Pharmacology PDF - Introduction to CNS Drugs

F.03 Part 1 INTRODUCTION TO CNS DRUGS: DRUGS ACTING ON THE CNS DR. JOHN HAROLD B. HIYADAN | 11/14/24 OUTLINE I. Organization IV. Retrograde of the CNS Signaling A. CNS...

F.03 Part 1 INTRODUCTION TO CNS DRUGS: DRUGS ACTING ON THE CNS DR. JOHN HAROLD B. HIYADAN | 11/14/24 OUTLINE I. Organization IV. Retrograde of the CNS Signaling A. CNS A. Selectivity of CNS B. Neurons drug actions C. Neuroglia V. Cellular Organization of the D. Blood Brain Brain Barrier A. Hierarchical II. Ion Channel & Systems Neurotransmitter B. Non-Specific or A. Voltage-gated Channel Diffuse Neuronal B. Ligand-gated Ion Systems Channel VI. Central C. Metabotropic Neurotransmitters Receptors A. Amino Acid D. Some toxins used to Neurotransmitter characterize ion channels B. Monoamine III. Synapse & Synaptic Neurotransmitter Potentials C. Neuropeptides A. Excitatory postsynaptic D. Orexin potential (EPSP) E. Other Signaling Substances B. Inhibitory postsynaptic potential (IPSP) C. Sites of Drug action D. Presynaptic Alteration E. Synaptic Alteration F. Post synaptic Alteration I. ORGANIZATION OF THE CNS A. CNS  Composed of the brain and spinal cord.  Responsible for integrating sensory information and generating motor output and other behaviors needed to successfully interact with the environment and enhance species Neuropeptides survival.  Throughout CNS, neurons are either clustered into groups called Nuclei.  Present in layered structures such as the cerebellum or hippocampus. B. NEURONS  Electrically excitable cells.  Process and transmit information via an electrochemical process.  There are many types of neurons in the CNS and are classified in multiple ways:  By function  By location  By neurotransmitter release  Have hundreds of dendrites but generally have only one axon. B.1 Dendrites  Forms highly branched complex dendritic “trees,” receive and integrate the input from other neurons and conduct this information to the cell body. B.2 Axons  Carries the output signal of a neuron from the cell body.  Axon terminal contacts other neurons at specialized junctions called synapses, where neurotransmitter chemicals are released that interact with receptors on other neurons. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 1 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  C. NEUROGLIA  Aka “Glia”  Large number of nonneuronal support cells.  Perform a variety of essential functions in the CNS. C.1 Astrocytes  Most abundant cell in the brain.  Play homeostatic support roles:  providing metabolic nutrients to neurons  maintaining extracellular ion concentrations  Astrocyte processes, which are closely associated with neuronal synapses.  involved in the removal and recycling of neurotransmitters after release.  play increasing roles in regulating neurotransmission. C.2 Oligodendrocytes  Cells that wrap around the axons of projection neurons in the CNS forming the myelin sheath, which insulates the axons and increases the speed of signal propagation.  Damage to oligodendrocytes occurs in multiple sclerosis, and thus, they are a target of drug discovery efforts. C.3 Microglia  Major immune defense system in the brain.  specialized macrophages derived from the bone marrow that settle in the CNS.  Involved in the neuroinflammatory processes including neurodegenerative diseases. Figure 1. Neurons and glia in the CNS. A typical neuron has a cell body (or soma) that receives the synaptic responses from the dendritic tree. These synaptic responses are integrated at the axon initial segment, which has a high concentration of voltage-gated sodium channels. If an action potential is initiated, it propagates down the axon to the synaptic terminals, which contact other neurons. The axon of long-range projection neurons is insulated by a myelin sheath derived from specialized membrane processes of oligodendrocytes, analogous to the Schwann cells in the peripheral nervous system. Astrocytes perform supportive roles in the CNS, and their processes are closely associated with neuronal synapses. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14 th ed. Pg. 368 D. BLOOD BRAIN BARRIER(BBB)  Protective functional separation of the circulating blood from the extracellular fluid of the CNS that limits the penetration of substances, including drugs.  The separation is accomplished by the presence of tight junctions between the capillary endothelial cells as well as a surrounding layer of astrocyte end-feet.  Drugs must either be highly hydrophobic or engage specific transport mechanisms.  Many nutrients including glucose and the essential amino acids, have specific transporters that allow them to cross BBB. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 2 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  L-DOPA  A precursor of the neurotransmitter dopamine.  Can enter the brain using an amino acid transporter.  Dopamine  Cannot cross the BBB.  Circumventricular organs lack a normal BBB, this includes regions that sample the blood, such as:  the area postrema vomiting center (located on the medulla).  regions that secrete neurohormones into the circulation. Figure 2. BBB. On the right side, the BBB is made up of tight junctions between the capillary endothelial cells as well as the surrounding layers of the astrocyte end-feet; Because of that, substances outside of the CNS cannot just enter the CNS because of this BBB. Lifted from Lecturer’s ppt II. ION CHANNEL & NEUROTRANSMITTER RECEPTORS A. VOLTAGE-GATED CHANNEL  Respond to changes in the membrane potential of the cell.  Highly concentrated on the initial segment of the axon. Initiates the all-or-nothing fast action potential, especially the sodium voltage channel, and along the length of the axon where they propagate the action potential to the nerve terminal.  All-or-nothing means that the cell must reach -50mV before eliciting an action potential. The charge is the determinant if the action is excitatory(≥50mV) or inhibitory(≤50mV).  Many types of voltage-sensitive calcium and potassium channels on the cell body, dendrites, and initial segment, which act on a much slower time scale and modulate the rate at which the neuron discharges.  Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptors:  Ligand-gated channels, or ionotropic receptors.  Metabotropic receptors. Figure 3. Voltage-gated ion channel. A voltage sensor component of the proteins controls the gating (broken arrow) of the channel. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14 th ed. Pg. 369 NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 3 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  B. LIGAND-GATED ION CHANNEL  First class of neurotransmitter receptor.  Consist of multiple subunits.  Binding of the neurotransmitter ligand directly opens the channel (If an NT binds with a channel, it opens a channel that is if the NT is an excitatory or inhibitory but depends on the type of the channel that is being opened).  Activation of these channels typically results in a brief (a few milliseconds to tens of milliseconds) opening of the channel.  Weakly sensitive to membrane potential (They are not opened by the membrane potential unlike in the voltage-gated channel wherein they are opened/affected by action potential that is propagated)  Responsible for fast synaptic transmission. Figure 4. Ligand-gated ion channel. The binding of the neurotransmitter to the ionotropic channel receptor controls the gating (broken arrow) of the channel. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14th ed. Pg. 369 C. METABOTROPIC RECEPTORS  Second class of neurotransmitter receptor.  Seven transmembrane G protein-coupled receptors. Figure 5. Metabotropic receptor. G protein-coupled(metabotropic) receptor, which when bound, activates a heterotrimeric G protein. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14 th ed. Pg. 369  Binding to the receptor engages a G protein, which results in:  First = Modulation of voltage-gated channels (membrane-delimited pathways): G protein (often the βγ subunit) interacts directly with a voltage-gated ion channel. In general, two types of voltage-gated ion channels are the targets of this type of signaling: o G proteins inhibit channel function in the presynaptic. o G proteins activate K receptors post-synaptically, resulting in post-synaptic inhibition.  Second = Modulate voltage-gated channels less directly by the generation of diffusible second messengers: o Example of this type of action is provided by the β adrenoceptor, which generates cAMP (diffusible second messenger) via the activation of adenylyl cyclase. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 4 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  o Second messenger-mediated effects can occur over considerable distances. o The effects of metabotropic receptor activation can last tens of seconds to minutes. o Metabotropic receptors predominate in the diffuse neuronal systems. Figure 6. Membrane-delimited regulation of ion channels and diffusible second messenger-mediated regulation of ion channels by metabotropic receptors. 2 ways metabotropic receptors can regulate ion channels. The activated G protein can interact directly to modulate an ion channel or the (D)G protein can activate an enzyme that generates a diffusible second messenger (E), eg, cAMP, which can interact with the ion channel or can activate a kinase that phosphorylates and modulates a channel. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14th ed. Pg. 369 D. SOME TOXINS USED TO CHARACTERIZE ION CHANNELS  Tetrodotoxin  Caused by not properly cooked puffer fish which leads to paralysis because the sodium channel is blocked.  Betrachotoxin  if it slows the activation -> EXCITATION resulting to tetanic contractions or contraction of the muscles or even seizures because sodium channels are being activated.  Charybdotoxin  If you block the big Ca-activated K channel -> leads to EXCITATION resulting in -> contraction of the muscles and seizures.  GABAA Receptor  Blocked by picrotoxin.  GABAA is an inhibitory NT.  Strychnine  Glycine is also inhibitory.  Seen in rat poison.  AMPA Receptor  Excitatory receptor.  If blocked will result in paralysis. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 5 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  No need to memorize, remember Tetrodotoxin** Table 1. Types of channels and their associated toxins. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14th ed. Pg. 370 III. SYNAPSE & SYNAPTIC POTENTIALS  An action potential propagating down the axon of the presynaptic neuron enters the synaptic terminal and activates voltage-sensitive calcium channels in the membrane of the terminal.  The calcium channels responsible for the release of neurotransmitters are generally resistant to the calcium channel-blocking agents but are sensitive to blockade by certain marine toxins and metal ions.  As calcium flows into the terminal, the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane.  The neurotransmitter contained in the vesicles is released into the synaptic cleft and diffuses to the receptors on the postsynaptic membrane.  The neurotransmitter binds to its receptor and opens channels (either directly or indirectly) causing a brief change in membrane conductance (permeability to ions) of the postsynaptic cell. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 6 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  Figure 7. Postsynaptic potentials and action potential generation. A shows the voltage recorded upon entry of a micro-electrode into a postsynaptic cell and subsequent recording of a resting membrane potential of -60 mV. Stimulation of an excitatory pathway (E1, left) generates transient depolarization called an excitatory postsynaptic potential (EPSP). Simultaneous activation of multiple excitatory synapses (E1 E2, middle) increases the size of the depolarization, so that the threshold for action potential generation is reached. Alternatively, a train of stimuli from a single input can temporally summate to reach the threshold (E1 +E2, right). B demonstrates the interaction of excitatory and inhibitory synapses. On the left, a suprathreshold excitatory stimulus(E3) evokes an action potential. In the center, an inhibitory pathway(I)generates a small hyperpolarizing current called an inhibitory postsynaptic potential (IPSP). On the right, if the previously suprathreshold excitatory input (E3) is given shortly after the inhibitory input(I), and the IPSP prevents the excitatory potential from reaching the threshold. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14th ed. Pg. 371. A. EXCITATORY POSTSYNAPTIC POTENTIAL(EPSP)  Small depolarization or excitatory postsynaptic potential (EPSP) is recorded.  This potential is due to the excitatory transmitter acting on an ionotropic receptor, causing an increase in cation permeability.  As additional excitatory synapses are activated, there is a graded summation of the EPSPs to increase the size of the depolarization: SPATIAL SUMMATION.  A repetitive firing of an excitatory input, the TEMPORAL SUMMATION of the EPSPs may also reach the action potential threshold. B. INHIBITORY POSTSYNAPTIC POTENTIAL (IPSP)  When an inhibitory pathway is stimulated, the postsynaptic membrane is hyperpolarized owing to the selective opening of chloride channels, producing an Inhibitory Postsynaptic Potential (IPSP).  However, because the equilibrium potential for chloride is only slightly more negative than the resting potential (~ −65 mV), the hyperpolarization is small and contributes only modestly to the inhibitory action.  Opening of the chloride channel during the IPSP makes the neuron “leaky” so that changes in membrane potential are more difficult to achieve. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 7 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  B.1 Presynaptic inhibition  Second type of inhibition.  First describe for sensory fibers entering the spinal cord, where excitatory synaptic terminals receive synapses called axoaxonic synapses.  