Task 3 - Neurotransmission PDF

Task 3 - Neurotransmission Learning Goals What does the process of neurotransmission consist of? What are receptors and what types of receptors are there? How can drugs influence neurotransmission? What are the different types of neurotransmitters? What function does each type of neurotransmitter h...

Task 3 - Neurotransmission Learning Goals What does the process of neurotransmission consist of? What are receptors and what types of receptors are there? How can drugs influence neurotransmission? What are the different types of neurotransmitters? What function does each type of neurotransmitter have? What does the process of neurotransmission consist of? What are receptors and what types of receptors are there? Many terminal buttons contain 2 types of synaptic vesicles: large and small. Small synaptic vesicles (found in all terminal buttons) contain molecules of a neurotransmitter. They are produced in the Golgi apparatus in the soma and are carried by fast axoplasmic transport to the terminal button. Some are also produced from recycled material in the terminal button. Large synaptic vesicles contain 1 or more neuropeptides (short proteins composed of 3-36 amino acids). They are produced only in the soma and are transported through the axoplasm to the terminal buttons. Some neurons contain more than 1 neurotransmitter in their axon terminals (a phenomenon called coexistence/co-localization/co-release). Release of neurotransmitters Docking - a cluster of protein molecules in the vesicles' membrane attach to other protein molecules located in the presynaptic membrane, effectively "parking" (docking) the vesicle against the presynaptic membrane. Release zone - the region of the presynaptic membrane that faces the synaptic cleft, where neurotransmitters are released from. The release zone contains voltage-dependent calcium channels. When the action potential arrives, the Ca2+ ions (which like the Na+ ions are concentrated more in the extracellular fluid) flow into the cell propelled by electrostatic pressure and diffusion. Later, calcium transporters, similar in operation to the sodium-potassium pumps, remove the intracellular Ca2+. If neurons are placed into a solution that contains no Ca2+ ions, an action potential no longer causes release of neurotransmitters. Some of the Ca2+ ions that flow in bind with the clusters of protein molecules that join the membrane of the synaptic vesicles with the presynaptic membrane. This produces a fusion pore - a hole through both membranes that enables them to fuse together. There are 3 pools of synaptic vesicles: Release-ready vesicles - docked and ready to release contents when action potential occurs (less than 1% of the ones found in the terminal). Recycling pool - 10-15% of the total pool of vesicles. Reserve pool - the remaining 85-90%. If an axon fires at a low rate, only vesicles from the release- ready pool are used. As rate increases, the recycling pool and then the reserve pool are used. Kiss and run - many vesicles release most/all of their neurotransmitter, the fusion pore closes, the vesicles leave the docking site and get filled with neurotransmitter again. Merge and recycle - some vesicles (mostly those in the recycling pool) merge with the cell membrane and lose their identity. Little buds of membrane later pinch off into the cytoplasm and become new synaptic vesicles. The proper proteins are inserted into the new vesicles' membranes, and the vesicles are filled with neurotransmitter. Bulk endocytosis (endocytosis is the process of entering a cell) is the process by which vesicles in the reserve pool are Body and Behavior Page 1  cell) is the process by which vesicles in the reserve pool are recycled: large pieces of terminal membrane fold inward, Time: nothing happens, because diffusion and electrostatic pressure balance the Cl- ion perfectly. Body and Behavior Page 2  ○ At resting potential => nothing happens, because diffusion and electrostatic pressure balance the Cl- ion perfectly. ○ When already depolarized => Cl- enters the cell resulting in the restoration of resting potential. Therefore, the opening of chloride channels results into IPSPs. When calcium channels are opened, Ca2+ ions flow inside the cell, resulting in an EPSP (just like sodium channels). Furthermore, in the dendrites of the postsynaptic cell, Ca2+ binds with and activates special enzymes, which can produce biochemical and structural changes in the postsynaptic neuron. One of the ways in which learning affects the connections between neurons involves changes in dendritic spines initiated by the opening of calcium channels. Neural integration Neural integration - the interaction of the effects of excitatory and inhibitory synapses on a particular neuron. IPSPs can counteract EPSPs, leading to action potential not being triggered even in the presence of PSPs. PSPs are graded responses: their amplitudes depend on the intensity of signals that elicit them. The transmission of PSPs is decremental: they decrease in amplitude as they travel towards the axon initial segment. If the sum of the depolarizations and hyperpolarizations reaching the axon initial segment is sufficient to surpass the threshold of