Cellular Neurotransmitters, Receptors and Pharmacology of Drugs.pptx
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Cellular Neurotransmitters, Receptors and Pharmacology of Drugs used to treat neurological disorders
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Cellular Neurotransmitters, Receptors and Pharmacology of Drugs.pptx
- 1. Cellular Neurotransmitters, Receptors and Pharmacology of Drugs used to treat neurological disorders Dr. RUTAYISIRE François Xavier PGY2 Basic Neurosciences module University of Rwanda Supervisor: Dr. MUNYEMANA Paulin
- 2. History • The nervous system has intrigued scientists and philosophers since ancient times. • Galen, thought that the brain pumped a vapor called psychic pneuma through hollow nerves and squirted it into the muscles to make them contract. • The French philosopher Rene´ Descartes still argued for this theory in the seventeenth century. • (1737–98) Luigi Galvani discovered the role of electricity in muscle contraction. • (1843–1926) Camillo Golgi developed an important method for staining neurons with silver.
- 3. • This enabled Santiago Ramo´n y Cajal (1852–1934), to trace the course of nerve fibers over long distances through serial tissue sections. He demonstrated that the nervous pathway was not a continuous “wire” or tube, but a series of cells separated by the gaps we now call synapses. • 1906 Golgi and Cajal, even though they intensely disliked each other, shared the Nobel Prize for Physiology or Medicine for these important discoveries. Cajal’s theory suggested another direction for research: • How do neurons communicate? Two key issues in neurophysiology are (1) How does a neuron generate an electrical signal? and (2) How does it transmit a meaningful message to the next cell? • In 1921, Otto Loewi conclusively demonstrated that neurons communicate by releasing chemicals.
- 4. Neurotransmitters • Language of the nervous system • More than 100 neurotransmitters have been identified since Loewi’s time. • Neurotransmitters can be defined as molecules that are synthesized by a neuron, released when a nerve signal reaches an axon terminal or varicosity of the nerve fiber, and have a specific effect on a receiving cell’s physiology.
- 6. 2. An action potential invades the presynaptic terminal. 3. Depolarization of presynaptic terminal causes opening of voltage-gated Ca2+ channels 4. Influx of Ca2+ through channels Ca2+ 5. Ca2+ causes vesicles to fuse with presynaptic membrane 6. Transmitter is released into synaptic cleft via exocytosis 7. Transmitter binds to receptor molecules in postsynaptic membrane. 8. Opening or closing of postsynaptic channels 9. Postsynaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the postsynaptic cell. 11. Retrieval of vesicular membrane from plasma membrane Glial Cell Transmitter molecules Across dendrites Transmitter molecules Postsynaptic current flow Transmitter receptor Ions Myelin
- 7. Neurotransmitter Receptors • Proteins that are embedded in the plasma membrane of postsynaptic cells and have an extracellular neurotransmitter binding site that detects the presence of neurotransmitters in the synaptic cleft. There are two broad families of receptor proteins 1. Ionotropic receptors 2. Metabotropic receptors
- 8. Ligand-gated ion channels G-protein-coupled receptors
- 10. Muscarinic and other metabotropic neurotransmitter receptors.
- 11. Receptor pharmacology Neuro transmitter Receptor Excitation or inhibition Neuro transmitter Receptor No effect Receptor Same action as native transmitter Neurotransmitter Binds to receptor and evokes excitation or inhibition Agonist Binds to receptor and evokes the same response as the native transmitter. Antagonist Binds to receptor and does not evoke any response. Prevents the native transmitter or any agonist from binding to the receptor
- 12. Consequences of Neurochemical Imbalance in the Brain Neurotransmitter Excess Low or Total Lack Acetylcholine Dopamine γ-Aminobutyric acid (GABA) Glutamate Norepinephrine Serotonin Delirium/confusion; Psychosis Psychoses CNS depression; Respiratory depression; Sedation Seizures; Neuronal degeneration Anxiety; Panic; Anorexia; Excitability; Insomnia Sleep; Hallucinations; ↓Appetite; Anxiety Alzheimer’s disease Parkinson’s disease; Depression; ADH/ADHD Seizures; Movement disorders Schizophrenia; Depression; Cognitive impairment Depression; ADH/ADHD Depression; Pain sensitivity; Anxiety; Obsessive compulsive disorder
- 14. References • Dale Purves book of neuroscience 6th edition • K.S. Saladin anatomy & physiology: the unity of form and function, 9th edition
Editor's Notes
- Synthesised in the neurones, close to the site of release Stored on the terminal until required for release Released into synaptic cleft in response to an action potential Binds to receptors in post-synaptic membrane Causes changes in membrane potential Excitatory receptors cause depolarisation Inhibitory receptors cause hyperpolarisation
- Acetylcholine is synthesized in nerve terminals from the precursors acetyl coenzyme A (acetyl CoA, which is synthesized from glucose) and choline, in a reaction catalyzed by choline acetyltransferase (ChAT. After synthesis in the cytoplasm of the neuron, a vesicular ACh transporter (VAChT) loads approximately 10,000 molecules of ACh into each cholinergic vesicle. terminated by reuptake but by a powerful hydrolytic enzyme, acetylcholinesterase (AChE). and rapidly hydrolyzes ACh into acetate and choline. Among the many interesting drugs that interact with cholinergic enzymes are the organophosphates. Organophosphates can be lethal because they inhibit AChE, allowing ACh to accumulate at cholinergic synapses. This buildup of ACh depolarizes the postsynaptic muscle cell and renders it refractory to subsequent ACh release, causing neuromuscular paralysis and other effects. The high sensitivity of