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  1. 1. ©Dr. Anwar SiddiquiPhysiology Seminar11/08/2012NEUROTRANSMITTER
  2. 2. INTRODUCTION• Neurotransmitters are endogenous chemicals that transmitsignals from a neuron to a target cell across a synapse• Synapses are the junctions where neurons release a chemicalneurotransmitter that acts on a postsynaptic target cell, whichcan be another neuron or a muscle or gland cell• Some chemicals released by neurons have little or no directeffects on their own but can modify the effects ofneurotransmitters. These chemicals are calledneuromodulators.
  3. 3. Criteria That Define a Neurotransmitter
  4. 4. THE FATHER OF NEUROSCIENCE• Otto Loewi (Germanpharmacologist)• Discovered the chemical nature ofneurotransmission (Acetylcholine)across synapse• Loewi was awarded the NobelPrize in Physiology (1936)
  5. 5. The Experiment :
  6. 6. Identified neurotransmitters and neuromodulators can be dividedinto two major categories:SMALL-MOLECULE TRANSMITTERSMonoamines (eg, Acetylcholine, Serotonin, Histamine),Catecholamines (Dopamine, Norepinephrine Epinephrine)Amino Acids (eg, Glutamate, GABA, Glycine).LARGE-MOLECULE TRANSMITTERS.Include a large number of peptides called neuropeptides includingsubstance P, enkephalin, vasopressin, and a host of others.There are also other substances thought to be released into thesynaptic cleft to act as either a transmitter or modulator of synaptictransmission. These include purine derivatives like Adenosine,Adenosine Triphosphate (ATP) and Nitric Oxide (NO).
  7. 7. Neurotransmitter receptorsTwo broad classes:LIGAND-GATED ION CHANNELSOpen immediately upon neurotransmitter bindingG PROTEIN–COUPLED RECEPTORS.Neurotransmitter binding to a G protein–coupled receptor induces theopening or closing of a separate ion channel protein over a period ofseconds to minutes. These are “slow” neurotransmitter receptors.Each ligand has many subtypes of receptors : selective effect atdifferent sitesPresynaptic receptors, or Autoreceptors : provide feedback control
  8. 8. • Receptors are concentrated in clusters in postsynaptic structures closeto the endings of neurons that secrete the neurotransmitters specificfor them. This is generally due to the presence of specific bindingproteins for them.In the case of nicotinic acetylcholine receptors at the neuromuscularjunction, the protein is rapsynIn the case of excitatory glutamatergic receptors, a family of PB2-binding proteins is involved.GABAA receptors are associated with the protein gephyrin, which alsobinds glycine receptors, andGABAC receptors are bound to the cytoskeleton in the retina by theprotein MAP-1B.
  9. 9. DESENSITIZATIONProlonged exposure to their ligands causes most receptors tobecome unresponsive. This can be of two types:Homologous desensitization, with loss of responsivenessonly to the particular ligand and maintained responsivenessof the cell to other ligandsHeterologous desensitization, in which the cell becomesunresponsive to other ligands as well.
  10. 10. Reuptake• From the synaptic cleft back into the cytoplasm of the neuronThe reuptake systems employ two families of transporter proteins:Members include transporters for norepinephrine, dopamine,serotonin, GABA, and glycine, as well as transporters for proline,taurine, and the acetylcholine precursor choline. In addition, theremay be an epinephrine transporter.The other family is made up of at least three transporters thatmediate glutamate uptake by neurons and two that transportglutamate into astrocytes.
  11. 11. • There are in addition two vesicular monoamine transporters, VMAT1and VMAT2, that transport neurotransmitters from the cytoplasm tosynaptic vesicles. They are coded by different genes but haveextensive homology:Both have a broad specificity, moving dopamine, norepinephrine,epinephrine, serotonin, and histamine from the cytoplasm intosecretory granules.Both are inhibited by reserpine, which accounts for the markedmonoamine depletion produced by this drug.Like the neurotransmitter membrane transporter family, they have 12transmembrane domains, but they have little homology to the othertransporters.• There is also a vesicular GABA transporter (VGAT) that moves GABAand glycine into vesicles and a vesicular acetylcholine transporter.
