1. Introduction to Central Nervous System CHEM E-120 2011

2. CHEM E-1202 Nervous System Central Nervous System (CNS) – Brain – Spinal cord – Processes and stores motor and sensory information Important regions of the brain involved in psychiatric disorders – Cerebral Cortex - Frontal lobe, motor cortex – Limbic Lobe - drives, emotions, memory Hippocampus, Amygdala – Basal ganglia (movement control) Caudate nucleus Lenticular nucleus – putamen – globus pallidus – Thalamus - functions as a relay to cortex – Hypothalamus- controls autonomic function Peripheral Nervous System (PNS) – Nerve network from (efferent) and to (afferent) the spinal cord, connects CNS to muscles and organs 1/27/2010

3. CHEM E-1203 Limbic System A group of interconnected structures (cells) that mediate emotions, learning and memory. Structures are interposed between the hypothalamus and neocortex. Amygdala and hippocampus – Primitive parts of the brain involved in behavioral control – Amygdala and its neural connections are centrally involved in emotional experiences and responses. Receives specific sensory inputs of sight, sound, touch, smell, and taste, and more general sensory inputs of levels of physical and emotional comfort and discomfort. – Hippocampus has a primary role in some forms of learning and memory. Hypothalamus – Connecting point in pathways concerned with autonomic, endocrine, emotional, and somatic functions that are designed to maintain homeostasis. Function extends into drives and emotional behaviors. 1/27/2010

4. CHEM E-1204 Figure 23-1 Three-dimensional reconstruction of the hypothalamus and surrounding cerebral structures. The hypothalamus has been rendered with a flat anterior surface because the preoptic area (see Fig. 23-4), which envelops the anterior end of the third ventricle but is in front of the plane sometimes used to separate the diencephalon and telencephalon, was not included. *, claustrum; Am, amygdala; Ca, caudate nucleus; CC, corpus callosum; GP, globus pallidus; Hy, hypothalamus; IC, internal capsule; In, insula; LVa, anterior horn of the lateral ventricle; P, putamen; Th, thalamus. Limbic System 1/27/2010

5. CHEM E-1205 Figure 23-15 Three-dimensional re-construction of the hippocampus, fornix, and amygdala inside a translucent CNS, seen from the left (A), above (B), in front (C), and behind (D). Limbic System 1/27/2010

6. CHEM E-1206 Figure 23-18 Major inputs to the basolateral (blue), central (red), and medial (green) nuclei of the amygdala (Am). Only inputs from visual association cortex to the basolateral nuclei are shown, although there are similar projections from most or all unimodal sensory areas. The inputs from limbic cortex to the basolateral nuclei also include a major projection from the insula, which is not present in this view. B, brainstem (periaqueductal gray, parabrachial nuclei, other nuclei); Hy, hypothalamus; S, septal nuclei; T, thalamus (multiple nuclei). (Modified from Warwick R, Williams PL: Gray's anatomy, Br ed 35, Philadelphia, 1973, WB Saunders.) Neuronal Inputs to the Amygdala 1/27/2010

7. CHEM E-1207 Figure 23-21 Major outputs from the basolateral (blue), central (red), and medial (green) nuclei of the amygdala (Am). These take three routes: (1) the stria terminalis, which reaches the septal nuclei (S) and hypothalamus (Hy); (2) the ventral amygdalofugal pathway (see Fig. 23-20B and C) to the hypothalamus (Hy), thalamus (T; mainly the dorsomedial nucleus), widespread areas of ventromedial prefrontal and insular cortex, ventral striatum (VS), olfactory structures, and various brainstem sites (B); and (3) direct projections to the hippocampus (HC) and temporal and other neocortical areas. Only visual cortical areas are shown, although there are similar projections to most or all primary and unimodal sensory areas. (Modified from Warwick R, Williams PL: Gray's anatomy, Br ed 35, Philadelphia, 1973, WB Saunders.) Neuronal Outputs from the Amygadala 1/27/2010

