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