Axoaxonic synapses reduce the amount of transmitter released from the terminals of sensory fibers. C. SITES OF DRUG ACTION  Virtually all the drugs that act in the CNS produce their effects by modifying some step in chemical synaptic transmission.  Transmitter-dependent actions can be divided into presynaptic and postsynaptic categories. Figure 8. Schematic drawing of steps at which drugs can alter synaptic transmission. (1) Action potential in propagation; (2) synthesis; (3) storage; (4) metabolism; (5) release; (6) reuptake; (7) degradation; (8) receptor for the transmitter; (9) receptor-induced increase or decrease in ionic conductance; (10) retrograde signaling. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14 th ed. Pg. 372 D. PRESYNAPTIC ALTERATION  Drugs acting on the synthesis, storage, metabolism, and release of neurotransmitters fall into the presynaptic category:  1st = Synaptic transmission can be depressed by blockade of transmitter synthesis or storage: o Reserpine depletes monoamine synapses of transmitters by interfering with intracellular storage.  2nd = Drugs can also alter the release of transmitters: o Amphetamine induces the release of catecholamines from adrenergic synapses.  3rd = Capsaicin causes the release of the peptide substance P from sensory neurons.  4th = Tetanus toxin blocks the release of transmitters (inhibitory glycine). NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 8 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  E. SYNAPTIC ALTERATION  After a CNS transmitter has been released into the synaptic cleft, its action is terminated either by uptake or by enzymatic degradation.  For most neurotransmitters, there are uptake mechanisms into the synaptic terminal, and also into surrounding neuroglia.  Cocaine  Blocks the uptake of catecholamines at adrenergic synapses and thus potentiates the action of these amines.  Acetylcholine is inactivated by enzymatic degradation, not reuptake.  Anticholinesterases block the degradation of acetylcholine and thereby prolong its action.  No uptake mechanism has been found for any of the numerous CNS peptides, and it has yet to be demonstrated whether specific enzymatic degradation terminates the action of peptide transmitters. F. POST SYNAPTIC ALTERATION  In the postsynaptic region, the transmitter receptor provides the primary site of drug action:  1. Drugs can act either as neurotransmitter agonists. o such as the opioids, which mimic the action of enkephalin.  2. Receptor antagonism/ blockade is a common mechanism of action for CNS drugs. o Strychnine’s blockade of the receptor for the inhibitory transmitter glycine leading to convulsions, illustrates how the blockade of inhibitory processes results in excitation.  3. Drugs can also act directly on the ion channel of ionotropic receptors. o anesthetic ketamine blocks the NMDA subtype of glutamate ionotropic receptors by binding in the ion channel pore.  4. Drugs can act at any of the steps downstream of the receptor. o methylxanthines, which can modify neurotransmitter responses mediated through the second-messenger cAMP. At high concentrations, Methylxanthines elevate the level of cAMP by blocking its metabolism and thereby prolong its action. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 9 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  IV. RETROGRADE SIGNALING Figure 9. Retrograde signaling Lifted from Lecturer’s ppt  The traditional view of the synapse is that it functions like a valve, transmitting information in one direction.  However, it is now clear that the synapse can generate signals that feedback onto the presynaptic terminal to modify the transmitter release.  Endocannabinoids are the best-documented example of such retrograde signaling.  Postsynaptic activity leads to the synthesis and release of endocannabinoids, which then bind to receptors on the presynaptic terminal.  Nitric oxide (NO) has long been proposed as a retrograde messenger, its physiologic role in the CNS is still not well understood. A. SELECTIVITY OF CNS DRUG ACTIONS  TWO Primary factors:  Different neurotransmitters are released by different groups of neurons. o These transmitters are often segregated into neuronal systems that subserve broadly different CNS functions.  There is a multiplicity of receptors for each neurotransmitter. o For example, there are at least 14 different serotonin receptors encoded by different genes. o These receptors often have differential cellular distributions throughout the CNS, allowing for the development of drugs that selectively target particular receptor and CNS functions. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 10 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  V. CELLULAR ORGANIZATION OF THE BRAIN A. HIERARCHICAL SYSTEMS Figure 10. Hierarchical pathways in the CNS. A shows parts of three excitatory relay neurons(blue)and two types of local inhibitory interneuron pathways, recurrent and feed-forward. The inhibitory neurons are shown in gray. B shows the pathway responsible for axoaxonic presynaptic inhibition in which the axon of an inhibitory neuron (gray)synapses onto the presynaptic axon terminal of an excitatory fiber(blue)to inhibit its neurotransmitter release. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14th ed. Pg. 373  Include all the pathways directly involved in sensory perception and motor control.  Composed of large myelinated fibers that can often conduct action potentials at a rate of more than 50 m/s.  Uses ionotropic receptors (fast but short-lived transmission).  Within each nucleus and in the cortex, there are two types of cells: relay or projection neurons and local circuit neurons. A.1 Relay or Projection neurons  Relay neurons: excitatory (glutamate).  Forms the interconnecting pathways that transmit signals over long distances.  Their cell bodies are relatively large, and their axons can project long distances but also emit small collaterals that synapse onto local interneurons.  These neurons are excitatory, and their synaptic influences, which involve ionotropic receptors, are very short-lived. A.2 Local circuit neurons  Local circuit neurons: inhibitory (GABA or Glycine).  Typically smaller than projection neurons.  Their axons arborize in the immediate vicinity of the cell body.  They synapse primarily on the cell body of the projection neurons but can also synapse on the dendrites of projection neurons as well as with each other. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 11 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  B. NONSPECIFIC OR DIFFUSE NEURONAL SYSTEMS  Neuronal systems containing many of the other neurotransmitters, including monoamines and acetylcholine.  These neurotransmitters are produced by only a limited number of neurons whose cell bodies are located in small discrete nuclei, often in the brain stem.  Example: noradrenergic cell bodies in locus coeruleus located in the caudal pontine central gray matter from the limited nuclei, these neurons project widely and diffusely projecting throughout the brain and spinal cord.  Axons from these diffusely projecting neurons are fine and unmyelinated they conduct very slowly, at about 0.5 m/s.  Axons branch repeatedly and are extraordinarily divergent.  Branches from the same neuron can innervate several functionally different parts of the CNS, synapsing onto and modulating neurons within the hierarchical systems.  Most neurotransmitters utilized by diffuse neuronal systems, including norepinephrine.  Act predominantly on metabotropic receptors and therefore initiate long-lasting synaptic effects. Figure 11. Diffuse neurotransmitter pathways in the CNS. For each of the neurotransmitter pathways shown, the cell bodies are located in discrete brain stem or basal forebrain nuclei and project widely throughout the CNS. These diffuse systems largely modulate the function of the hierarchical pathways. Serotonin neurons, for example, are found in the midline raphe nuclei in the forebrain and send extraordinarily divergent projections to nearly all regions of the CNS. Other diffusely projecting neurotransmitter pathways include the histamine and orexin systems (not shown). A1–A7, adrenergic brain stem nuclei; Ch5-Ch8, cholinergic brain stem nuclei; DB, diagonal band of Broca; MSN, medial septal nucleus; SN, substantia nigra; VTA, ventral tegmental area. VI. CENTRAL NEUROTRANSMITTERS  Criteria for neurotransmitter identification:  Localization: A suspected transmitter must reside in the presynaptic terminal of the pathway of interest.  Release: A suspected transmitter must be released from a neuron in response to neuronal activity and in a calcium- dependent manner.  Synaptic Mimicry: Application of the candidate substance should produce a response that mimics the action of the transmitter released by nerve stimulation, and application of a selective antagonist should block the response. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 12 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  A. AMINO ACID NEUROTRANSMITTERS A.1 GLUTAMATE  Excitatory synaptic transmission is mediated by glutamate.  Released into the synaptic cleft by Ca2+-dependent exocytosis.  Cleared by glutamate transporters present on surrounding glia.  Is converted to glutamine-by-glutamine synthetase.  