Download presentation
Presentation is loading. Please wait.
1
Introduction to CNS pharmacology
By S.Bohlooli, PhD School of Medicine, Ardabil University of Medical Sciences
2
Ion channels & neurotransmitter receptors
Voltage gated channels Ligand gated channels Ionotropic receptors Metabotropic receptors Membrane delimited Diffusible second messenger
3
Figure Types of ion channels and neurotransmitter receptors in the CNS. A shows a voltage-gated channel in which a voltage sensor component of the protein controls the gating (broken arrow) of the channel. B shows a ligand-gated channel in which the binding of the neurotransmitter to the ionotropic channel receptor controls the gating (broken arrow) of the channel. C shows a G protein-coupled (metabotropic) receptor, which when bound, activates a G protein that then interacts directly with an ion channel. D shows a G protein-coupled receptor, which when bound, activates a G protein that then activates an enzyme. The activated enzyme generates a diffusible second messenger, eg, cAMP, which interacts with an ion channel.
4
Nicotinic acetylcholine receptor
Figure The adult nicotinic acetylcholine receptor (nAChR) is an intrinsic membrane protein with five distinct subunits (a2bdg) A: Cartoon of the one of five subunits of the AChR in the end plate surface of adult mammalian muscle. Each subunit contains four helical domains labeled M1 to M4. The M2 domains line the channel pore. B: Cartoon of the full AChR. The N termini of two subunits cooperate to form two distinct binding pockets for acetylcholine (ACh). These pockets occur at the a-b and the d-a subunit interfaces.
5
The synapse & synaptic potentials
Excitatory Excitatory post-synaptic potential (EPSP) Ionotropic receptor Inhibitory Inhibitory post-synaptic potential (IPSP) Presynaptic inhibition
6
(+/-) Show / Hide Bibliography
Table Some toxins used to characterize ion channels. Channel Types Mode of Toxin Action Source Voltage-gated Sodium channels Tetrodotoxin (TTX) Blocks channel from outside Puffer fish Batrachotoxin (BTX) Slows inactivation, shifts activation Colombian frog Potassium channels Apamin Blocks "small Ca-activated" K channel Honeybee Charybdotoxin Blocks "big Ca-activated" K channel Scorpion Calcium channels Omega conotoxin (w-CTX-GVIA) Blocks N-type channel Pacific cone snail Agatoxin (w-AGA-IVA) Blocks P-type channel Funnel web spider Ligand-gated Nicotinic ACh receptor a-Bungarotoxin Irreversible antagonist Marine snake GABAA receptor Picrotoxin Blocks channel South Pacific plant Glycine receptor Strychnine Competitive antagonist Indian plant AMPA receptor Philanthotoxin Wasp Copyright © 2007 by The McGraw-Hill Companies, Inc. All rights reserved. (+/-) Show / Hide Bibliography Send Feedback Customer Service Title Updates User Responsibilities Training Center What's New Teton Server (4.5.0) - ©2006 Teton Data Systems Send Us Your Comments
7
Figure 21-2. Excitatory synaptic potentials and spike generation
Figure Excitatory synaptic potentials and spike generation. The figure shows entry of a microelectrode into a postsynaptic cell and subsequent recording of a resting membrane potential of -70 mV. Stimulation of an excitatory pathway (E) generates transient depolarization. Increasing the stimulus strength (second E) increases the size of the depolarization, so that the threshold for spike generation is reached.
8
Figure 21-3. Interaction of excitatory and inhibitory synapses
Figure Interaction of excitatory and inhibitory synapses. On the left, a suprathreshold stimulus is given to an excitatory pathway (E) and an action potential is evoked. On the right, this same stimulus is given shortly after activating an inhibitory pathway (I), which results in an inhibitory postsynaptic potential (IPSP) that prevents the excitatory potential from reaching threshold.
9
Site of drug action Figure Sites of drug action. Schematic drawing of steps at which drugs can alter synaptic transmission. (1) Action potential in presynaptic fiber; (2) synthesis of transmitter; (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
Identification of central neurotransmitters
More difficult for CNS Anatomic complexity Limitation of available techniques
11
Criteria for neurotransmitter identification
Localization Microcytochemical immonocytochemical Release Simulation of Brain slices Calcium dependency of release Synaptic mimicry Microiontophoresis Physiological view Pharmacological view
12
Cellular organization of the brain
Hierarchical systems Sensory perception, motor control Phasic information, delineated pathways Two types of neurons Projection or relay Local circuit neurons Limited number of transmitters Nonspecific or diffuse neuronal systems Affecting global function of CNS Small number of neurons, projections to wide area of CNS
13
Figure 21-5. Pathways in the central nervous system
Figure Pathways in the central nervous system. A shows parts of three relay neurons (color) and two types of inhibitory pathways, recurrent and feed-forward. The inhibitory neurons are shown in gray. B shows the pathway responsible for presynaptic inhibition in which the axon of an inhibitory neuron (gray) synapses on the axon terminal of an excitatory fiber (color).
