important result of the activation of glutamate  Noradrenergic (norepinephrine) receptors is increased levels of cytosolic Ca2+  Serotonergic(serotonin) Role of Glutamate in Synaptic Plasticity  Strength of excitatory connection between  Cholinergic(acetylcholine) presynaptic and postsynaptic neurons exhibit a high degree of use-dependent plasticity  Dopaminergic(dopamine) (synaptic transmission may either be enhance or *Refer to Figure 6.7 depressed) Excitatory Amino Acid Systems o Long-term potentiation- long term L-glutamate- primary neurotransmitter of all excitatory increase in strength of excitatory synapse neurons in the CNS (includes all pyramidal neurons of o Long term depression- converse cerebral cortex and neurons in the relay nuclei of all phenomenon sensory and motor pathways)  Mechanism of long-term potentiation and long- Biosynthesis and Reuptake of L-Glutamate term depression vary for different excitatory L-glutamate- most abundant amino acid in the brain and synapse and may occur at both presynaptic and is derived from: postsynaptic levels  α-ketoglutarate- intermediate metabolite of Krebs Cycle in neurons Involves activation of glutamate receptors, increase  Glutamine- synthesized in astrocytes intracellular Ca2+ and activation of protein kinases or phosphatases that affect the state of phosphorylation of  Stored in small clear vesicles and released by AMPA and NMDA receptors, other synaptic proteins or exocytosis by specific transporters transcription factors, particularly CREB Page 6 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 Inhibitory Amino Acid Systems o Lateral inhibition- local GABAergic neurons Two main inhibitory amino acid neurotransmitters inhibit other projection neurons that surround  GABA- occurs in local inhibitory neurons throughout the active neuron the CNS (includes cerebral cortex, thalamus, and all  Important for mechanisms of sensory sensory and motor relay nuclei) discrimination and fine motor control o Primary neurotransmitter in circuits of the  In cerebral cortex and hippocampus: GABAergic basal ganglia and cerebellum involved in neurons prevent the propagation of recurrent motor control excitatory influences among pyramidal neurons  Glycine- mediates inhibitory transmission in the o Impairment results to paroxysmal synchronized brainstem and spinal cord discharged of population of cortical Biosynthesis, Reuptaek and Metabolism of GABA pyramidal neurons and cause seizure  Synthesis and metabolism of GABA are intimately  Some GABAergic neurons form interconnected linked with L-glutamate and involve interactions network in cerebral cortex, thalamus and brainstem between GABAergic neurons and astrocytes o Important for the synchronization of activity o GABAergic terminals- GABA is synthesized across widely distributed but functionally from L-glutamate by the action of glutamic related population of neurons acid decarboxylases (requires pyridoxyl  GABA is the primary neurotransmitter of neurons in phosphate, derivative of vitamin B6) GABA is the striatum and basal ganglia and of Purkinje cells in incorporated into the synaptic vesicles by the cerebellum vesicular GABA transporter and released by exocytosis Cholinergic Systems o After release, GABA is taken up by astrocytes Includes and presynaptic GABAergic terminals  Spinal and brainstem somatic motor neurons Receptor Mechanisms innervating skeletal muscles Two classes of receptor  Spinal and brainstem preganglionic neurons  GABAA receptors- ligand gated Cl- channels innervating autonomic ganglia o Activation is triggered by rapid influx of Cl-  Parasympathetic ganglion neurons innervating which brings the membrane potential close the viscera to equilibrium potential of that ion (-75mV)-  Neurons in the basal forebrain (septal area and may produce either hyperpolarization or nucleus basalis) innervating the cerebral cortex depolarization  Neurons in the tegmentum of the pons and o Activation elicits fast inhibitory because the midbrain innervating the thalamus and medulla membrane in unable to reach threshold to  Local neurons in the striatum trigger an action potential (AP) Biosynthesis and Metabolism of ACh  GABAB receptors- G-protein coupled channels  Synthesized from acetyl coenzyme A and choline receptors by the action of choline acetyltransferase o Activation of postsynaptic GABAB receptors-  Ach is incorporated into synaptic vesicles by increases permeability of voltage –gated K+ specific vesicular transporter and released by channels, which slows hyperpolarization and exocytosis synaptic inhibition  Synaptic actions are terminated through