Introduction to Central Nervous System Pharmacology Abraham Daniel C. Cruz, MD Instructor A, Department of Pharmacology By the end of the lecture, the student should be able to: 1. Have a brief review basic neurophysiology 2. Describe neuroanatomical characteristics that affect neuropharmacology 3. Characterize common central neurotransmitters and their actions Ion Channels Voltage gated ion channels Na+ channels concentrated on the initial segment of the axon o fast action potentials o signal from cell body to nerve terminal o + Ca , K + channels on cell body, initial segment of dendrites o slower time scale o modulate rate of neuron discharge o Chemically activated channels (ligand-gated) Opened by action of neurotransmitters/other chemical agents Channel is an integral part of the receptor complex 2 types Directly coupled (no 2 nd messenger system)/ionotropic o G protein-coupled/metabotropic o Insensitive or weakly sensitive to membrane potential Concentrated on sub-synaptic membranes General Concept Activation of chloride or potassium ion channels c hannels commonly generates INHIBITORY postsynaptic potentials Activation of sodium and calcium channels AND inhibition of potassium channels generate EXCITATORY postsynaptic potentials Targets for Drug Action Ion Channels Receptors Channel-linked receptors o G-protein coupled receptors o Kinase-linked receptors o Receptors linked to gene transcription o Enzymes (NT synthesis, metabolism) Transport Proteins
Blood Brain Barrier Concentration of an agent in the blood differs from the brain dif fusion of substances from the A permeability barrier to the passive diffusion bloodstream into various regions of the CNS Retard the movement of substances from brain to blood as well as from blood to brain Brain clears metabolites of transmitters into the cerebrospinal fluid fl uid by excretion through the acid transport system of the choroid plexus Brain capillaries: Tight junctions between capillary endothelial cells (inhibits o paracellular transport) Few pinocytic vesicles o Foot processes of astrocytes encasing capillaries o Exceptionally high number of mitochondria o Less prominent in the hypothalamus and in several small, specialized organs lining the third and fourth ventricles of the brain: (signal reception or secretion of substances directly into bloodstream) Pituitary gland o Median eminence o Area postrema o Preoptic recess o Paraphysis o Pineal gland o Subfornical organ o Subcommissural organ o Endothelium of choroid plexus o Cerebral ischemia, inflammation modify the BBB Little evidence of a barrier between the circulation a nd the peripheral nervous system Small molecules enter the CNS more rapidly than large molecules. Larger proteins do not enter the CNS at all Ordinarily, substances bound to serum protein cannot penetrate the CNS Substances that are highly soluble in lipid enter (and leave) the CNS more readily than those that are poorly soluble in lipid Carrier mediated (facilitated diffusion) mechanisms transport some substances, such as glucose (GLUT -1) and essential amino acids, into the brain. These transport systems can affect both entry and exit of substances. Bypassing the Blood-Brain Barrier with Drugs into the CSF Deliver drug directly into meningitis or cancerous cells in the CSF o Vasoactive compounds such as bradykinin and histamine o
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do not alter BBB in normal people can enhance permeability of BBB in pathological conditions for delivery of chemotherapeutic agents into the brain Synthesize drugs with high BBB permeability to improve entry into the brain (increase lipid solubility)
Chemical Mediators and the CNS FAST neurotransmitters Operate through directly-linked ligand-gated ion channels o (glutamate, GABA) SLOW neurotransmitters and neuromodulators Operate mainly through G-protein-coupled receptors (dopamine, o neuropeptides) Some agents may act through both ligand-gated channels and Gprotein-coupled receptors (glutamate, 5-HT, acetylcholine) Neuromodulators Nitric oxide, arachidonic acid may be produced by non-neuronal o cells Identification of Central Neurotransmitters Localization (transmitter must be shown to be present in the presynaptic terminals of the synapse and in the neurons from which those presynaptic terminals arise) Release (transmitter must be released from the presynaptic nerve concomitantly with presynaptic nerve activity) Synaptic Mimicry (When applied experimentally to the target cells, the effects of the putative transmitter must be identical to the effects of stimulating the presynaptic pathway) *difficult to do in the CNS due to its anatomic complexity and o available techniques Cellular Organization of the Brain Hierarchical Systems Systems involved in sensory perception & motor control o Clearly delimited in their anatomic distribution o o Composed of large myelinated fibers o Major excitatory transmitters are aspartate and glutamate Numerous inhibitory interneurons, GABA, glycine o Drugs that affect hierarchical systems often have profound o effects on excitability of the CNS Ex. CNS stimulants, sedative-hypnotics, anti-seizure drugs o
Diffuse Systems Broadly distributed o
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Single cells frequently send processes to many different areas Axons are fine and branch repeatedly Transmitter is released from many sites along the path of the axon (varicosities) Norepinephrine, dopamine, serotonin or peptides Marked effects on attention, appetite, emotional states Ex. Antidepressants, mood stabilizers, antipsychotics
Actions of Drugs in the CNS Specificity & Nonspecificity of CNS Drug Actions Specific - affects an identifiable molecular mechanism unique to o target cells that bear receptors for that drug Non-specific - produces effects on many different target cells and o acts by diverse molecular mechanisms A property of the dose-response relationship of the drug and the o cell or mechanisms under scrutiny. A drug that is highly specific when tested at a low concentration o may exhibit nonspecific actions at substantially higher doses. Generally acting drugs may not act equally on all levels of the o CNS (sedatives, hypnotics, and general anesthetics) Drugs with specific actions may produce nonspecific effects if the o dose and route of administration produce high tissue concentrations.