excitation, an action potential is generated. It was believed that the location of a synapse on the postsynaptic neuron's membrane is a crucial factor in determining the influence of the PSPs on the neuron's firing. However, some neurons have a mechanism for amplifying dendritic signals that originate far from their axon initial segments. Make distinction between action potentials and postsynaptic potentials: the former are neither graded (they are all-or-none) nor decremental (they arrive at the terminal buttons at full intensity). Neural integration happens in 2 ways: over space and time. Spatial summation - simultaneous PSPs produced on different physical locations across the cell body are integrated, taking into account their intensity and type (inhibitory/excitatory). Temporal summation - PSPs produced in rapid succession sum to form a greater signal. Termination of postsynaptic potentials Reuptake - special transporter molecules force neurotransmitter molecules from the synaptic cleft directly into the cytoplasm (the same way sodium-potassium transporters move Na+ and K+ across the membrane). Enzymatic deactivation (degradation) - an enzyme destroys molecules of the neurotransmitter. PSPs are terminated by enzymatic deactivation for acetylcholine (ACh) and for neurotransmitters that consist of peptide molecules. Other types of synapses Axodendritic synapses - synapses of axon terminal buttons on dendrites or dendritic spines. Axosomatic synapses - synapses of axon terminal buttons on cell bodies. Axoaxonic synapses - synapses that occur between 2 terminal buttons. Axoaxonic synapses do not contribute directly to neural integration, but they alter the neurotransmitter amount released by the buttons of the postsynaptic axon (presynaptic modulation). Presynaptic inhibition - if the activity of an axoaxonic synapse decreases the release of neurotransmitter. Presynaptic facilitation - if the activity of an axoaxonic synapse increases the release of neurotransmitter. Dendrodendritic synapses - synapses between dendrites (formed by very small neurons which have extremely short processes and lack axons). Little is known about the function of these neurons. Some larger neurons also form dendrodendritic synapses. Some are chemical (i.e. there are synaptic vesicles in one of the dendrites and a postsynaptic thickening in the membrane of the other). Others are electrical: the membranes meet and almost touch, forming a gap junction. Both membranes contain channels (connexins) that permit ions to diffuse from one cell to another (thus changes in membrane potential Body and Behavior Page 3  permit ions to diffuse from one cell to another (thus changes in membrane potential of 1 neuron induces changes in the membrane of the other). The function gap junctions is not known. Other forms of chemical communication Neuromodulators - chemicals released by neurons that travel farther and are dispersed more widely than neurotransmitters, thus modulating the activity of many neurons in a particular part of the brain, affecting general behavioral states such as vigilance, fearfulness, and sensitivity to pain. They are usually peptides (chains of amino acids). Hormones - secreted by cells of endocrine glands or cells in various organs (e.g. stomach, guts, kidneys, brain). After secretion, hormones are released into the extracellular fluid. Then they are distributed to the rest of the body through the bloodstream. Hormones affect the activity of cells (including neurons) that contain specialized receptors on the surface of their membrane or deep within their nuclei. ○ Cells that contain receptors for a particular hormone are referred to as target cells for that hormone. How can drugs influence neurotransmission? Psychopharmacology - the study of the effects of drugs that have an effect on the nervous system and behavior. Drug - an exogenous (produced from outside the body) chemical not necessary for normal cellular functioning that significantly alters the functions of certain cells of the body when taken in relatively low doses. Drug effects - changes that can be observed in an individual's physiological processes and behavior after drug intake. Sites of drug action - the points at which molecules of drugs interact with molecules located on/in cells of the body, thus affecting some biochemical processes of these cells. Drugs that affect synaptic transmission are classified into 2 general categories: Agonists - drugs that facilitate the effects of a particular neurotransmitter. Antagonists - drugs that inhibit the effects of a particular neurotransmitter. Drug effects on neurotransmitter synthesis Most neurotransmitters are produced from molecules called precursors. Some drugs produce their effects by acting as precursors to increase the amount of neurotransmitter synthesized and eventually released into the synapse. Precursor drugs are agonists, because they increase neurotransmission. Example: L-Dopa is a precursor for dopamine. Some symptoms of Parkinson's disease are due to death of dopamine-releasing cells in the substantia nigra. A treatment of this disease involves administering L-Dopa, which is used by the remaining cells to synthesize additional dopamine, thus replacing some