o Activation of presynaptic- inhibits the release hydrolysis by acetylcholinesterase of neurotransmitter Receptor Mechanisms o In the brainstem and spinal cord- glycine Ach acts through two classes of receptors contributes to fast inhibitory postsynaptic  Nicotinic receptors- cation channels receptors transmission by acting on specific glycine that allow the influx of Na or CA (or both) receptors that allow rapid influx of C; producing fast excitatory postsynaptic potentials  Glycine receptors are blocked by in the target cells strychnine, a toxin that produces severe  Muscarinic receptors- G-protein coupled hyperexcitability receptors that mediate the slow excitatory (M1- Functions of the GABAergic Neurons in the CNS type) or inhibitory (M2) synaptic effects of  Local GABAergic inhibitory neurons- acts as acetylcholine interneurons in feed-forward and feedback circuits in Functions of ACh all motor and sensory pathways  Mediates important synaptic effects in the PNS o Basic microcircuit: triad consisting of and CNS  Excitatory projection (relay) neuron o Release at the synapse between the motor  Local GABAergic interneuron neuron and skeletal muscle (NMJ) acting through muscle-type nicotinic receptors to Page 7 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 elicit muscle depolarization that leads to o Once inside the terminal, dopamine is muscle contraction (neuromuscular metabolized by monoamine oxidase B to transmission) its final metabolite (HOMOVANILIC ACID) o Preganglionic neurons in brainstem and spinal Receptor Mechanisms cord release Ach in autonomic ganglia where  Dopamine receptors are G-protein coupled Ach acts on ganglio-type nicotinic receptors receptors and is subdivided into two main to activate sympathetic and families parasympathetic postganglionic neurons o D1-type receptors- activate adenylate o Neurotransmitter of parasympathetic ganglia cyclase and trigger cAMP-dependent neurons innervating all visceral organs and phosphorylation of different types of ion sympathetic ganglia neurons innervating channels and proteins sweat glands o D2-type receptors- inhibit adenylate cycles,  In CNS activate K channels, inhibit Ca channels and o Major role in mechanisms of arousal, attention mediate the postsynaptic and presynaptic and memory inhibitory effects of dopamine  Cholinergic neuron in tegmentum of the Functions of Dopamine in CNS pons and midbrain project to thalamus  Major role in initiation of voluntary motor and other rregions for arousal and sleep- behaviour triggered by novel or rewarding wake cycle stimulus  Input to cerebal cortex arises from neurons o Dopaminergic inputs from substantia nigra in basal forebrain which is important for pars compacta and ventral tegmental area attention and memory (effects are to the striatum provide a reward signal to the mediated by muscarinic receptors which basal ganglia that initiates a specific motor increase responses of cortical neurons act at the expense of all other motor acts facilitation long-term potentiation)  Also important for endocrine function (influence o Critical neurotransmitter of neurons in the anterior pituitary tonically inhibits secretion consciousness system of prolactin, actions in the medulla induces o Most of central effects are mediated by mechanism of vomiting muscarinic by activation of presynaptic nicotinic receptors regulates the release of many neurotransmitters Dopaminergic Systems Dopamine is the neurotransmitter of 2 main groups of neurons in CNS  Mesencephalic dopaminergic- includes substantia nigra pars compacta and ventral tegmental area o Substantia nigra-pars compacta- innervates the striatum o Ventral tegmental area- innervates the frontal lobes and limbic system  Hypothalamic dopaminergic group- controls the function of the anterior pituitary Biosynthesis, Reuotake and Metabolism of Dopamine  Synthesized from the amino acid L-tyrosine by action of tyrosine hydroxylase (rate limiting step in Noradrenergic, Serotonergic, and Histaminergic Systems all catecholamine biosynthesis resulting to  Diffuse Projection systems in the brain- consists of production of L-dopa) neurons located in restricted regions of brainstem o L-Dopa is metabolized by L-amino acid or hypothalamus and whose axons provide decarboxylase to dopamine collaterals to widespread regions of CNS  Incorporated into synaptic vesicles by vesicular o Neurotransmitters: norepinephrine, serotonin, monoamine transporter coupled to the proton histamine ATPase and released by exocytosis  Locus cerelus- main source of noradrenergic  Effects are terminated by its reuptake by innervation in