insects to AChE inhibitors has made organophosphates popular insecticides. Glutamate is the most important transmitter for normal brain function. Nearly all excitatory neurons in the CNS are glutamatergic, and it is estimated that more than half of all brain synapses release this neurotransmitter. glutamine to glutaminase to Glutamate packaged into synaptic vesicles by vesicular glutamate transporters (VGLUTs). removed from the synaptic cleft by the excitatory amino acid transporters (EAATs). AMPA receptors, NMDA receptors, and kainate receptors are named after the agonists that activate them: AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate), NMDA (N-methyl-d-aspartate), and kainic acid. always produces excitatory postsynaptic responses. GABA and Glycine: Most inhibitory synapses in the brain and spinal cord use either γ-aminobutyric acid (GABA) or glycine as neurotransmitters. The enzyme glutamic acid decarboxylase (GAD), which is found almost exclusively in GABAergic neurons, catalyzes the conversion of glutamate to GABA. GAD requires a co-factor, pyridoxal phosphate, for activity. Because pyridoxal phosphate is derived from vitamin B6, a deficiency of this vitamin can lead to diminished GABA synthesis. Once GABA is synthesized, it is transported into synaptic vesicles via a vesicular inhibitory amino acid transporter (VIAAT). Benzodiazepines such as diazepam (Valium), hypnotic drus used to induce sleep. Barbiturates such as phenobarbital and pentobarbital are other hypnotics that also bind to the extracellular domains of the α and β subunits of some GABA receptors and potentiate GABAergic transmission; these drugs are used therapeutically for anesthesia and to control epilepsy. injection anesthetic ketamine also binds to the extracellular domain of GABA receptors. Another drug that binds to the transmembrane domain of GABA receptors is ethanol; at least some aspects of drunken behavior are caused by ethanol-mediated alterations in ionotropic GABA receptors. Serotonin, or 5-hydroxytryptamine (5-HT): Serotonin is found primarily in groups of neurons in the raphe region of the pons and upper brainstem, which have widespread projections to the forebrain. and regulate sleep and wakefulness. 5-HT occupies a place of prominence in neuropharmacology because a large number of antipsychotic drugs that are valuable in the treatment of depression and anxiety act on serotonergic pathways. 5-HT is synthesized from the amino acid tryptophan, which is an essential dietary requirement. Tryptophan is taken up into neurons by a plasma membrane transporter and hydroxylated in a reaction catalyzed by the enzyme tryptophan-5-hydroxylase. Loading of 5-HT into synaptic vesicles is done by the VMAT that is also responsible for loading other monoamines into synaptic vesicles. The synaptic effects of serotonin are terminated by transport back into nerve terminals via a specific serotonin transporter (SERT) that is present in the presynaptic plasma membrane and is encoded by the 5HTT gene. Many antidepressant drugs are selective serotonin reuptake inhibitors (SSRIs) that inhibit transport of 5-HT by SERT. The primary catabolic pathway for 5-HT is mediated by MAO.
- Dopamine is present in several brain regions although the major dopamine-containing area of the brain is the corpus striatum, which receives major input from the substantia nigra and plays an essential role in the coordination of body movements. In Parkinson’s disease, for instance, the dopaminergic neurons of the substantia nigra degenerate, leading to a characteristic motor dysfunction. Dopamine is also believed to be involved in motivation, reward, and reinforcement. many drugs of abuse work by affecting dopaminergic circuitry in the CNS. Dopamine is produced by the action of dihydroxyphenylalanine decarboxylase on DOPA. Dopamine is loaded into synaptic vesicles via a vesicular monoamine transporter (VMAT). Dopamine action in the synaptic cleft is terminated by reuptake of dopamine into nerve terminals or surrounding glial cells by a Na+-dependent dopamine co-transporter, termed DAT. Cocaine apparently produces its psychotropic effects by inhibiting DAT, thereby increasing dopamine concentrations in the synaptic cleft. Amphetamine, another addictive drug, also inhibits DAT. The two major enzymes involved in the catabolism of dopamine are monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT. Inhibitors of these enzymes, such as phenelzine and tranylcypromine, are used clinically as antidepressants. Norepinephrine (also called noradrenaline) is used as a neurotransmitter in the locus coeruleus, a brainstem nucleus that projects diffusely to a variety of forebrain targets and influences sleep and wakefulness, arousal, attention, and feeding behavior. Both norepinephrine and epinephrine act on α- and β-adrenergic receptors. Agonists and antagonists of adrenergic receptors, such as the β-blocker propranolol (Inderol), are used clinically for a variety of conditions ranging from cardiac arrhythmias to migraine headaches. Histamine is found in neurons in the hypothalamus that send sparse but widespread projections to almost all regions of the brain and spinal cord The central histamine projections mediate arousal and attention, similar to central ACh and norepinephrine projections. Histamine also controls the reactivity of the vestibular system. Antihistamines that cross the blood brain barrier, such as diphenhydramine (Benadryl), act as sedatives by interfering with the roles of histamine in CNS arousal. Antagonists of the H1 receptor also are used to prevent motion sickness, perhaps because of the role of histamine in controlling vestibular function. H2 receptors control the secretion of gastric acid in the digestive system, allowing H2 receptor antagonists to be used in treating a variety of upper gastrointestinal disorders