of the lost neurotransmission and reducing symptoms of the disease. Neurotransmitter synthesis from precursors is controlled by enzymes. A drug that deactivates one of these enzymes is an antagonist, because it prevents the neurotransmitter from being produced. Drug effects on neurotransmitter storage & release Vesicle transporters - molecules located in the membrane of the synaptic vesicles that fill the vesicles with neurotransmitter. These are different from the terminal membrane transporters, which move the molecules from the synapse into the cytoplasm of the presynaptic cell. Some drugs can block vesicle transporters by binding with a particular site on the transporter and deactivating it. Such drugs are antagonists. The vesicles remain empty and nothing is released when they eventually release their contents into the synapse. Some antagonists deactivate the protein that cause docked synaptic vesicles to fuse with the presynaptic membrane. Example: Botox prevents the release of acetylcholine, which is responsible for signaling muscle contractions in the PNS. Some agonists have the opposite effect: they bind with these proteins and directly trigger the release of neurotransmitter. Drug effects on receptors Some drugs bind with the postsynaptic receptors, just as the neurotransmitter does. Such drugs can serve either as agonist or an antagonist. Direct agonist - a drug that mimics the effects of a neurotransmitter. Molecules of such a drug attach to the binding site to which the neurotransmitter would normally attach. The binding causes the receptor to respond in the same way as when the neurotransmitter is present. Direct antagonist / receptor blocker - a drug that binds with the postsynaptic receptor but blocks it from being activated. They occupy the receptor's binding site and prevent the neurotransmitter from activating the receptor. Some receptors have multiple binding sites - neurotransmitters bind with one site, and other substances bind with others. Binding of a molecule with one of these alternative sites is referred to as noncompetitive binding. Indirect antagonist - a drug that binds noncompetitively and prevents the receptor's ion channel from opening. Indirect agonist - a drug that binds noncompetitively and facilitates the opening of the ion channel. Drugs can act as antagonists by activating presynaptic receptors (which cause less neurotransmitter to be released). Drugs can also act as agonists by blocking presynaptic autoreceptors (which causes increased release of the neurotransmitter). Drug effects on reuptake/destruction of neurotransmitters Some agonists attach to the terminal membrane transporters responsible for reuptake and inactivate them, thus blocking reuptake. Other agonists can bind with enzymes that normally destroy the neurotransmitter and prevent the enzymes from working. Body and Behavior Page 4 What are the different types of neurotransmitters? What function does each type of neurotransmitter have? Amino acids Glutamate and gamma-aminobutyric acid (GABA) are the most common neurotransmitters in the CNS. Glutamate GABA Neurotransmitter Glutamate is the main excitatory neurotransmitter in the CNS. Gamma-aminobutyric acid (GABA) is the most prevalent production, Glutamate is synthesized from a precursor (glutamine) by the inhibitory neurotransmitter in the CNS. However, it has storage and enzyme glutaminase. After synthesis, it is stored in vesicles. excitatory effects at some synapses. release GABA is produced from a precursor (glutamic acid) by the enzyme (glutamic acid decarboxylase - GAD). Receptors There are 4 main types of glutamate receptors: There are several GABA receptors. Many drugs interact with Ionotropic: the NMDA, AMPA and kainate receptors. the GABAA receptor. The chemicals NMDA, AMPA and kainate serve as agonists at The GABAA receptor is ionotropic and controls Cl direct agonists at the receptors named after them. Alcohol channels, therefore producing rapid IPSPs. It contains serves as an antagonist of NMDA receptors. several binding sites, the primary being for GABA. A The AMPA receptors is the most common glutamate receptor. second site of the GABAA receptor binds with It controls a sodium channel, which opens and produced EPSPs benzodiazepines (e.g. Valium and Xanax), which reduce when glutamate attaches to its binding site. anxiety symptoms and seizure activity, and produce The kainate receptor has similar effects. muscle relaxation. The NMDA receptor contains at least 6 binding sites. When it is The GABAB receptor is metabotropic, typically open, the ion channel it controls permits both Na+ and Ca2+ producing a slow IPSP. ions to enter the cell. This causes an EPSPs, but the Ca2+ ions serve as second messenger, which binds with and activates various enzymes around the cell. These enzymes can for A seizure is an uncontrollable firing of neurons in the brain, example alter the characteristics of a synapse that provide one caused by too much excitatory synapse activity. It is believed of the building blocks of a newly formed memory. that one of the causes of seizure disorders is an abnormality Glutamate by itself cannot open the Ca2+ channel. For that to in the biochemistry of GABA-secreting neurons or in