The high concentration of glutamate in synaptic vesicles is achieved by the vesicular glutamate transporter (VGLUT).  Activates both inotropic and metabotropic receptor.  GLUTAMATE ION RECEPTORS (based on the action of selective agonist):  1, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA).  2, Kainic acid (KA).  3, N-methyl-d-aspartate (NMDA).  AMPA RECEPTORS  Present on all neurons, are heterotetramers assembled from four subunits (GluA1-GluA4).  Majority of AMPA receptors contain the GluA2 subunit and are permeable to Na and K, but not to calcium.  AMPA receptors, typically present on inhibitory interneurons, lack the GluA2 subunit and are also permeable to Ca. Figure 12. Relationship between AMPA and NMDA receptor. Figure 13. Ionic glutamate receptor. Lifted from lecturer’s ppt  NMDA  Are as ubiquitous as AMPA receptors.  Present on essentially all neurons in the CNS.  All NMDA receptors require the presence of the subunit GluN1.  Contains one or two GluN2 subunits (GluN2A- GluN2D).  All NMDA receptors are highly permeable to Ca 2+ as well as to Na+ and K+  Receptor activation does not occur at resting membrane potential (NMDA receptor pore is blocked by extracellular Mg2+). NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 13 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  Figure 14. NMDA receptor  THREE Requirements for NMDA receptor channel opening: o Glutamate must bind the receptor. o Glycine must bind the receptor. o The membrane must be depolarized to expel Mg 2+ Figure 14. NMDA receptor Activation.  KAINATE RECEPTORS  Expressed at high levels in the hippocampus, cerebellum, and spinal cord.  Not as uniformly distributed as AMPA.  Formed from a number of subunit combinations (GluK1–GluK5).  Similar to AMPA receptors, kainate receptors are permeable to Na+ and K+  Some subunit combinations can also be permeable to Ca 2+  Domoic acid, a toxin produced by algae and concentrated in shellfish, is a potent agonist at Kainate and AMPA receptors.  METABOTROPIC GLUTAMATE RECEPTORS: o Group I receptors  Typically located postsynaptically and activates phospholipase C, leading to inositol triphosphate mediated intracellular Ca2+ release (inhibition). o Group II and Group III receptors  Located on presynaptic nerve terminals.  Inhibitory auto receptors: causes the inhibition of Ca2+ channels, resulting in inhibition of transmitter release.  activated only when the concentration of glutamate rises to high levels during repetitive stimulation of the synapse, also causes the inhibition of adenylyl cyclase and decreases cAMP generation. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 14 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  Figure 15. Kainate receptor Activation A.2 Glycine  GABA and glycine are inhibitory NTs, which are typically released from local interneurons.  Glycine is restricted to the spinal cord and brain stem, whereas interneurons releasing GABA are present throughout the CNS.  Glycine receptors are pentameric structures that are selectively permeable to Cl-.  Strychnine, which is a potent spinal cord convulsant and has been used in some rat poisons, selectively blocks glycine receptors. A.3 GABA  Two main types:  1 = GABAA (Fast component) o GABA-A receptors are ionotropic receptors and like glycine receptors, are pentameric structures that are selectively permeable to Cl-. o These receptors are selectively inhibited by picrotoxin and bicuculine, both of which cause generalized convulsions.  2 = GABAB (slow component) o GABA-B receptors are metabotropic receptors that are selectively activated by the antispastic drug Baclofen. o These receptors are coupled to G proteins that, depending on their cellular location, either inhibit Ca2+ channels or activate K+ channels.  The GABAB component of the inhibitory postsynaptic potential is due to a selective increase in K+ conductance.  This inhibitory postsynaptic potential is long-lasting and slow because the coupling of receptor activation to K+ channel opening is indirect and delayed. A.4 ACETYLCHOLINE  First compound to be identified pharmacologically as a transmitter in the CNS  Most CNS responses to acetylcholine are mediated by a large family of G protein-coupled muscarinic receptors  Acetylcholine causes slow inhibition of the neuron by activating the M2 subtype of receptor, which opens K+ channels  A far more widespread muscarinic action in response to acetylcholine is a slow excitation that in some cases is mediated by M1 receptors by decreasing the membrane permeability to potassium  CNS nuclei of acetylcholine neurons with diffuse projections:  1 = Neostriatum  2 = Medial septal nucleus  3= The reticular formation that appears to play an important role in cognitive function, especially memory  Dementia of Alzheimer’s type is reportedly associated with a profound loss of cholinergic neurons NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 15 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  B. MONOAMINE NEUROTRANSMITTERS  Monoamines include the catecholamines (dopamine and norepinephrine) and 5-hydroxytryptamine.  