14
Central neurotransmitters
Amino acids Neutral amino acids Acidic amino acids Acetylcholine Monoamines Dopamine Norepinephrine 5-hydroxytryptamine Peptides Nitric oxide endocananbiniods
15
Receptor Subtypes and Preferred Agonists
Table Summary of neurotransmitter pharmacology in the central nervous system. (Many other central transmitters have been identified [see text].) Transmitter Anatomy Receptor Subtypes and Preferred Agonists Receptor Antagonists Mechanisms Acetylcholine Cell bodies at all levels; long and short connections Muscarinic (M1): muscarine Pirenzepine, atropine Excitatory: ¯ in K+ conductance; ↑ IP3, DAG Muscarinic (M2): muscarine, bethanechol Atropine, methoctramine Inhibitory: ↑ K+ conductance; ¯ cAMP Motoneuron-Renshaw cell synapse Nicotinic: nicotine Dihydro-b-erythroidine, a-bungarotoxin Excitatory: ↑ cation conductance
16
Transmitter Anatomy Receptor Subtypes and Preferred Agonists Receptor Antagonists Mechanisms Dopamine Cell bodies at all levels; short, medium, and long connections D1 Phenothiazines Inhibitory (?): cAMP D2: bromocriptine Phenothiazines, butyrophenones Inhibitory (presynaptic): Ca2+; Inhibitory (postsynaptic): in K+ conductance, cAMP GABA Supraspinal and spinal interneurons involved in pre- and postsynaptic inhibition GABAA: muscimol Bicuculline, picrotoxin Inhibitory: Cl–conductance GABAB: baclofen 2-OH saclofen Inhibitory (presynaptic): Ca2+ conductance; Inhibitory (postsynaptic): K+ conductance
17
Transmitter Anatomy Receptor Subtypes and Preferred Agonists Receptor Antagonists Mechanisms Glutamate Relay neurons at all levels and some interneurons N-Methyl-D-aspartate (NMDA): NMDA 2-Amino-5-phosphonovalerate, dizocilpine Excitatory: cation conductance, particularly Ca2+ AMPA: AMPA CNQX Excitatory: cation conductance Kainate: kainic acid, domoic acid Metabotropic: ACPD, quisqualate MCPG Inhibitory (presynaptic): Ca2+ conductance cAMP; Excitatory: K+ conductance, IP3, DAG Glycine Spinal interneurons and some brain stem interneurons Taurine, -alanine Strychnine Inhibitory: Cl–conductance
18
Transmitter Anatomy Receptor Subtypes and Preferred Agonists Receptor Antagonists Mechanisms 5-Hydroxytryptamine (serotonin) Cell bodies in midbrain and pons project to all levels 5-HT1A: LSD Metergoline, spiperone Inhibitory: K+ conductance, cAMP 5-HT2A: LSD Ketanserin Excitatory: K+ conductance, IP3, DAG 5-HT3: 2-methyl-5-HT Ondansetron Excitatory: cation conductance 5-HT4 Excitatory: K+ conductance
19
Transmitter Anatomy Receptor Subtypes and Preferred Agonists Receptor Antagonists Mechanisms Norepinephrine Cell bodies in pons and brain stem project to all levels 1: phenylephrine Prazosin Excitatory: K+ conductance, IP3, DAG 2: clonidine Yohimbine Inhibitory (presynaptic): Ca2+ conductance; Inhibitory: K+ conductance, cAMP 1: isoproterenol, dobutamine Atenolol, practolol Excitatory: K+ conductance, cAMP 2: albuterol Butoxamine Inhibitory: may involve in electrogenic sodium pump; cAMP
20
Transmitter Anatomy Receptor Subtypes and Preferred Agonists Receptor Antagonists Mechanisms Histamine Cells in ventral posterior hypothalamus H1: 2(m-fluorophenyl)-histamine Mepyramine Excitatory: K+ conductance, IP3, DAG H2: dimaprit Ranitidine Excitatory: K+ conductance, cAMP H3: R--methyl-histamine Thioperamide Inhibitory autoreceptors
21
Transmitter Anatomy Receptor Subtypes and Preferred Agonists Receptor Antagonists Mechanisms Opioid peptides Cell bodies at all levels; long and short connections Mu: bendorphin Naloxone Inhibitory (presynaptic): Ca2+ conductance, cAMP Delta: enkephalin Inhibitory (postsynaptic): K+ conductance, cAMP Kappa: dynorphin Tachykinins Primary sensory neurons, cell bodies at all levels; long and short connections NK1: Substance P methylester, aprepitant Aprepitant Excitatory: K+ conductance, IP3, DAG NK2 NK3 Endocannabinoids Widely distributed CB1: Anandamide, 2-arachidonyglycerol Rimonabant
22
Schematic diagram of a glutamate synapse
Schematic diagram of a glutamate synapse. Glutamine is imported into the glutamatergic neuron (A) and converted into glutamate by glutaminase. The glutamate is then concentrated in vesicles by the vesicular glutamate transporter. Upon release into the synapse, glutamate can interact with AMPA and NMDA ionotropic receptor channels (AMPAR, NMDAR) in the postsynaptic density (PSD) and with metabotropic receptors (MGluR) on the postsynaptic cell (B). Synaptic transmission is terminated by active transport of the glutamate into a neighboring glial cell (C) by a glutamate transporter. It is synthesized into glutamine by glutamine synthetase and exported into the glutamatergic axon. (D) shows a model NMDA receptor channel complex consisting of a tetrameric protein that becomes permeable to Na+ and Ca2+ when it binds a glutamate molecule.
Similar presentations