GABA happen, a molecule of glycine must be attached to the glycine receptors. binding site, located on the outside of the receptor. Also, a Mg+ ion must not be attached to the magnesium binding site, located deep within the channel. There is normally a Mg+ ion there, which is repelled when the postsynaptic membrane is depolarized => the NMDA receptor only opens if glutamate is present and the PS membrane is depolarized. That makes the NDMA receptor a voltage- and neurotransmitter-dependent ion channel. Metabotropic: the metabotropic glutamate receptor. Some metabotropic glutamate receptors also serve as presynaptic autoreceptors. Reuptake and Glutamate is removed from the synapse by excitatory amino acid GABA is removed from the synapse by GABA transporters. destruction transporters and broken down into glutamine by the enzyme GABA is broken down by the enzyme aminotransferase. glutamine synthase. A failure to remove glutamate from the synapse can produce glutamate excitotoxicity and damage neurons by prolonged over excitation. Acetylcholine Acetylcholine (Ach) functions both in the CNS and the PNS. ACh-releasing neurons are called cholinergic. ACh is composed of 2 precursors: choline and acetyl coenzyme A. The enzyme choline acetyltransferase (ChAT) is required to produce ACh from the precursors. ACh is the primary neurotransmitter secreted by axons that terminate at muscle cells to control muscle contraction. In the CNS, most cholinergic neurons are found in specific locations and pathways. Body and Behavior Page 5  In the CNS, most cholinergic neurons are found in specific locations and pathways. The acetylcholinergic neurons located in the dorsolateral pons play a role in REM sleep. Those located in the basal forebrain (including the medial septal nucleus, the nucleus of the diagonal band, and the nucleus basalis) project to the hippocampus and amygdala, as well as through the cerebral cortex. They are involved in learning and memory. Those located in the medial septum modulate the functions of the hippocampus, which include the formation of particular kinds of memories. There are 2 families of types of ACh receptors: The nicotinic receptors are ionotropic ACh receptors and they are stimulated by nicotine. Muscle fibers in the PNS, which must be able to contract quickly, contain the rapid-acting, ionotropic nicotinic receptors. Some nicotinic receptors are found at axoaxonic synapses in the brain, where they produce presynaptic facilitation. Activation of these receptors is partially responsible for the reinforcing effects of nicotine. The muscarinic receptors are metabotropic ACh receptors and they are stimulated by muscarine (a drug found in a poisonous mushroom). These receptors predominate in the CNS. After being released by the terminal buttons, ACh is broken down into its precursors by the enzyme acetylcholinesterase. After being broken down into its precursors, only choline is recycled by cholinergic cells. In such cells there are choline transporters for reuptake of choline. The monoamines The monoamine neurotransmitters are produced by systems of cell bodies in the brain stem, whose axons branch repeatedly and give rise to a huge number of terminal buttons distributed throughout many regions of the brain => monoaminergic neurons modulate the function of many brain regions, increasing/decreasing the activities of particular brain functions. Catecholamine synthesis consists of several steps, during which the precursor molecule is slightly modified until it achieves its final shape. 1. The precursor for dopamine and norepinephrine is tyrosine, an amino acid that must be obtained from our diet. 2. Tyrosine is modified by the enzyme tyrosine hydroxylase and become L-DOPA (L-3,4-dihydroxyphenylalanine). 3. L-DOPA is then modified by the enzyme DOPA decarboxylase and becomes dopamine. 4. The enzyme dopamine β-hydroxylase converts dopamine into norepinephrine. Neurons that release norepinephrine have an extra enzyme, which converts dopamine into norepinephrine. 5. Norepinephrine is converted to epinephrine. Neurons that release epinephrine have all the enzymes present in neurons that release norepinephrine, along with an extra enzyme that converts norepinephrine to epinephrine. Dopamine Dopamine produces both EPSPs and IPSPs, depending on the postsynaptic receptor. The 3 most important dopamine pathways originate in midbrain structures: the substantia nigra and the ventral tegmental area: Nigrostriatal/mesostriatal pathway- neurons, whose cell bodies are located in the substantia nigra and whose axons project to the striatum (caudate nucleus + putamen). The mesostriatal dopamine pathway plays a crucial role in motor control. Degeneration of neurons in the nigrostriatal system causes Parkinson's disease (causing tremors, limbs rigidity, poor balance, and difficulty initiating movements). Mesolimbic system - neurons, whose cell bodies are located in the ventral tegmental area, and project their axons to several parts of the limbic system, including the nucleus accumbens, amygdala and hippocampus. This system is important in reward and reinforcement. Mesocortical system - neurons, whose cell bodies are also located in the ventral tegmental area, and project their axons to the prefrontal cortex. These neurons have an excitatory effect on the frontal cortex and affect the Body and Behavior Page 6  These neurons have an excitatory effect on the frontal cortex and affect the formation of short-term memories, planning, and strategy preparation for problem solving. Abnormalities in the mesolimbocortical pathway are associated with some symptoms of schizophrenia. 