General (Nonspecific) CNS Depressants Anesthetic gases, the aliphatic alcohols, and some hypnotico sedative drugs Agents share the ability to depress excitable tissue at all levels o of the CNS, leading to a decrease in the amount of transmitter released by the nerve impulse, as well as to general depression of postsynaptic responsiveness and ion movement o At sub-anesthetic concentrations, these agents (e.g., ethanol) etha nol) can exert relatively specific effects on certain groups of neurons, which may account for differences in their behavioral effects, especially the propensity to produce dependence
General (Nonspecific) CNS Stimulants Stimulation may be accomplished by one of two general o mechanisms: blockade of inhibition OR direct neuronal excitation increased transmitter release more prolonged transmitter action labilization of the postsynaptic membrane
decreased synaptic recovery time Pentylenetetrazol are related agents that are capable of powerful excitation of the CNS; methylxanthines have a much weaker stimulant action
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Drugs That Selectively Modify CNS Function Anticonvulsants, antiparkinsonism drugs, opioid and nonopioid analgesics, appetite suppressants, antiemetics, analgesic-antipyretics, certain stimulants, neuroleptics (antidepressants and anti-manic and antipsychotic agents), tranquilizers, sedatives, and hypnotics. May cause either depression or excitation A drug may produce both effects simultaneously on different systems Some agents in this category have little effect on the level of excitability in doses that are used therapeutically. Central Neurotransmitters Amino Acids neutral o Glycine GABA acidic o Glutamate Aspartate Acetylcholine Monoamines Dopamine o Norepinephrine o 5-hydroxytryptamine o Peptides Nitric Oxide Glycine Inhibitory Increase membrane permeability to chloride ions (mimicking IPSP) Concentrations high in gray matter of the spinal cord Released from spinal cord inhibitory local circuit neurons involved in postsynaptic inhibition Facilitates excitatory responses mediated by NMDA – N – Methyl – D – Aspartate (channel opening requires glycine and glutamate) Binds to multimeric ligand-gated chloride channel Receptor resembles the GABA A –receptor No therapeutic drugs which act by modifying glycinergic transmission Strychnine, a spinal cord convulsant, selectively antagonizes both glycine and IPSPs in the spinal cord
Tetanus toxin acts selectively to prevent glycine release from inhibitory interneurons of the spinal cord
GABA (Gamma-aminobutyric acid) Mediates both fast and slow IPSPs Main inhibitory transmitter in the brain (30% of all synapses) Formed from glutamate by glutamic acid decarboxylase Destruction catalysed by GABA-transaminase (inhibited by vigabatrine) GABAA receptor Open chloride channels Antagonists block fast IPSPs Antagonized by picrotoxin and bicuculline, which are generalized convulsants GABAB receptor Couple to G proteins that either inhibit Ca ++ (presynaptic) or activate K+ (postsynaptic - EFFLUX) channels Antagonists block slow IPSP Selectively activated by baclofen GHB – Gamma-hydroxybutyric acid agonist at the newly-characterized GHB receptor excitatory weak agonist at the GABA B receptor inhibitory naturally-occurring substance that acts in a similar fashion to some neurotransmitters in the mammalian brain probably synthesized from GABA in GABAergic neurons, and released when the neurons fire Medical use (1960’s) – anesthetic, – anesthetic, hypnotic, antidepressant Non-medical use CNS depressant – intoxicant, date rape drug, party drug o (Georgia Home Boy, Liquid Ecstasy, Liquid X, and Liquid G, Fantasy) Glutamate Very high concentrations in the CNS Produced from glucose via Krebs cycle, glutamine synthesized by glial cells enz ymes Metabolic and neurotransmitter pools linked by transaminase enzymes that catalyse the interconversion of glutamate and a-oxoglutarate a -oxoglutarate Excitation caused by activation of ionotropic (ligand gated ion channel) or metabotropic (G protein-coupled) receptors Ionotropic receptors NMDA receptors (Na+, K+, Ca+) o