8. CHEM E-1208 Cells in the CNS Diverse cell types organized into assemblies and patterns such that specialized components are integrated into the physiology of the whole organ. Neurons - most polymorphic cell in the human body (relay information) 6 - 80 µm in diameter Axons - emerge from one pole of the cell body (white matter, lipid myelin sheath) send information Dendrites - emerge from the opposite pole of the cell receive information neurons interact via a synapse Neuroglia (metabolic and structural support) 3 main types Contain no synaptic junction Main cells of blood-brain-barrier 10 - 50 times more glia the neuron cells 1/27/2010

9. CHEM E-1209 Figure 1-4 Examples of multipolar (A to E), bipolar (F), and unipolar (G) neurons, all drawn to about the same scale to demonstrate the range of neuronal sizes and shapes. All were stained by the Golgi method; dendrites are indicated by green arrows, axons by blue arrows. A, Purkinje cell from the cerebellar cortex. B, Granule cell from the cerebellar cortex. C, Projection neuron from the inferior olivary nucleus. D, Spinal cord motor neuron. E, Large pyramidal neuron from the cerebral cortex. F, Olfactory receptor neurons. G, Dorsal root ganglion cells (whose processes have axonal properties along almost their entire course). The tiny inset at the upper right shows the actual size of the pyramidal neuron. (Modified from Ramón y Cajal S: Histologie du système nerveux de l'homme et des vertébrés, Paris, 1909, 1911, Maloine.) Neuron Size and Shape 1/27/2010

10. CHEM E-12010 Synapse Gap between two neurons (axon-dendrite) across which neurotransmitters diffuse. Excitory synapse Inhibitory synapse Modulatory synapse 20 - 40 nm gap - (electrical synapse 3.5 nm) Presynaptic nerve terminal postsynaptic nerve terminal Presynaptic and Postsynaptic nerve terminals contain cell surface proteins which interact with neurotransmitters and ions. Presynaptic neuron transmitts the signal Postsynaptic neuron receives a signal Most drugs elicit a response via interactions at the synapse 1/27/2010

11. CHEM E-12011 Figure 1-3 Schematic view of a typical neuron, indicating synaptic inputs to its dendrites (although other sites are possible) and information flow down its axon, reaching synaptic endings on other neurons. Information flow is unidirectional due to molecular specializations of various parts of neurons. The pink segments covering the axon represent the myelin sheath that coats many axons, and the gap in the axon represents a missing extent that might be as long as a meter in the longest axons. Neuron Cell Body Axon contains proteins called kinesin and dynenin (molecular motors) that transport organelles, mRNA and signaling molecules from the cell body to axonal terminus Node of Ranvier Presynaptic terminal Postsynaptic dendrite 1/27/2010

12. CHEM E-12012 FIGURE 1-9 A dendrite ( D ) is flanked by two axon terminals packed with clear, spherical synaptic vesicles. Details of the synaptic region are clearly shown. ×75,000. (Basic Neurochemistry) 1/27/2010

13. CHEM E-12013 Action Potential An electrical signal (velocity of 1-100 m/sec) produced in a neuron by a change in ion concentrations. Action potentials are the signals by which the brain receives, analyzes, and conveys information. Though the action potential is electrical in nature, the signal is relayed via neurotransmitters across the synapse. At equilibrium, the cell membrane of the neuron has an overall negative charge relative to the exterior of the cell due to K + ions leaking out of the cell. resting membrane potential - -40 to -90 mV (~ -65 mV) IonExtracelluar concentration (mM)Intracellular concentration (mM) Na + 140 15 K + 4130 Ca 2+ 2.51-2 (sequestered) Cl - 1205 See Kandel Chapter 2 1/27/2010

14. CHEM E-12014 Action Potential 1/27/2010 A stimulatory signal (e.g. neurotransmitter (1), voltage change) results in opening of Na + channels. Neuron becomes more (+) - depolarization, at a certain potential (threshold) the cell will “fire an action potential” down the axon. When the potential reaches the axon terminus - neurotramsmitter release. Increase in membrane potential (hyperpolarization) - inhibitory response

15. CHEM E-12015 Blood-Brain Barrier (BBB) A physical barrier that controls the movement of chemicals f rom extracellular fluid in the body (blood) into the extracellular fluid of the brain. In the brain the endothelial cells in blood capillaries form a very tight junction that prevents many chemicals from passive diffusion across the capillary cell membrane into the brain. Lipid-soluble substances can often diffuse across BBB Active transporters exist in the capillary cell membrane glucose amino acids hormones Efflux transporters P-glycoprotein (P-gp) MRP Organic anion transporters (OAT3) Transporters can be on blood side or CNS side of membranes. 1/27/2010

