class intro to cns
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Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.
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Classes of CNS Transmitters
Neurotransmitter % ofSynapses
Function Primary ReceptorClass
MonoaminesCatecholamines: DA, NE,EPIIndoleamines: serotonin(5-HT)
2-5 Slow change inexcitability (secs)
GPCRs
Acetylcholine (ACh) 5-10 Slow change inexcitability (secs)
GPCRs
Amino acidsInhibitory: GABA, glycine
Excitatory: Glutamate,aspartate
15-20
75-80
Rapid inhibition(msecs)
Rapid excitation(msecs)
Ion channels
Ion channels
Neurotransmitter Cell Bodies Terminals
Norepinephrine(NE)
Locus coeruleusLateral tegmentalarea
Very widespread: cerebral cortex,thalamus, cerebellum, brainstemnuclei, spinal cordBasal forebrain, thalamus,hypothalamus, brainstem, spinalcord
Epinephrine (EPI) Small, discretenuclei in medulla
Thalamus, brainstem, spinal cord
Dopamine (DA) Substantia nigra(pars compacta)Ventral tegmentalareaArcuate nucleus
StriatumLimbic forebrain, cerebral cortexMedian eminence
Serotonin (5-HT) Raphe nuclei(median and dorsal),pons, medulla
Very widespread: cerebral cortex,thalamus, cerebellum, brainstemnuclei, spinal cord
Localization of Monoamines in the Brain
The blood-brain barrier (BBB) is a membrane thatcontrols the passage of substances from the blood intothe central nervous system.It is a physical barrier between the local blood vesselsand most parts of the central nervous system itself,and stops many substances from travelling across it.The BBB is permeable to alcohol, and some heavymetals can cross the blood-brain barrier as well.
The BBB can be broken down by:Hypertension (high blood pressure): high bloodpressure opens the BBBDevelopment: the BBB is not fully formed at birth.Hyperosmolitity: a high concentration of a substance inthe blood can open the BBB.Microwaves: exposure to microwaves can open theBBB.Radiation: exposure to radiation can open the BBB.Infection: exposure to infectious agents can open theBBB.Trauma, Ischemia, Inflammation, Pressure: injury tothe brain can open the BBB.
Catecholamine synthesisSynthesis of catecholamines
PeptidesExamples: substance P, somatostatin, leu-enkephalin, met-enkephalin, vasoactive intestinal polypeptide (VIP), bombesin
Peptide synthesized in rough endoplasmic reticulumPackaged in Golgi apparatusTransported down axon to presynaptic ending of the axonterminalsecretory vesicles transported down axon byorthograde axonal transport
Small molecule transmitters (amino acids and amines)Examples of amino acid neurotransmitters: gamma-amino butyric acid (GABA), glutamate (Glu), glycine (Gly)Examples of amine neurotransmitters: acetylcholine(ACh), dopamine (DA), epinephrine, histamine,norepinephrine (NE), serotonin (5-HT)
Occurs in axon terminalPrecursor molecule is transformed by synthetic enzymeinto neurotransmitter moleculeNeurotransmitter molecules are gathered by transportermolecules and packaged in synaptic vesicles
Sympathetic nerves take up amines and release them asneurotransmitters
Axonal uptake or Uptake I is a high efficiency system, morespecific for NA By norepinephrine transporter (NET) Located in neuronal membrane Inhibited by Cocaine, TCAD, Amphetamines
Vesicular uptake- By vesicular monoamine transporter (VMAT-2) Also capture DA for synthesis of NA Inhibited by Reserpine
Extraneuronal uptake is less specific for NA Located in smooth muscle/ cardiac muscle By extraneuronal amine transporter Inhibited by steroids/ phenoxybenzamine No Physiological or Pharmacological importance
NE can be transported back into the pre-synaptic neuron(reuptake). Enzymes involved in metabolism are
Mono Amine Oxidase (MAO)Intracellular bound to mitochondrial membranePresent in NA terminals and liver/ intestine
Catechol-o-methyl-transferase (COMT)Neuronal and non-neuronal tissueActs on catecholamines and byproducts
End product of EPI metabolism VMA-vanilyl mandelic acidEnd product of DOPA metabolism HVA-homovallinic acidNE can activate the presynaptic receptors (α-2 for negativefeedback), 5HTMAO 5HIAAAmphetamines and cocaine block the reuptake of catecholamines,thereby prolonging their synaptic action
Selectivity for the targeted pathwayReceptor subtypesAllosteric sites on receptorsPresynaptic and postsynaptic actionsPartial/inverse agonist (activity dependent)
Plasticity reveals adaptive changes in drug responsePharmacokinetic: drug metabolismPharmacodynamic: cellular
Acetylcholine is the transmitter used by motor neurons ofthe spinal cordReleased at all vertebrate neuro-muscular junctionsPresent in autonomic & parasympathetic neuronsCholinergic fibres All somatic motar neuronsAll preganglionic fibres and Post ganglionicparasympathetic fibresException-post ganglionic sympathetic fibres to apocrineglands
DOPAMINE RECEPTORSThere are at least 5 subtypes of receptors:
D1 and D5: mostly involved in postsynapticinhibition.