CNS stimulants cocaine and amphetamine appear to act primarily at catecholamine synapses.  Cocaine blocks the reuptake of dopamine and norepinephrine.  Amphetamines cause presynaptic terminals to release these transmitters. B.1 Dopamine  Substantia nigra neostriatum link: therapeutic action of the anti-parkinsonism drug levodopa.  Ventral tegmental-limbic structure link: the therapeutic action of the antipsychotic drugs.  Dopamine-containing neurons in the ventral hypothalamus play an important role in regulating pituitary function.  5 dopamine receptors have been identified, and they fall into 2 categories:  D1-like (D1 and D5).  D2- like (D2, D3, D4).  All dopamine receptors are metabotropic  Dopamine generally exerts a slow inhibitory action on CNS neurons by opening potassium channels via the Gi coupling protein. B.2 Norepinephrine  Noradrenergic neurons are located in the locus coeruleus or the lateral tegmental area of the reticular formation.  All noradrenergic receptor subtypes are metabotropic.  In many regions of the CNS, norepinephrine actually enhance excitatory inputs by both indirect and direct mechanisms:  Indirect mechanism involves disinhibition. o inhibitory local circuit neurons are inhibited.  Direct mechanism blockade of potassium conductance that slows neuronal discharge mediated by either α1 or β receptors.  Norepinephrine can hyperpolarize (inhibits neurons) by increasing potassium conductance- mediated by α2 receptors and has been characterized most thoroughly on locus coeruleus neurons.  Facilitation of excitatory synaptic transmission is in accordance with many of the behavioral processes thought to involve noradrenergic pathways.  attention and arousal. B.3 5-Hydroxytryptamine (serotonin)  From midline raphe nuclei of the pons and upper brain stem- projects diffusely to other areas.  All receptors are metabotropic except 5-HT3 (ionotropic).  Ionotropic 5-HT3 receptor exerts a rapid excitatory action at a very limited number of sites in the CNS.  In most areas of the CNS, 5-HT has a strong inhibitory action mediated by 5-HT1A receptors and is associated with membrane hyperpolarization caused by an increase in potassium conductance  Some cell types are slowly excited by 5-HT owing to its blockade of potassium channels via 5-HT2 or 5-HT4 receptors.  Both excitatory and inhibitory actions can occur on the same neuron.  5-HT has been implicated in the regulation of virtually all brain functions, including perception, mood, anxiety, pain, sleep, appetite, temperature, neuroendocrine control, and aggression. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 16 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  B.4 Histamine  Exclusively made by neurons in the tuberomammillary nucleus (TMN) in the posterior hypothalamus.  These neurons project widely throughout the brain and spinal cord where they modulate arousal, attention, feeding behavioral and memory.  Histamine receptors (H1 to H4) are metabotropic.  Centrally acting antihistamines are generally used for their sedative properties.  Antagonism of H1 receptors is a common side effect of many drugs including some tricyclic antidepressants and antipsychotics. C. NEUROPEPTIDES  Unlike the classical neurotransmitters which are packaged in small synaptic vesicles, neuropeptides are generally packaged in large, dense core vesicles.  Released neuropeptides may act locally or may diffuse long distances and bind to distant receptors.  Most neuropeptide receptors are metabotropic and, like monoamines, primarily serve modulatory roles in the nervous system.  Example: Substance P is contained in and released from small unmyelinated primary sensory neurons in the spinal cord and brain stem and causes a slow excitatory postsynaptic potential in sensory fibers that are known to transmit noxious stimuli. D. OREXIN  Are peptide neurotransmitters produced in neurons in the lateral and posterior hypothalamus.  Project widely throughout the CNS.  Are also called hypocretins due to the near-simultaneous discovery by two independent laboratories.  Like most neuropeptides, orexin is released from large, dense core vesicles and binds to two G-protein coupled receptors.  Orexin neurons also release glutamate and are thus excitatory.  The orexin system projects widely throughout the CNS to influence physiology and behavior.  