5 metabotropic types of dopamine receptors have been identified and named the D1, D2, D3, D4 and D5, in the order of their discovery. The destruction of catecholamines is regulated by monoamine oxidase (MAO). Norepinephrine Norepinephrine (NE) = noradrenaline is found in both the CNS and the PNS. Norepinephrine-producing cells are called noradrenergic. The cell bodies of most noradrenergic neurons are located in 7 regions of the pons and medulla and 1 region of the thalamus. Almost every region of the brain receives input from these neurons. Locus coeruleus - a nucleus in the dorsal pons, the axons of whose neurons project to many brain areas. The primary effect of activation of these neurons is an increase in vigilance - attentiveness to events in the environment. Noradrenergic projections contribute to diverse behavioral and physiological processes: mood, arousal, sexual behavior etc. Most neurons do not release norepinephrine through terminal buttons, but from axonal varicosities (beadlike swellings of the axonal branches). There are 4 types of adrenergic receptors: α1- and α2-adrenergic receptors and β1- and β2- adrenergic receptors, that are sensitive to both norepinephrine and Epinephrine. All of them are metabotropic. Serotonin Serotonin (5-HT, or 5-hydroxytryptamine) plays a role in the regulation of mood, control of eating, sleep and dreaming, arousal, and in the regulation of pain. The cell bodies of most serotonergic neurons are located in 9 clusters, most of which are in the raphe nuclei of the midbrain, pons and medulla. The 2 most important clusters of serotonergic cell bodies are located in the dorsal and medial raphe nuclei. They project axons to the cerebral cortex, the basal ganglia and the dentate gyrus (a part of the hippocampus). Serotonin plays a role in the control of sleep states, mood, sexual behavior, anxiety, and many others. Several antidepressant drugs increase the availability of serotonin in synapses. For example, Prozac inhibits the reuptake of serotonin into axon terminals. Like norepinephrine, serotonin is also released from varicosities rather than terminal buttons. The precursor for serotonin is the amino acid tryptophan. The enzyme tryptophan hydroxylase acts on tryptophan, producing 5-HTP. The enzyme 5-HTP decarboxylase converts 5-HTP into serotonin. Histamine The activity of histaminergic neurons is strongly correlated with the states of sleep and wakefulness. Antihistamines (drugs that block histamine receptors) cause drowsiness. The cell bodies of histaminergic neurons are only found in 1 place in the brain: the tuberomammillary nucleus, located in the posterior hypothalamus. They send their axons to many regions of the cerebral cortex and brain stem. Histamine is produced from the precursor histidine by the enzyme histidine decarboxylase. Neuropeptides Peptides consists of 2 or more amino acids linked together by peptide bonds. The precursors of peptides are large polypeptides that are broken into smaller neurotransmitter molecules. Both the polypeptides and the enzymes needed to break them apart are manufactured by neurons. Pituitary peptides - neuropeptides that were first identified as hormones released by the pituitary (e.g. oxytocin and vasopressin). Body and Behavior Page 7 Pituitary peptides - neuropeptides that were first identified as hormones released by the pituitary (e.g. oxytocin and vasopressin). Hypothalamic peptides - neuropeptides that were first identified as hormones released by the hypothalamus. Brain-gut peptides - neuropeptides that were first discovered in the gut. Opioid peptides - neuropeptides that are similar in structure and functions to the active ingredients of opiate drugs such as morphine. Miscellaneous peptides - all the other neuropeptides. Gas neurotransmitters Some neurons use gas molecules that dissolve in water (soluble gases) to communicate information. The best studied of these is nitric oxide (NO). Gas neurotransmitters are produced in locations different than the axon terminals and simply diffuse out of the neuron as soon as they are produced. Gas neurotransmitters do not bind to receptors, but diffuse into the target cell and stimulate the production of second messengers. NO can serve as a retrograde transmitter, diffusing from the postsynaptic neuron back to the presynaptic neuron, in which way it can be involved in learning and memory. NO is implicated in bodily processes, such as hair growth and penile erection. Lipids Endocannabinoids - ligands for the receptors that are responsible for the physiological effects of the active ingredient in marijuana. Tetrahydrocannabinol (THC) stimulates cannabinoid receptors located in specific regions of the brain. Lipid neurotransmitters are produced on demand. They are therefore not stored in synaptic vesicles. Body and Behavior Page 8