16. CHEM E-12016 Figure 6-27 Barrier systems in and around the brain. Substances can leave extracerebral capillaries but are then blocked by the arachnoid barrier. They can also leave choroidal capillaries but are then blocked by the choroid epithelium. They cannot leave any other capillaries that are inside the arachnoid barrier (except for those in the circumventricular organs). The ventricular and subarachnoid spaces are in free communication with each other, and both communicate with the extracellular spaces of the brain. Brain Barrier Systems 3 distinct membrane (meninges) layers surround the brain. The meninges are connected to the skull. The brain is mechanically suspended within the meninges. 1/27/2010

17. CHEM E-12017 Figure 6-28 CNS capillaries with and without barrier properties. A, Capillary in a hypothalamic nucleus (supraoptic nucleus) of a rat. The continuous endothelial wall and the lack of pinocytotic vesicles are apparent; tight junctions are also present between endothelial cells but cannot be seen at this magnification. B, Capillary in the subfornical organ, which is a circumventricular organ near the roof of the third ventricle adjacent to the interventricular foramen. The walls of this capillary are quite permeable and are characterized by fenestrations (f), pinocytotic vesicles (v), and substantial spaces (s) around the capillary. (From Gross PM: Brain Res Bull 15:65, 1985.) BBB in Capillary Cell 1/27/2010

18. CHEM E-12018 BBB in Capillary Cell Cerebral endothelial cells are unique in that they form complex tight junctions (TJ) produced by the interaction of several transmembrane proteins that effectively seal the paracellular pathway. These complex molecular junctions make the brain practically inaccessible for polar molecules, unless they are transferred by transport pathways of the BBB that regulate the microenvironment of the brain. There are also adherens junctions (AJ), which stabilize cell–cell interactions in the junctional zone. In addition, the presence of intracellular and extracellular enzymes such as monoamine oxidase (MAO), γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase, peptidases, nucleotidases and several cytochrome P450 enzymes endow this dynamic interface with metabolic activity. Large molecules such as antibodies, lipoproteins, proteins and peptides can also be transferred to the central compartment by receptor-mediated transcytosis or non- specific adsorptive-mediated transcytosis. The receptors for insulin, low-density lipoprotein (LDL), iron transferrin (Tf) and leptin are all involved in transcytosis. P-gp, P-glycoprotein; MRP, multidrug resistance associated protein family. Nature Reviews Drug Discovery 2007, 6, 650 1/27/2010

19. CHEM E-12019 Neurotransmitters Chemicals that are synthesized in a neuron and stored in synaptic vesicles. Released upon stimulation of the neuron and interact with another neuron through the synapse Function is to transmit and regulate information Act upon receptors – Dopamine binds to a dopamine receptor Not uniformly distributed throughout CNS A neuron can contain several neurotransmitters and receptors Regulated by feedback mechanisms Release from synaptic vesicles is activated by Ca 2+ 1/27/2010

20. CHEM E-12020 Neurotransmitters - Criteria 1.The chemical must be found in the presynaptic neuron and must be released when the neuron is stimulated. 2. The chemical must be inactivated after it is released. reuptake degradation 3. If the chemical is applied exogenously at the postsynaptic membrane, the effect will be the same as when the presynaptic neuron is stimulated. 4. The chemical applied to the synapse must be affected in a manner similar to that of the naturally occurring chemical 1/27/2010

21. CHEM E-12021 Neurotransmitters - Classification Cholinegeric SystemAcetylcholine (Ach) Monoamine SystemDopamine (D) Norepinephrine (NE) Epinephrine (E) Serotonin (HT) Amino Acids  - aminobutyric acid (GABA) inhibitory Glutamate (Glu) excitory Gylcine (Gly) Aspartate (Asp) NeuropeptidesEnkephalins Endophins Substance P 1/27/2010

22. CHEM E-12022 Neurotransmitters - Acetylcholine The neurotransmitter in the cholinergic system Binds to two receptors: Muscarinic acetylcholine receptor (M) G-protein coupled receptor Nicotinic acetylcholine receptor (nAChR) ligand-gated Na + ion channel Foye: Chapter 12 1/27/2010