In particular, orexin neurons exhibit firing patterns associated with wakefulness and project to and activate monoamine and acetylcholine neurons involved in sleep-wake cycles.  Animals lacking orexin or its receptors have narcolepsy and disrupted sleep-wake patterns.  The orexin system is involved in energy homeostasis, feeding behavior, autonomic function, and reward. E. OTHER SIGNALING SUBSTANCES E.1 ENDOCANNABINOIDS  Δ-tetrahydrocannabinol (Δ - THC) affects the brain mainly by activating a specific cannabinoid receptor, CB1.  Endogenous brain lipids, including anandamide and 2- arachidonylglycerol (2-AG) are CB1 ligands.  2-AG and CB1 are not stored but instead are rapidly synthesized by neurons in response to calcium influx or activation of metabotropic receptors (e.g., by acetylcholine and glutamate).  Endogenous cannabinoids can function as retrograde synaptic messengers:  Are released from postsynaptic neurons and travel backward across synapses, activating CB1 receptors on presynaptic neurons and suppressing transmission release.  Cannabinoids may affect memory, cognition, and pain perception by this mechanism. NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 17 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  Figure 16. Endogenous cannabinoid system. Activation of postsynaptic group I metabotropic glutamate receptors(mGluR1/5) leads to the G protein-mediated membrane-delimited activation of phospholipase C(PLC)that produces the second messengers inositol trisphosphate (IP3, not shown) and diacylglycerol (DAG). DAG can then be converted to the endogenous cannabinoid 2- arachidonoylglycerol (2-AG) by DAG lipase.2-AG is then released by unknown mechanisms to diffuse across the synaptic cleft where it acts as a full agonist at CB cannabinoid receptors on the presynaptic terminals. Activation of CB receptors by either endocannabinoids or exogenous cannabinoids such as A-tetrahydrocannabinol (THC) results in the inhibition of presynaptic neurotransmitter release. Lifted from Basic & Clinical Pharmacology, Katzung, B.G., 14th ed. Pg. 380 E.2 NITRIC OXIDE  The CNS contains a substantial amount of nitric oxide synthase (NOS) within certain classes of neurons.  This neuronal NOS is an enzyme activated by calcium-calmodulin.  Activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide.  Nitric oxide diffuses freely across membranes to be a retrograde messenger that enhances glutamate release.  Act on vascular smooth muscle- Potent vasodilator. Figure 17. Synaptic plasticity: Nitric Oxide NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 18 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  E.3 PURINES  Receptors for purines, particularly adenosine, ATP, UTP, and UDP, are found throughout the body, including the CNS.  High concentrations of ATP are found in and released from catecholaminergic synaptic vesicles, and ATP may get converted to adenosine extracellularly by nucleotidases.  Adenosine in the CNS acts on metabotropic A1 receptors.  Presynaptic A1 receptors inhibit calcium channels and inhibit release of both amino acid and monoamine transmitters.  ATP co-released with other neurotransmitter can bind to two classes of receptors:  The P2X family ATP receptors include nonselective ligand-gated cation channels.  P2Y family which is metabotropic.  The physiologic roles for ATP co-release remain elusive, but pharmaco-logical studies suggest these receptors are involved in memory, wakefulness, and appetite and may play roles in multiple neuropsychiatric disorders. RECALL CHECK POINT! 1. Which ion is crucial for neurotransmitter release at the synapse? 2. This potential is due to the excitatory transmitter acting on an ionotropic receptor, causing an increase in cation permeability 3. a potent spinal cord convulsant and has been used in some rat poisons, selectively blocks glycine receptors 4. Exclusively made by neurons in the tuberomammillary nucleus (TMN) in the posterior hypothalamus 5. Are peptide neurotransmitters produced in neurons in the lateral and posterior hypothalamus 1. Calcium 2. EXCITATORY POSTSYNAPTIC POTENTIAL(EPSP) 3. Strychnine 4. Histamine 5. Orexin NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 19 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  APPENDIX NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 20 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 21 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 22 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 23 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen  NOTE TAKERS: GERR PANGIT MED210 SEM1 Page 24 of 24 Last date edited: 11/26/2024 | Editor / QC: Felix Baiguen