non-NMDA receptors AMPA (Na+, K+) KA (Na+, K+) NMDA receptors play critical role in synaptic plasticity (learning and memory) Release of glutamate during neuronal injury can further cell death by activating NMDA receptors Selective blockers of NMDA receptors Ketamine & Phencyclidine – tranquilizers; (+) behavioral o symptoms Memantine – introduced for treatment of Alzheimer’s disease o Felbamate – antiseizure agent o o
Acetylcholine First identified CNS transmitter Found in the neostriatum, medial septal nucleus and the reticular formation of the brain Role in cognitive functioning, especially memory Widely distributed in the brain Forebrain, midbrain, brainstem, little in the cerebellum o Anterior horns and roots of the spinal cord, motor nuclei of the o cranial nerves Muscarinic receptors that act presynaptically inhibit acetylcholine release from cholinergic neurons; muscarinic antagonists increase acetylcholine release Post-synaptic Ach receptors Most CNS responses to Ach are mediated by G -protein linked o muscarinic receptors rather than faster nicotinic receptors Mainly excitatory o Of the nicotinic receptors in the CNS (less common), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are best characterized Examples of drugs affecting cholinergic activity in the brain Acetylcholinesterase inhibitors (tacrine) – Alzheimer’s disease o Muscarinic blocking agents (benztropine) - parkinsonism o Catecholamines Dopamine Slow inhibitory effects action on CNS neurons Distribution is more restricted than noradrenaline Major pathways/projections Nigrostriatal pathway (motor control) o Mesolimbic / Mesocortical pathway (behavioral effects) o
Tuberohypophyseal system (endocrine control) Dopamine Receptors D1 Family – D1 D5 o D2 Family – D2 D3 D4 (pharmacologically more important in the o CNS) All belong to the family of G-protein-coupled transmembrane o receptors Signal transduction linked via adenylate cyclase and/or o phospholipid hydrolysis to control K + and Ca+ channels, arachidonic acid release Clinical conditions associated with dopamine Schizophrenia o High dopamine in mesolimbic Low dopamine in mesocortical o Parkinson’s Disease Degeneration of dopaminergic neurons Addiction o Reward pathway o
Norepinephrine Most neurons are in the locus ceruleus or lateral tegmental area of the reticular formation Hyperpolarize neurons by increasing K + conductance Enhance excitatory inputs by Indirect mechanisms (disinhibition of inhibitory local circuits) Direct mechanisms (by blocking K conductance that slow neuronal discharge) Facilitation of excitatory inputs responsible for behavioral processes (attention, arousal, etc.) ADHD Clinical effects Excitatory effects – α1 and β1 receptors o o Inhibitory effects – α2 and β2 o Blood Pressure Regulation Central and peripheral noradrenergic synapses Clonidine and Methyldopa decrease the discharge of sympathetic nerves – alpha 2 (autoreceptor) agonists Serotonin (5 – Hydroxytryptamine) Contained in unmyelinated fibers that innervate most regions of the CNS Distribution of neurons is similar to noradrenergic neurons Involved in hallucinations, regulatory functions (sleep, temperature, appetite and neuroendocrine control) 5-HT receptors - all are G-protein-coupled except for 5 -HT 3
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5-HT1A receptors Strong inhibitory action Increase K conductance resulting in membrane hyperpolarization Autoreceptors in the raphe nuclei Widely distributed in the cortex Main target of drugs used to treat anxiety and depression 5-HT2A receptors Excitatory post-synapatic effect, abundant in the cortex and hippocampus Target of various hallucinogenic drugs Use of antagonist for the treatment of migraine 5-HT3 receptors Found in the area postrema, parts of the brainstem, dorsal horn of the spinal cord Use: antagonists used in chemotherapy-induced emesis