D2, D3, and D4: involved in both pre-andpostsynaptic inhibition.D2: the predominant subtype in the brain:
regulates mood, emotional stability in the limbicsystem and movement control in the basal ganglia.
The nigrostriatal pathway (substantia nigra to striatum)extrapyramidal motor control coordination ofvoluntary movement
Mesolimbic- mesocortical (ventral tegmental ton.accumbens, hippocampus, and cortex)emotion
Cognition, behaviorTuberoinfundibular- (arcuate nucleus of hypothalamus tomedian eminence then anterior pituitary)
prolactin release, pituitary system (endocrine)The medulla oblongata (vomit)Medullary - periventricular pathway ( eating behavior)
Behavioral – depression, anxiety, decreasedmotivation, personality changes,Sensory – non-specific pains,, restless legs and othersleep problemsAutonomic – constipation, bladder dysfunction,impotence, low blood pressure
MuhammadAli
The synthesis pathway continues from dopamine:Dopamine beta-hydroxylase (DBH) makes dopamineinto norepinephrine
If the neuron is noradrenergic, the pathway stops here,Or If the neuron is adrenergic the pathway cancontinues Phentolamine N-methyl transferase(PNMT) makes norepinephrine into epinephrine
Arousal, Mood, Blood pressure control
In the CNS, norepinephrine is used by neurons ofthe locus coruleus, a nucleus of the brainstem withcomplex modulatory functionsIn the peripheral nervous system, norepinephrine isthe transmitter of the sympathetic nervous systemNorepinephrine can then be converted toepinephrine
Sleep, Mood, Sexual function and AppetiteLSD- 5HT2 agonist – Visual hallucinations5-HT has a modulatory effect on dopaminergicneurones
Glutamate hypothesisPhencyclidine, ketamineGlutamate-NMDA antagonists –can produce psychoticsymptoms
Depression is due to deficiency of nor-epinephrine &serotoninNormally action of released NE & serotonin is terminated byactive reuptake into the nerve terminal from the synapse viaspecific transporters.TCAs block the amine transporters (uptake pumps) for nor-epinephrine (NET) & serotonin (SERT) in brain.Facilitation of NE & serotonin transmission ---- improvessymptoms of depression .
Memory (ChEI in Alzheimers disease)Basal forebrain to cortex/hippocampus (A)
Extrapyramidal motor responses (benztropine forParkinsonian symptoms)
Striatum (B)
Vestibular control (scopolamine patch for motion sickness)
Nigrostriatal pathwayextrapyramidal motor responses
Interneurons throughout the braininhibit excitability, stabilize membrane potential, preventrepetitive firing
Metabotropic GABA B receptorsThese receptors are GPCRSLargely presynaptic, inhibit transmitter releaseMost important role is in the spinal cordBaclofen, an agonist at this receptor, is a muscle relaxant
There are two GABA binding sites per receptor.
Benzodiazepines and the newer hypnotic drugs bindto allosteric sites on the receptor to potentiate GABAmediated channel opening.
Babiturates act at a distinct allosteric site to alsopotentiate GABA inhibition.