23. CHEM E-12023 Neurotransmitters – Cholinergic System 1/27/2010

24. CHEM E-12024 Neurotransmitters - Muscarinic Ach receptors M1M1 G q/11, increases phospholipase C activity ↑ Cognitive function ↑Seizure activity ↑Secretions ↑ Autonomic ganglia depolarization ↓ DA release and locomotion M3M3 G q/11 ↑ Food intake, body fat deposits Inhibits dopamine release Synthesis of nitric oxide M5M5 G q/11 Facilitates dopamine release Augments drug seeking behavior and reward M2M2 G i /G o decreases adenylyl cyclase activity and increases K + currents, decreases Ca 2+ currents Neural inhibition in CNS ↑ Tremors hypothermia & analgesia M4M4 G i /G o nhibition of autoreceptor- and heteroreceptor-mediated transmitter release in CNS Analgesia Cataleptic activity; Facilitates dopamine release Foye p 365 1/27/2010

25. CHEM E-12025 Neurotransmitters - Nicotinic ACh receptors CNS - 5 transmembrane proteins that are composed of  and/or  subunits. Each subunit contains 4 segments. Related in structure and sequence to GABA, glycine, 5HT 3 receptors  2-10 subunit that binds acetylcholine  2-4  4  2 subunit predominates in the CNS (  4 ) 2 (  4 ) 3 agonist inc Na + and K + permeability (  7 ) 5 agonist inc Ca 2+ permeability Function at presynaptic locations to regulate release of Glu, D, HT, Ach, and neuropeptides 1/27/2010

26. CHEM E-12026 Monoamine System Monoamine unbalance often plays a major role in the etiology of psychiatric disorders. 1/27/2010

27. CHEM E-12027 Neurotransmitters - Dopamine Phenotype effects in knockout mice D 1 reduced agonist response, hyperlocomotion D 2 Parkinsonian-like motor impairment D 3 Hyperactivity D 4 reduced locomotion, hypersensitivity to ethanol and stimulants D 5 reduced agonist induced locomotion, startle, and prepulse inhibition 1/27/2010 2 families of dopamine binding receptors D 1 -like(increase cAMP)D 2 -like decrease cAMP, open K + channels, close Ca 2+ channels D 1, D 5 D 2, D 3, D 4

28. CHEM E-12028 Neurotransmitters - Dopamine 1/27/2010

29. CHEM E-12029 Neurotransmitters - Norepinephrine/ Epinephrine Bind to GPCR adrenergic receptors. Role in CNS not clearly understood. 1/27/2010 beta-blockers for treatment hypertension

30. CHEM E-12030 Neurotransmitters - Norepinephrine 1/27/2010

31. CHEM E-12031 Neurotransmitters - Serotonin Binds to the serotonin receptor and transporter Important in depression, anxiety, and schizophrenia 3 main families 5-HT 1 - GPCR, 5 subtypes have 40-60% sequence homology, inhibit adenylyl cyclase 5-HT 2 - GPCR, 3 subtypes have 45-50% sequence homology, stimulate phospholipase C 5-HT 3 - ligand-gated ion channel, 6 subtypes, stimulate adenylyl cyclase Indole ethylamine 1/27/2010

32. CHEM E-12032 Neurotransmitters - Serotonin 1/27/2010

33. CHEM E-12033 Monoamine Transporters Very important mechanism to reduce the concentration of the neurotransmitter in the synapse by reuptake into the presynaptic terminus. DAT - dopamine transporter localized on dopamine neuron NET - norepinephrine transporter localized on adrenergic neurons VMAT-2 - vesicular membrane transporter - concentrates catecholamines in vesicules in the presynaptic neuron NETDATVMAT-2 MechanismNaCl-dependent H + -dependent Amino acids617620742 Chromosome16510 1/27/2010

34. CHEM E-12034 Neurotransmitters - GABA Major inhibitory neurotransmitter - mM concentrations GABA A - ligand-gated Cl - ion channel GABA B - GPCR with structural similarity to glutamate receptors found on terminals of neurons that use other transmitters (norepinephrine, dopamine, serotonin) Presynaptic activation of GABA B decreases release of other transmitters GABA B receptors exist as heterodimers 1/27/2010