  12. 12. Monoamineissynthesizedinthecytoplasmandthesecretorygranules(1)anditsconcentrationinsecretorygranulesismaintained(2)bythetwovesicularmonoaminetransporters(VMAT).Themonoamineissecretedbyexocytosisofthegranules(3),anditacts(4)onreceptors(Y-shapedstructureslabeledR).Manyofthesereceptorsarepostsynaptic,butsomearepresynapticandsomearelocatedonglia.Inaddition,thereisextensivereuptakeintothecytoplasmofthepresynapticterminal(5)viathemonoamineneurotransmittertransporter(NTT)forthemonoaminethatissynthesizedintheneuron.
  13. 13. Reuptake is a major factor in terminating the action oftransmitters, when inhibited, the effects of transmitter releaseare increased and prolonged. This has clinical consequences.Several effective antidepressant drugs are inhibitors of thereuptake of amine transmitters.Cocaine is believed to inhibit dopamine reuptake.Glutamate uptake into neurons and glia is important becauseglutamate is an excitotoxin that can kill cells by overstimulatingthem. There is evidence that during ischemia and anoxia, loss ofneurons is increased because glutamate reuptake is inhibited.
  14. 14. AcetylcholineAcetylcholine, which is theacetyl ester of choline, islargely enclosed in small,clear synaptic vesicles inhigh concentration in theterminal boutons ofcholinergic neurons
  15. 15. • Acetylcholine is the transmitter at the neuromuscular junction, inautonomic ganglia, and in postganglionic parasympathetic nerve-target organ junctions and some postganglionic sympatheticnerve-target junctions. It is also found within the brain, includingthe basal forebrain complex and pontomesencephalic cholinergiccomplex . These systems may be involved in regulation of sleep-wake states, learning, and memory.
  16. 16. • Cholinergic neurons activelytake up choline via atransporter. Choline is alsosynthesized in neurons.• The enzyme cholineacetyltransferase is found inhigh concentration in thecytoplasm of cholinergicnerve endings. Acetylcholineis then taken up into synapticvesicles by a vesiculartransporter (VAChT).• Removed via Hydrolysis tocholine and acetate, areaction catalyzed by theenzymeACETYLCHOLINESTERASE.
  17. 17. Acetylcholine ReceptorsMuscarinicNicotinic
  18. 18. Muscarinic receptors• Muscarine, the alkaloid responsible for the toxicity of toadstools, has littleeffect on the receptors in autonomic ganglia but mimics the stimulatoryaction of acetylcholine on smooth muscle and glands.• These actions of acetylcholine are therefore called muscarinic actions, andthe receptors involved are muscarinic cholinergic receptors.• They are blocked by the drug atropine.• Five types, encoded by five separate genes, have been cloned.• The exact status of M5 is uncertain, but the remaining four receptors arecoupled via G proteins to adenylyl cyclase, K+ channels, and/orphospholipase C .• M1 is abundant in the brain.• The M2 receptor is found in the heart.• The M4 receptor is found in pancreatic acinar and islet tissue.• The M3 and M4 receptors are associated with smooth muscle.
  19. 19. Nicotinic receptors• In Sympathetic Ganglia, the actions of Ach are unaffected byatropine but MIMICKED BY NICOTINE. Consequently, these actionsof Ach are nicotinic actions and the receptors are nicotiniccholinergic receptors.• Nicotinic receptors are subdivided into those at neuromuscularjunctions and those found in autonomic ganglia and the centralnervous system• Both muscarinic and nicotinic acetylcholine receptors are found inlarge numbers in the brain.• The nicotinic acetylcholine receptors are members of a superfamilyof ligand-gated ion channels
  20. 20. • Each nicotinic cholinergic receptor is made up of five subunits that form acentral channel which, when the receptor is activated, permits the passageof Na+ and other cations. A prominent feature of neuronal nicotiniccholinergic receptors is their high permeability to Ca2+.• The 5 subunits come from a menu of 16 known subunits, α1–α9, β1–β5, γ , δand ε , coded by 16 different genes.• THE MUSCLE TYPE NICOTINIC RECEPTOR found in the fetus is made up oftwo α1 subunits, a β1 subunit, a γ subunit, and a δ subunit . In adult,the γsubunit is replaced by a δ subunit, which decreases the channel open timebut increases its conductance.• The nicotinic cholinergic RECEPTORS IN AUTONOMIC GANGLIA usuallycontain α3 subunits in combination with others.Many of the nicotinic cholinergic receptors in the brain are locatedpresynaptically on glutamate-secreting axon terminals, and they facilitate therelease of this transmitter. However, others are postsynaptic. Some are locatedon structures other than neurons, and some seem to be free in the interstitialfluid, that is, they are perisynaptic in location.