These drugs act as CNS depressants
Picrotoxin blocks the GABA-gated chloride channel
GABA –Gamma Amino Butyric Acid is a majorinhibitory neurotransmitter in CNS
Benzodiazepines potentiate GABA ergic inhibition atall levels of neuroxis—spinal cord, hypothalamus,hippocampus, substantia nigra, cerebellar cortex andcerebral cortex
Pentameric structure 5 subunits Macromolecular complex of ion channel
Loss of GABA-ergic transmission contributes toexcessive excitability and impulse spread in epilepsy.
Picrotoxin and bicuculline ( GABA receptor blocker)inhibit GABAA receptor function and are convulsants.
BDZs and barbiturates increase GABAA receptorfunction and are anticonvulsants.
Drugs that block GABA reuptake (GAT) and metabolism( GABA-T) to increase available GABA areanticonvulsants
Major role is in the spinal cord
Glycine receptor is an ionotropic chloride channelanalagous to the GABAA receptor.
Strychnine, a competitive antagonist of glycine,removes spinal inhibition to skeletal muscle andinduces a violent motor response.
Neurotransmitter at 75-80% of CNS synapses
Synthesized within the brain fromGlucose (via KREBS cycle/α-ketoglutarate)Glutamine (from glial cells)
Actions terminated by uptake through excitatoryamino acid transporters (EAATs) in neurons andastrocytes
Blocked at resting membrane potential (coincidencedetector)Requires glycine bindingPermeable to Ca++ as well as Na
NMDA receptors involvement in disease- seizure disorders
- learning and memory- neuronal cell death
NMDA receptor as acoincidencedetector :requirement formembranedepolarization
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NMDA receptor is Ca++ permeable
It is the GluR2 subunit that makes most AMPAreceptors Ca++ impermeable
The GluR2 subunit contains one amino acidsubstitution : arginine (R) versus glutamine (Q) in allother GluRs
Transmitter Anatomy Receptor Subtypes andPreferred Agonists
ReceptorAntagonists
Mechanisms
Acetylcholine Cell bodies at all levels; longand 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 cellsynapse
Nicotinic: nicotine Dihydro--erythroidine, -bungarotoxin
Excitatory: cation conductance
Dopamine Cell bodies at all levels;short, medium, and longconnections
D1 Phenothiazines Inhibitory (?): cAMP
D2: bromocriptine Phenothiazines,butyrophenones
Inhibitory (presynaptic): Ca2+;Inhibitory (postsynaptic): in K+
conductance, cAMP
GABA Supraspinal and spinalinterneurons 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
Transmitter Anatomy Receptor Subtypes andPreferred Agonists
Receptor Antagonists Mechanisms
Glutamate Relay neurons atall levels and someinterneurons
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, domoicacid
Metabotropic: ACPD,quisqualate
MCPG Inhibitory (presynaptic): Ca2+conductance cAMP; Excitatory:K+ conductance, IP3, DAG
Glycine Spinalinterneurons andsome brain steminterneurons
Taurine, -alanine Strychnine Inhibitory: Cl–conductance
5-Hydroxytryptamine (serotonin)
Cell bodies inmidbrain and ponsproject 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
Transmitter Anatomy Receptor Subtypes andPreferred Agonists
ReceptorAntagonists
Mechanisms
Norepinephrine
Cell bodies in ponsand brain stemproject 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: Salbutamol Butoxamine Inhibitory: may involvein electrogenic sodiumpump; cAMP
Histamine Cells in ventralposteriorhypothalamus
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
Transmitter Anatomy Receptor Subtypes andPreferred Agonists
Receptor Antagonists Mechanisms
Opioid peptides Cell bodies at all levels;long and shortconnections
Mu: bendorphin Naloxone Inhibitory(presynaptic): Ca2+conductance, cAMP
Delta: enkephalin Naloxone Inhibitory(postsynaptic): K+conductance, cAMP
Kappa: dynorphin Naloxone
Tachykinins Primary sensoryneurons, cell bodies atall levels; long andshort connections
NK1: Substance Pmethylester, aprepitant
Aprepitant Excitatory: K+conductance, IP3, DAG
NK2
NK3
Endocannabinoids Widely distributed CB1: Anandamide, 2-arachidonyglycerol
Rimonabant Inhibitory(presynaptic): Ca2+conductance, cAMP
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