35. CHEM E-12035 GABA A Receptor  and  subunits determine pharmacological specificity at the GABA and BZ sites while the  subunits are necessary for BZ binding 1/27/2010

36. CHEM E-12036 Neurotransmitters - GABA High_Yield NeuroAnatomy p155 1/27/2010

37. CHEM E-12037 Neurotransmitters - Glutamate Major excitory neurotransmitter in the brain. Excites ~ 90% of all neuron ~ 80-90% of all synapses are glutamatergic. Concentrations range from 4-15  mol/g tissue Glutamate receptors: 1. Ionotropic - ligand-gated ion channels that are opened upon binding of glutamate 3 classes: NMDA (EC 50 = 1  mol/l), AMPA (EC 50 = 400  mol/l), KA 2. Metabotropic GPCR 8 classes: mGluR1 - mGluR8 1/27/2010

38. CHEM E-12038 Neurotransmitters - Glutamate High_Yield NeuroAnatomy p156 1/27/2010

39. CHEM E-12039 G-protein Coupled Receptor – GPCR Membrane bound receptor bound to a G-protein that is in the cytoplasm 7 transmembrane domains Receptor3 extracellular domains 3 intracellular domains three distinct subunits , ,  G-proteinbind to GTP and GDP G s - stimulation of adenyl cyclase G i - inhibition of adenyl cyclase ~ 60% of drugs act on GPCR’s 1/27/2010 Cell Surface Proteins

40. CHEM E-12040 G-protein Coupled Receptor - GPCR 1/27/2010

41. CHEM E-12041 Neurotransmitters - Muscarinic Ach receptors Siegal Basic Neurochemistry FIGURE 11-11 Predicted amino acid sequence and transmembrane domain structure of the human M 1 muscarinic receptor. Amino acids that are identical among the m 1, m 2, m 3 and m 4 receptors are dark orange. The shaded cloud represents the approximate region that determines receptor G-protein coupling. Arrows denote amino acids important for specifying G protein coupling. Amino acids predicted to be involved in agonist or antagonist binding are denoted by white letters [50]. 1/27/2010

42. CHEM E-12042 Cell Surface Proteins - Transporter SERT has ~ 50% homology with DAT/NET SERT located on serotonergic neurons 1/27/2010

43. CHEM E-12043 Receptors vs transporters 1/27/2010

44. CHEM E-12044 Cell Surface Proteins – Ion channels When ACh or agonists bind to nicotinic ACh receptors the channel open to a diameter of 6.5Å. Selective for Na + and K + 1/27/2010 ligand-gated ion channels voltage-gated ion channels

45. 1/27/2010CHEM E-12045 GABA A Receptor – Ligand Gated Ion Channel Possible sites of binding of alcohol α1β2γ2 α4β1δ α4β3δ α6β3δ activity β3 > β2 δ KO mice drink less alcohol

46. CHEM E-12046 FIGURE 10-1 Depolarization opens voltage-sensitive Ca 2+ channels in the presynaptic nerve terminal ( 1 ). The influx of Ca 2+ and the resulting high Ca 2+ concentrations at active zones on the plasmalemma trigger ( 2 ) the exocytosis of small synaptic vesicles that store neurotransmitter (NT) involved in fast neurotransmission. Released neurotransmitter interacts with receptors in the postsynaptic membrane that either couple directly with ion channels ( 3 ) or act through second messengers, such as ( 4 ) G- protein-coupled receptors. Neurotransmitter receptors, also in the presynaptic nerve terminal membrane ( 5 ), either inhibit or enhance exocytosis upon subsequent depolarization. Released neurotransmitter is inactivated by reuptake into the nerve terminal by ( 6 ) a transport protein coupled to the Na + gradient, for example, dopamine, norepinephrine, glutamate and GABA; by ( 7 ) degradation (acetylcholine, peptides); or by ( 8 ) uptake and metabolism by glial cells (glutamate). The synaptic vesicle membrane is recycled by ( 9 ) clathrin-mediated endocytosis. Neuropeptides and proteins are stored in ( 10 ) larger, dense core granules within the nerve terminal These dense core granules are released from ( 11 ) sites distinct from active zones after repetitive stimulation. 1/27/2010