  21. 21. Serotonin• Serotonin is formed in thebody by hydroxylation anddecarboxylation of theessential amino acidTRYPTOPHAN• Tryptophan hydroxylase inthe human CNS is slightlydifferent from thetryptophan hydroxylase inperipheral tissues, and iscoded by a different gene.
  22. 22. SEROTONIN (5-HYDROXYTRYPTAMINE; 5-HT) is present in highestconcentration in bloodplatelets and in thegastrointestinal tract, whereit is found in theenterochromaffin cells andthe myenteric plexus.It is also found within thebrain stem in the midlineraphé nuclei which project toportions of thehypothalamus, the limbicsystem, the neocortex, thecerebellum, and the spinalcord There is evidence for a relationship betweenbehavior and brain serotonin content.
  23. 23. • After release fromserotonergic neurons, muchof the released serotonin isrecaptured by an activereuptake mechanism andinactivated by MONOAMINEOXIDASE (MAO) to form 5-hydroxyindoleacetic acid (5-HIAA).• This substance is theprincipal urinary metaboliteof serotonin, and its urinaryoutput is used as an index ofthe rate of serotoninmetabolism in the body
  24. 24. Serotonergic Receptors• 5-HT1 - 5-HT7 receptors• Most of these are G protein-coupled receptors• 5-HT1 => 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, & 5-HT1F• 5-HT2 => 5-HT2A, 5-HT2B, & 5-HT2C• 5-HT2A receptors mediate platelet aggregation and smooth musclecontraction.• 5-HT3 receptors are ligand-gated ion channels present in the GIT & thearea postrema & are related to vomiting.• 5-HT4 receptors are also present in the GIT, where they facilitatesecretion and peristalsis, & in the brain.• 5-HT5 => 5-HT5A & 5-HT5B• 5-HT6 & 5-HT7 are distributed throughout the limbic system, and the 5-HT6 receptors have a high affinity for antidepressant drugs.
  25. 25. Histamine• Histamine is formed by decarboxylation of the amino acidhistidine .
  26. 26. • Histaminergic neurons have their cell bodies in thetuberomammillary nucleus of the posterior hypothalamus, and theiraxons project to all parts of the brain, including the cerebral cortexand the spinal cord.• Histamine is also found in cells in the gastric mucosa and in heparin-containing cells called mast cells that are plentiful in the anterior andposterior lobes of the pituitary gland as well as at body surfaces.• The three known types of histamine receptors— H1, H2, and H3—areall found in both peripheral tissues and the brain.• Mostof the H3 receptors are presynaptic, and they mediateinhibition of the release of histamine and other transmitters via a Gprotein. H1 receptors activate phospholipase C, and H2 receptorsincrease the intracellular cAMP concentration.• Evidence links brain histamine to arousal, sexual behavior, bloodpressure, drinking, pain thresholds, and regulation of the secretion ofseveral anterior pituitary hormones.
  27. 27. Catecholamines• Norepinephrine, Epinephrine, & Dopamine• The chemical transmitter present at most sympatheticpostganglionic endings is norepinephrine. It is stored in thesynaptic knobs of the neurons that secrete it in characteristic smallvesicles that have a dense core.• NOREPINEPHRINE and its methyl derivative, EPINEPHRINE, aresecreted by the adrenal medulla• Tyrosine hydroxylase, which catalyzes the RATE LIMITING step, issubject to feedback inhibition by dopamine and norepinephrine,thus providing internal control of the synthetic process.• The cell bodies of the norepinephrine-containing neurons arelocated in the locus ceruleus and other medullary and pontinenuclei .
  28. 28. RATE LIM STEP
  29. 29. Catabolism of Catecholamines• Removed from the synaptic cleft by binding to postsynaptic receptors,binding to presynaptic receptors , reuptake into the presynapticneurons, or catabolism. Reuptake is a major mechanism in the case ofnorepinephrine.• Epinephrine and norepinephrine are metabolized to biologicallyinactive products by oxidation and methylation. The former reaction iscatalyzed by MAO and the latter by catechol -O –methyltransferase(COMT).• EXTRACELLULAR epinephrine and norepinephrine are for the mostpart O-methylated, and measurement of the concentrations of the O-methylated derivatives normetanephrine and metanephrine in theurine is a good index of the rate of secretion of norepinephrine andepinephrine.• The O-methylated derivatives that are not excreted are largelyoxidized, and 3-methoxy-4-hydroxymandelic acid (vanillylmandelicacid, VMA) is the most plentiful catecholamine metabolite in theurine. Small amounts of the O-methylated derivatives are alsoconjugated to sulfate and glucuronide.