CNS dopamine transporter located in presynaptic o located in dorsal portion of pons dopaminergic terminal Page 8 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 o neurons project to cerebral cortex, basal o Serotonin- 5-hydroxyindoleacetic acid ganglia, thalamus, cerebellum and sensory o Histamine- methylimidazoleacetic acid and motor nuclei Receptor Mechanisms  lateral tegmental system- consist of neurons Synaptic effects of norepinephrine, serotonin and containing the norepinephrine or epinephrine histamine are complex and mediated by different types that are located mainly in reticular formation of of receptors the ventrolateral medulla and innervate  Norepinephrine acts on α1, α2, β-receptors hypothalamus and autonomic nuclei of the  Serotonin- 5-HT1, 5-HT2, 5-HT3, 5-HT4 receptors brainstem and SC  Histamine- H1, H2, H3 receptors o in periphery, norepinephrine is the NT of sympathetic ganglion neurons that *all monoaminergic receptors are G-protein coupled innervate all effector organs except sweat receptros that have complex postsynaptic and glands presynaptic effects except for 5-HT3 receptors  Raphe nuclei- located in midline along the length Activation of α1, 5- Increases neuronal of brainstem HT2, H1 excitability o NT is serotonin/ 5-hydroxytryptamine/ 5HT o Rostral and caudal groups send ascending α2, 5-HT1, H3 Elicit postsynaptic and or descending projection diffusely presynaptic inhibition throughout the CNS β-adrenergic, 5-HT4, Activate adenylyl o Histamine-containing neurons are located in H2 cyclase and several tuberomammillary nucleus; axons innervate cAMP-dependent all areas of CNS phosphorylation Biosynthesis, Reuotake and Metabolism of cascades Norepinephrine, Serotonin and Histamine A. Biosynthesis  Norepinehrine-synthesized from L-tyrosine by Functions of the Diffuse Monoaminergic Systems action of tyrosine hydroxylase and leads to  Widespread projections and complex receptor formation of L-dopa followed by mechanisms, central norepinephrine, serotonin decarboxylation by L-amino acid and histamine system, Ach, dopamine systems decarboxylase to dopamine modulate the activity of neuronal groups o In noradrenergic neurons: dopamine is distributed throughout the brain and SC transformed into norepinephrine by o Involved the mechanism for arousal, dopamine B-hydroxylase present in attention and response to stress (control of synaptic vesicle autonomic and hypothalamic functions, o In lateral tegmental system, adrenal pain suppression and motor responses) medulla- norepi is transformed into o Activity of monoaminergic systems epinephrine by phenylalanine N- depends on behavioural state of organism methyltransferase  All system are active during wakefulness  Serotonin- synthesized from L-tryptophan by and inactive during sleep tryptophan hydroxylase followed by  Noradrenergic neurons in locus ceruleus- decarboxyation by L-amino acid activated in response to novel, decarboxylase potentially challenging environmental  Histamine- from histidine by the action of stimuli histidine decarboxylase In periphery, norepinephrine is released from sympathetic B. Reuptake terminals and elicits numerous effects (vasoconstriction-  The 3 NT are incorporated into synaptic α1, receptors; stimulation of heart- β1; relaxation of vesicle by vesicular monoamine transporter visceral smooth muscle- β2 receptors o Norepinephrine- undergoes presynaptic reuptake by norepinephrine transporter Neuropeptide Systems while serotonin by serotonin transporter  abundant in the CNS and PNS o Histamine does not undergo reuptake  highest concentration is in the hypothalamus, C. Metabolism followed by the amygdala, autonomic nuclei and  The 3 NT are metabolized by monoamine the pain-modulating circuits of the brainstem and oxidases and methyltransferases, with the spinal cord following resulting metabolite  important neurotransmitters in the consciousness and o Norepinephrine (in CNS)- 3-methoxy-4- internal regulation systems hydroxyphenylglycol Page 9 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 Important neuropeptides include:  also have trophic and vasomotor effects 1. CRH- Corticotropin Releasing Hormone VIP, CGRP and substance P produce vasodilatation 2. AVP- Arginine vasopressin AVP and NPY case vasoconstriction 3. Substance P Functions of Neuropeptides 4. CGRP - Calcitonin gene-related peptide CRH – critical for responses to stress 5. VIP - Vasoactive intestinal polypeptide AVP – for fluid homeostasis 6. Neuropeptide Y Opioid peptides - for central pain control mechanisms 7. Opioid peptides – enkephalins, endorphins and Hypocretin – for control of