  30. 30. • In theNORADRENERGICNERVE TERMINALS, onthe other hand, someof the norepinephrine isconstantly beingconverted byintracellular MAO to thephysiologically inactivedeaminated derivatives,3,4-dihydroxymandelicacid (DOMA) and itscorresponding glycol(DHPG). These aresubsequently convertedto their correspondingO-methyl derivatives,VMA and 3-methoxy-4-hydroxyphenylglycol(MHPG).
  31. 31. α & β Receptors• Epinephrine and norepinephrine both act on and receptors,with norepinephrine having a greater affinity for α-adrenergicreceptors and epinephrine for β-adrenergic receptors.• G protein-coupled receptors, and each has multiple forms
  32. 32. Dopamine• In certain parts of the brain, catecholamine synthesis stops atdopamine• Active reuptake of dopamine occurs via a Na+- and Cl–-dependentdopamine transporter.• Dopamine is metabolized to inactive compounds by MAO and COMTin a manner analogous to the inactivation of norepinephrine• Dopaminergic neurons are located in several brain regions includingthe nigrostriatal system, which projects from the substantia nigra tothe striatum and is involved in motor control, and the mesocorticalsystem.• The mesocortical system projects to the nucleus accumbens andlimbic subcortical areas, and it is involved in reward behavior andaddiction.• Studies by PET scanning in normal humans show that a steady lossof dopamine receptors occurs in the basal ganglia with age. The lossis greater in men than in women.
  33. 33. Dopamine Receptors• Five different dopamine receptors have been cloned, and several ofthese exist in multiple forms.• Most, but perhaps not all, of the responses to these receptors aremediated by heterotrimeric G proteins.• Overstimulation of D2 receptors is thought to be related toschizophrenia.• D3 receptors are highly localized, especially to the nucleus accumbens
  34. 34. Glutamate• The amino acid glutamate is the main excitatory transmitter in the brainand spinal cord( 75% of the excitatory transmission in the brain. )• Glutamate is formed by reductive amination of the Krebs cycleintermediate α-ketoglutarate in the cytoplasm.• The reaction is reversible, but in glutaminergic neurons, glutamate isconcentrated in synaptic vesicles by the vesicle-bound transporter BPN1.• The cytoplasmic store of glutamine is enriched by three transporters thatimport glutamate from the interstitial fluid, and two additionaltransporters carry glutamate into astrocytes, where it is converted toglutamine and passed on to glutaminergic neurons.• Released glutamate is taken up by astrocytes and converted toglutamine, which passes back to the neurons and is converted back toglutamate, which is released as the synaptic transmitter.• Uptake into neurons and astrocytes is the main mechanism for removalof glutamate from synapses
  35. 35. Theglutamate–glutaminecyclethroughglutaminergicneurons and astrocytes.
  36. 36. Glutamate ReceptorsTwo types:METABOTROPIC RECEPTORSIONOTROPIC RECEPTORSTHE METABOTROPIC RECEPTORS• G protein-coupled receptors that increase intracellular IP3 and DAGlevels or decrease intracellular cAMP levels.• Eleven subtypes• Presynaptic & postsynaptic, and widely distributed in the brain.• They appear to be involved in the production of synaptic plasticity,particularly in the hippocampus and the cerebellum.• Knockout of the gene for one of these receptors, one of the forms ofmGluR1, causes severe motor incoordination and deficits in spatiallearning.
  37. 37. THE IONOTROPIC RECEPTORS• Ligand-gated ion channels.• There are three general types, each named for the congeners ofglutamate to which they respond in maximum fashion.Kainate receptors (kainate is an acid isolated from seaweed)Simple ion channels that, when open, permit Na+ influx and K+ efflux4 AMPA subunits have been identifiedAMPA receptors ( amino-3-hydroxy-5-methylisoxazole-4-propionate)Two populations : one is a simple Na+ channel and one also passesCa2+.5 kainate subunits have been identifiedNMDA receptors (N-methyl-D-aspartate).