the sleep cycle and food dynorphins intake 8. Hypocretins/Orexins Substance P and CGRP – neurotransmitters in nociceptive afferents 2 main systems of central peptidergicc neurons: NPY – participates in sympathetic neurotransmission 1. Diffuse Projection Systems VIP- participates in parasympathetic neurotransmission -from the hypothalamuus, amygdala and brainstem Other Neurochemical Messengers 2. Local or short projection neurons located through the PURINES CNS -ATP and adenosine may act both as a neurotransmitter -frequently coexist with other neurotransmitters and neuromodulators of the PNS and CNS (other neuropeptides, acetylchholine, monoamine or 1. ATP GABA) -acts through P2-purinoreceptors and has important functions in nociceptive and autonomic systems Biosynthesis, Release and Processing -astrocyte communication  synthesized in the cell bodies from messenger RNA 2. Adenosine  undergo posttranslational modification within the -acts through P1 or adenosine receptors endoplasmic reticulum and Golgi apparatus and -activation of receptors inhibits the presynaptic release of transported in large vesicles to the synaptic terminal other neurotransmitters and produces vasodilation by fast anterograde axonal transporrt  release is not restricted to presynaptic active zones NITRIC OXIDE but occurs at voltage-gated Ca2+ channels -important intercellular messenger synthesized from distributed throughout the presynaptic terminal arginine by nitric oxide synthases  contain both monoamine and neuropeptides, continuous low-frequency firing releases the monoamine and high-frequency burst firing releases the neuropeptide  do not undergo presynaptic reuptake  action is terminated by hydrolysis by extracellular peptidases Receptor Mechanisms  act mainly as synaptic modulators  have potent presynaptic and postsynaptic effects of slow onset and long duration  effects are mediated by G protein-coupled receptors  CRH, VIP, and CGRP- activate adenylyl cyclase  Substance P and hypocretins- inhibit K+ channels and increase neuronal excitability  Opioids – activate K+ channels. Reduce neuronal excitability and inhibit presynaptic Ca2+ channels, reducing NT release  prolonged neuromodulatory effects occur not only in the postsynaptic sites but also in a paracrine fashion by volume trannsmission  act at a distance from the site of release and affect neighboring neurons, glial cells and blood vessels  -some NP are released into the bloodstream(neuroendocrine effect) CLINICAL CCORRELATION Page 10 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 NEUROLOGIC DISORDERS -impairment of cholinergic input contribute to memory 1.Excitotoxicity and Neuronal Injury loss EXCITOTOXICITY - excessive activation of glutamate Dementia with Lewy bodies receptors can kill neurons and oligodendrocytes -severely affected central cholinergic system RAPID GLUTAMATE-INDUCED EXCITOTOXICITY – responsible for neuronal death in conditions such as Drugs that inhibit AchE increase the availability of ACh in çerebral hypoxia or ischemia, hypoglycemia, epilepsy the cerebral cortex and produce improvement in and traumatic injury of the brain or spinal cord cognitive function SLOW EXCITOTOXIC INJURY Drugs used to treat neurologic and psychiatric disorders, – lead to oxidative stress and apoptosis as mechanism of may block central muscarinic receptors – impair alertness, cell death in many neurodegenerative diseases attention and perception (confusional state or delirium) (Alzheimer disease and amyotrophic lateral sclerosis) 4.Parkinson Disease Cells become more vulnerable to acute excitotoxic injury -neurodegenerative disorder characterized by the loss of during energy deprivation dopaminergic neurons in the substantia nigra pars -impairment of pumping out of excess Na+ and compacta Ca2+ entering through AMPA and NMDA receptors -decreased activity in the striatum results in reduced -prevents uptake of glutamate by astrocytess spontaneous motor activity or akinesia, rigidity and other RAPID GLUTAMATE-INDUCED CELL DEATH manifestattions -as in energy failure -similar effects are produced by the intake of drugs that -massive influx of Na+ and Cl- , cellular swelling followed block dopamine receptors by massive influx of Ca2+ -after exposure to toxins or from blockade of Calcium dopaminergic receptors in the striatum by drugs used to -activates potentially damaging cascades involving treat psychosis or vomiting phospholipase A2, calpain and nitric oxide -antiparkinsonian drug include L-dopa (precursor of -leads to oxidative stress and disruption of plasma and dopamine) in combination with carbidopa (inhibitor