  38. 38. NMDA receptors• A cation channel: permits passage of relatively large amounts ofCa2+• Glycine facilitates its function by binding to it, & appears to beessential for its normal response to glutamate.• When glutamate binds to it, it opens, but at normal membranepotentials, its channel is blocked by a Mg2+ ion.• Phencyclidine and ketamine, which produce amnesia and a feelingof dissociation from the environment, bind to another site insidethe channel. Most target neurons for glutamate have both AMPAand NMDA receptors.
  39. 39. • Kainate receptors are located presynaptically on GABA-secretingnerve endings and postsynaptically at various localized sites in thebrain. Kainate and AMPA receptors are found in glia as well asneurons, but it appears that NMDA receptors occur only inneurons• The concentration of NMDA receptors in the hippocampus is high,and blockade of these receptors prevents long-term potentiation,a long-lasting facilitation of transmission in neural pathwaysfollowing a brief period of high-frequency stimulation. Thus, thesereceptors may well be involved in MEMORY AND LEARNING.
  40. 40. NMDA receptor
  41. 41. GABA• Major inhibitory mediator in the brain, including beingresponsible for presynaptic inhibition.• Formed by decarboxylation of glutamate . The enzymeglutamate decarboxylase (GAD), is present in nerve endings inmany parts of the brain.
  42. 42. • Metabolized primarily by transamination to succinic semialdehydeand thence to succinate in the citric acid cycle. GABA transaminase(GABA-T) catalyzes the transamination.• In addition, there is an active reuptake of GABA via the GABAtransporter. A vesicular GABA transporter (VGAT) transports GABAand glycine into secretory vesicles
  43. 43. GABA Receptors• Three subtypes of GABA receptors have been identified: GABAA,GABAB, and GABAC• The GABAA and GABAB receptors are widely distributed in the CNS,whereas in adult vertebrates the GABAC receptors are foundalmost exclusively in the retina.• The GABAA and GABAC receptors are ion channels made up of fivesubunits surrounding a pore . In this case, the ion is Cl– .• The GABAB receptors are metabotropic ,coupled to heterotrimericG proteins that increase conductance in K+ channels, inhibitadenylyl cyclase, and inhibit Ca2+ influx.• Increases in Cl– influx and K+ efflux and decreases in Ca2+ influx allhyperpolarize neurons, producing an IPSP. The G protein mediationof GABAB receptor effects is unique in that a G proteinheterodimer, rather than a single protein, is involved.
  44. 44. • There is a chronic low-level stimulation of GABAA receptors in the CNSthat is aided by GABA in the interstitial fluid. This backgroundstimulation cuts down on the "noise" caused by incidental discharge ofthe billions of neural units and greatly IMPROVES THE SIGNAL-TO-NOISERATIO in the brain. It may be that this GABA discharge declines withadvancing age, resulting in a loss of specificity of responses of visualneurons.• The increase in Cl– conductance produced by GABAA receptors ispotentiated by benzodiazepines, drugs that have marked anti-anxietyactivity and are also effective muscle relaxants, anticonvulsants, andsedatives. Benzodiazepines bind to the α subunits.• At least in part, barbiturates and alcohol also act by facilitating Cl–conductance.• Metabolites of the steroid hormones progesterone anddeoxycorticosterone bind to GABAA receptors and increase Cl–conductance.• It has been known for many years that progesterone anddeoxycorticosterone are sleep-inducing and anesthetic in large doses,and these effects are due to their action on GABAA receptors.
  45. 45. Glycine• Glycine has both excitatory and inhibitory effects in the CNS.• When it binds to NMDA receptors, it makes them more sensitive.Itappears to spill over from synaptic junctions into the interstitial fluid,and in the spinal cord, for example, this glycine may facilitate paintransmission by NMDA receptors in the dorsal horn.• Glycine is also responsible in part for direct inhibition, primarily in thebrain stem and spinal cord. Like GABA, it acts by increasing Cl–conductance. Its action is antagonized by strychnine.• The clinical picture of convulsions and muscular hyperactivityproduced by strychnine emphasizes the importance of postsynapticinhibition in normal neural function.
  46. 46. RECEPTOR• The glycine receptor responsible for inhibition is a Cl– channel.• It is a pentamer made up of two subunits:The ligand-binding α subunitThe structural β subunit.• Recently, solid evidence has been presented that three kinds ofneurons are responsible for direct inhibition in the spinal cord:neurons that secrete glycine,neurons that secrete GABA, andneurons that secrete both.Presumably, neurons that secrete only glycine have the glycinetransporter GLYT2, those that secrete only GABA have GAD, andthose that secrete glycine and GABA have both. This third type ofneuron is of special interest because the neurons seem to haveglycine and GABA in the same vesicles.
  47. 47. Anesthesia• Alcohols, barbiturates, and many volatile inhaled anestheticsas well act on ion channel receptors and specifically on GABAAand glycine receptors to increase Cl– conductance. Regionalvariation in anesthetic actions in the CNS seems to parallel thevariation in subtypes of GABAA receptors.• Other inhaled anesthetics do not act by increasing GABAreceptor activity, but appear to act by inhibiting NMDA andAMPA receptors instead.• Local anesthetics produce anesthesia by blocking conductionin peripheral nerves via reversibly binding to and inactivatingNa+ channels. When depolarization and propagation areinterrupted, the individual loses sensation in the area suppliedby the nerve.
  48. 48. Large-Molecule Transmitters:Neuropeptides• Substance P & Other Tachykinins:• Substance P is a polypeptide containing 11 amino acid residues that isfound in the intestine, various peripheral nerves, and many parts ofthe CNS.• It is one of a family of 6 mammalian polypeptides called tachykininsthat differ at the amino terminal end but have in common the carboxylterminal sequence.
  49. 49. • Substance P is found in high concentration in the endings ofprimary afferent neurons in the spinal cord, and it is probably themediator at the first synapse in the pathways for pain transmissionin the dorsal horn.• It is also found in high concentrations in the nigrostriatal system,where its concentration is proportional to that of dopamine, and inthe hypothalamus, where it may play a role in neuroendocrineregulation• In the intestine, it is involved in peristalsis.
  50. 50. Opioid PeptidesPeptides that bind to opioid receptors are called opioid peptides.The ENKEPHALINS are found in nerve endings in the gastrointestinaltract and many different parts of the brain, and they appear tofunction as synaptic transmitters. They are found in the substantiagelatinosa and have analgesic activity when injected into the brainstem. They also decrease intestinal motility.METABOLISMEnkephalins are metabolized primarily by two peptidases• Enkephalinase A, which splits the Gly-Phe bond, and• Enkephalinase B, which splits the Gly-Gly bond.• Aminopeptidase, which splits the Tyr-Gly bond, also contributes totheir metabolism.
  51. 51. RECEPTORS• µ , κ , δ• All three are G protein-coupled receptors, and all inhibit adenylylcyclase.• Activation of µ receptors increases K+ conductance, hyperpolarizingcentral neurons and primary afferents. Activation of κ and δreceptors closes Ca2+ channels.
  52. 52. Physiologic effects of opiatereceptor stimulation
  53. 53. Receptor affinity
  54. 54. Other PolypeptidesSOMATOSTATIN is found in various parts of the brain, where itapparently functions as a neurotransmitter with effects on sensory input,locomotor activity, and cognitive function.• In the endocrine pancreas, it inhibits insulin secretion and the secretionof other pancreatic hormones• In the gastrointestinal tract, it is an important inhibitory gastrointestinalregulator.A family of five different SOMATOSTATIN RECEPTORS have beenidentified (SSTR1 through SSTR5).• All are G protein-coupled receptors. They inhibit adenylyl cyclase andexert various other effects on intracellular messenger systems.• It appears that SSTR2 mediates cognitive effects and inhibition ofgrowth hormone secretion, whereas SSTR5 mediates the inhibition ofinsulin secretion.
  55. 55. • VASOPRESSIN & OXYTOCIN are not only secreted as hormones butalso are present in neurons that project to the brain stem and spinalcord• The brain contains BRADYKININ, ANGIOTENSIN II & ENDOTHELIN• The gastrointestinal hormones VIP, CCK-4, and CCK-8 are also foundin the brain. There are two kinds of CCK receptors in the brain, CCK-A and CCK-B.• GASTRIN, NEUROTENSIN, GALANIN, AND GASTRIN-RELEASINGPEPTIDE are also found in the gastrointestinal tract and brain
  56. 56. CALCITONIN GENE-RELATED PEPTIDE (CGRP)• Is a polypeptide that exists in two forms : CGRPα and CGRPβ• CGRP is present in the gastrointestinal tract, found in primary afferentneurons, neurons that project impulses to the thalamus, and neuronsin the medial forebrain bundle. It is also present along with substanceP in the branches of primary afferent neurons that end near bloodvessels.• Its injection causes vasodilation.• CGRPα and the calcium-lowering hormone calcitonin are bothproducts of the calcitonin gene.