of mitochondrial membranes and the cytoskeleton which peripheral decarboxylation of L-dopa) and direct produces cell death by necrosis dopamine receptor agonists SLOW GLUTAMATE-INDUCED INJURY -mechanism of apoptosis triggered by the release of 5.Disorders of Neuromuscular Transmission cytochrome c and other proapoptotic molecules from -impaired neurotransmission at the level of the Ca2+-loaded mitochondria neuromuscular junction produce a use-dependent muscle weakness that improves with rest 2.Seizures Lambert-Eaton Myasthenic Syndrome - auto antibodies -impaired GABAergic inhibition in the Cerebral cortex against voltage-gated Ca2+ channels in the active zones may lead to a paroxysmal and synchronized discharge of of the motor nerve terminal populations of pyramidal neurons and result in seizures Myasthenia gravis – auto antibodies against muscle -drugs used to treat seizures act either by increasing the nicotinic acetylcholine receptors availability of GABA or by facilitating GABA A receptor- mediated that increase Cl- permeability -other drugs act by blocking Na+ or Ca2+ channels in PSYCHIATRIC DISORDERS pyramidal neurons or by inhibiting the release of 1.Schizophrenia glutamate -brain disorder that affects cognition and behavior -chronic exposure to depressant drugs that facilitate -cognitive, emotional and motivational manifestations of GABAA receptor mechanisms, such as alcohol, schizophrenia resemble those that occur with damage to benzodiazepines, or barbiturates, desensitizes the the frontal lobe receptor -perceptual disorders including hallucinations, may in part -abrupt cessation of these drugs causes rebound CNS reflect dysfunction of the temporal lobe hyperexcitability leading to a withdrawal syndrome -areas receive abundant dopaminergic and serotonergic including anxiety, insomnia, tremor, and seizures innervation Classic antipsychotic drugs – block the D-receptors and 3.Dementia and Delirium control the hallucinations in schizophrenia Alzheimer disease – most common cause of dementia, -also potentially block these receptors in the striatum degenerative disorder of the brain -commonly cause motor side effects -loss of cholinergic neurons in the basal forebrain that Newer antipsychotic drugs – block both D2 and 5-HT2 innervate the cerebral cortex serotonergic receptors Page 11 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 2.Drug Addiction Dopaminergic inputs from the ventral tegmental area to Serotonin the limbic striatum and frontal cortex have a major role in -major role in depression and in manic-depressive (bipolar) mechanism of reward and reinforcement associated with and obsessive-compulsive disorders. drug addiction Increase in dopamine levels in striatum Anti anxiety drugs include benzodiazepines – which act -critical mechanisms for reinforcing and addictive effects through GABA A-receptor mechanisms of cocaine, amphetamine and nicotine -drugs that activate presynaptic a2 inhibitory -important component of opioid and alcohol abuse autoreceptors -drugs that increase norepinephrine levels and thus lead Cocaine and Amphetamine to activation of inhibitory autoreceptors and down- -increase dopamine by interfering with the function oof regulation of B receptors the presynaptic dopamine transporter thus reducing -SSRIs – inhibit locusts ceruleus neurons by increasing levels dopamine reuptake of serotonin Antidepressant drugs Nicotine -include drugs that decrease the presynaptic reuptake of -acts through presynaptic cholinergic nicotinic receptors monoamine including SSRIs , NRIs, 5-HT2 receptor Blockers to increase release of dopamine and MAO inhibitors Opiates References -inhibit GABAergic neurons in the ventral tegmental area, Benarroch, EE, Daube JR, Fleming KD, Westmoreland BF. thus disinhibiting the dopaminergic neurons Mayo Clinic Medical Neurosciences. 2008. Chapter 6, pp 189-214 3.Anxiety and Depression -abnormal function of Central noradrenergic and serotonergic circuits implicated in thee arousal, attention and affect, including anxiety and depression -excessive activity of the locus ceruleus noradrenergic neurons has been implicated in the manifestation of anxiety disorders, including panic disorder and PTSD Drugs that reduce firing of locus ceruleus neurons have anti anxiety effects Page 12 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 Page 13 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 Page 14 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 Page 15 of 16 Lecture # 4 (PRELIMS): Synaptic Transmission and Neurochemical Systems Instructor: Dr. lARA NEUROSCIENCE· March 5, 2019 Page 16 of 16