  57. 57. NEUROPEPTIDE Y• Is a polypeptide containing 36 amino acid residues that acts on atleast two of the 4 known G protein-coupled receptors: Y1, Y2, Y4, andY5.• Neuropeptide Y is found throughout the brain and the autonomicnervous system.• When injected into the hypothalamus, this polypeptide increasesfood intake, and inhibitors of neuropeptide Y synthesis decreasefood intake.• Neuropeptide Y-containing neurons have their cell bodies in thearcuate nuclei and project to the paraventricular nuclei
  58. 58. Other Chemical TransmittersPURINE & PYRIMIDINE TRANSMITTERS• ATP, URIDINE, ADENOSINE, AND ADENOSINE METABOLITESare neurotransmitters or neuromodulators.ADENOSINEis a neuromodulator that acts as a general CNS depressant andhas additional widespread effects throughout the body.• 4 receptors: A1, A2A, A2B, and A3. G protein-coupled &increase (A2A and A2B) or decrease (A1 and A3) cAMPconcentrations.• The stimulatory effects of coffee and tea are due to blockadeof adenosine receptors by caffeine and theophylline.
  59. 59. ATP• ATP has now been shown to mediate rapid synaptic responses in theautonomic nervous system and a fast response in the habenula.• ATP binds to P2X receptors which are ligand-gated ion channelreceptors; seven subtypes (P2X1–P2X7) have been identified.• P2X receptors have widespread distributions throughout the body;for example, P2X1 and P2X2 receptors are present in the dorsal horn,indicating a role for ATP in sensory transmission.• ATP also binds to P2Y receptors which are G protein-coupledreceptors. There are eight subtypes of P2Y receptors: P2Y1, P2Y2,P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14• It appears that soluble nucleotidases are released with ATP, andthese accelerate its removal after it has produced its effects.
  60. 60. CANNABINOIDS• Two receptors with a high affinity for tetrahydrocannabinol (THC),the psychoactive ingredient in marijuana, have been cloned.• The CB1 receptor triggers a G protein-mediated decrease inintracellular cAMP levels and is common in central pain pathways aswell as in parts of the cerebellum, hippocampus, and cerebralcortex.• The endogenous ligand for the receptor is ANANDAMIDE, aderivative of arachidonic acid. This compound mimics the euphoria,calmness, dream states, drowsiness, and analgesia produced bymarijuana.• There are also CB1 receptors in peripheral tissues, and blockade ofthese receptors reduces the vasodilator effect of anandamide.• A CB2 receptor has also been cloned, and its endogenous ligand maybe palmitoylethanolamide (PEA). However, the physiologic role ofthis compound is unsettled.
  61. 61. GasesNITRIC OXIDE (NO)• The compound released by the endothelium of blood vessels asEDRF, is also produced in the brain.• It is synthesized from arginine, a reaction catalyzed in the brain byone of the three forms of NO synthase.• NO synthase requires NADPH• It activates guanylyl cyclase and, unlike other transmitters, it is agas, which crosses cell membranes with ease and binds directly toguanylyl cyclase.• It may be the signal by which postsynaptic neurons communicatewith presynaptic endings in long-term potentiation and long-termdepression.
  62. 62. Other SubstancesPROSTAGLANDINS• Are derivatives of arachidonic acid found in the nervous system, presentin nerve-ending fractions of brain homogenates and are released fromneural tissue in vitro. A putative prostaglandin transporter with 12membrane-spanning domains has been described.• However, prostaglandins appear to exert their effects by modulatingreactions mediated by cAMP rather than by functioning as synaptictransmitters.NEUROACTIVE STEROIDS• They are not neurotransmitters in the usual sense.• Evidence has now accumulated that the brain can produce somehormonally active steroids from simpler steroid precursors, and the termneurosteroids has been coined to refer to these products. Progesteronefacilitates the formation of myelin, but the exact role of most steroids inthe regulation of brain function remains to be determined.
  63. 63. Thank you…