Neurotransmitters in CNS

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Neurotransmitters in CNS:

Neurotransmitters in CNS

PowerPoint Presentation:

Neurotransmitters in CNS Dr. NITIN N.PURAM MBBS,MD(Pharmacology )

Discovery of neurotransmitters :

Discovery of neurotransmitters Early 20th century Histological examinations of Ramón y Cajal German pharmacologist Otto Loewi 1921

Definitions:

Definitions Neurotransmitters Neuromodulators Neuromediators Neurotropic factors

Criteria for neurotransmitters:

Criteria for neurotransmitters

Categories of Neurotransmitters:

Categories of Neurotransmitters Excitatatory Amino Acids G lutamate Inhibitory Amino Acids GABA & Glycine Monoamine Mediators & Pathways Noradrenaline Dopamine 5 HT Acetylcholine Histamine

Speed & receptors…:

Speed & receptors… Fast neurotransmitters (e.g. glutamate, GABA) operate through ligand-gated ion channels Slow neurotransmitters and neuromodulators (e.g. dopamine, neuropeptides, prostanoids) operate mainly through G-protein-coupled receptors.

Glutamate:

Glutamate

Glutamate & GABA interlinked:

Glutamate & GABA interlinked

Glutamate Roles:

Glutamate Roles Synaptic plasticity Excitotoxicity Pain Perception Long term Potentiation

Glutamate receptors :

Glutamate receptors Ionotropic (fast): Na+ in AMPA : fast excitatory signals Kainate : fast excitatory, autoreceptor (↑ GLT release) Ionotropic (slow): Na+, Ca2+ in NMDA : sustained, high-frequency excitatory signals Activated by repeated excitatory stimulation: escalation Metabotropic (slow): K+ out; Ca2+ in

Main sites of drug action on NMDA and GABAA receptor:

Main sites of drug action on NMDA and GABA A receptor

NMDA receptors:

NMDA receptors Highly permeable to Ca 2+ , as well as to other cations Na + Activation of NMDA receptors  Ca 2+ entry. Blocked by Mg 2+ Activation requires glycine & glutamate Selective NMDA blocking agents Ketamine & Phencyclidine (PCP-angel dust) both dissociative anaesthetic

NMDA receptor antagonist.:

NMDA receptor antagonist. Competitive antagonists Selfotel: anxiolytic Uncompetitive channel blockers Amantadine: Parkinson's disease Alzheimer's Memantine: Alzheimer's disease Xenon: an anaesthetic. Eliprodil: an anticonvulsant with neuroprotective drug. Non-competitive antagonists Ketamine

GABA:

GABA

GABA:

GABA GABA functions as an inhibitory transmitter in many different CNS pathways. About 20% of CNS neurons are GABAergic; most are short interneurons, but long GABAergic tracts run to the cerebellum and striatum. GABA serves as a transmitter at about 30% of all the synapses in the CNS.

GABA Receptors:

GABA Receptors Two types of GABA Receptors: GABA-A Cl - channel  binding Cl - conductance in presynaptic neurons “fast” response (1msec) Benzodiazepines, barbiturates GABA-B G-protein coupled receptor K+ conductance “slow” response (1sec)

Main sites of drug action on NMDA and GABAA receptor:

Main sites of drug action on NMDA and GABA A receptor

PowerPoint Presentation:

GABAergic Drugs a)GABA A receptor Agonists barbiturates, benzodiazepines, carisoprodol, chloral hydrate, etomidate, glutethimide, muscimol, neuroactive steroids,, propofol,, . b)GABA A receptor Antagonists bicuculline, cicutoxin, flumazenil, furosemide, gabazine, picrotoxin,

GABAB receptor:

GABA B receptor

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GABA B Receptor Agonists baclofen, propofol, GABA B Receptor Antagonists: phaclofen, saclofen. GABA reuptake inhibitors: tiagabine. GABA-transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, GABA analogues: pregabalin, gabapentin.

Monoamine Transmitters:

Monoamine Transmitters Noradrenaline ( Norepineprine ) Dopamine 5 HT (Serotonin) Acetylcholine Histamine

Noradrenaline:

Noradrenaline

Noradrenaline Synthesis:

Noradrenaline Synthesis The basic processes responsible for the synthesis, storage, release and reuptake of noradrenaline are the same in the brain as in the periphery and the same types of adrenoceptor are also found in pre- and postsynaptic locations in the brain.

Noradrenaline Function:

Noradrenaline Function The actions of noradrenaline are mainly inhibitory (β-receptors), but some are excitatory (α- or β-receptors). Noradrenergic transmission functions in the 'arousal' system, controlling wakefulness and alertness blood pressure regulation control of mood (functional deficiency contributing to depression).

Noradrenaline excess :

Noradrenaline excess NA Sympathetic nervous system of brain ADD, ADHD ADD with comorbid anxiety Anxiety – PTSD Panic attacks Depression Sleep disturbances Mediating survival mechanisms

PowerPoint Presentation:

Copper & Ascorbic Acid What cofactors that drive Dopamine to Noradrenaline?

Noradrenaline Pathway:

Noradrenaline Pathway The cell bodies of noradrenergic neurons occur in small clusters in the pons and medulla, and they send extensively branching axons to many other parts of the brain and spinal cord The most prominent cluster is the locus coeruleus (LC) , located in the pons. descending control of pain pathways

Noradrenergic Drugs:

Noradrenergic Drugs Psychotropic drugs that act partly or mainly on noradrenergic transmission in the CNS include Antidepressants Cocaine Amphetamine. Antihypertensive drugs – clonidine & methyldopa

Dopamine:

Dopamine

Dopamine & Brain Function:

Dopamine & Brain Function The brain is designed to orientate itself to experience of high emotional valence Meaning of event Relevance Emotional significance Pain and pleasure Motivation Cerebral microcirculation

Dopamine Significance:

Dopamine Significance Dopamine is particularly important in relation to neuropharmacology; Parkinson's disease Schizophrenia – hyperdopaminergic state Attention deficit disorder Substance abuse Endocrine disorders Fatigue, concentration difficulty, low motivation (anhedonia)

Dopamine Synthesis :

Dopamine Synthesis Dopaminergic neurons lack dopamine β- hydroxylase, and thus do not produce noradrenaline . Tyrosine hydroxylase needs iron as cofactor

Dopamine Metabolism:

Dopamine Metabolism

Dopamine Distribution:

Dopamine Distribution Distribution of dopamine in the brain is more restricted than that of noradrenaline Dopamine is most abundant in the corpus striatum , a part of the extrapyramidal motor system concerned with the coordination of movement

Dopamine Pathways & Function:

Dopamine Pathways & Function Nigrostriatal pathway - 75% of the dopamine in brain Cell bodies in the substantia nigra whose axons terminate in the corpus striatum . Motor Control Parkinsons Disease – dopamine deficiency here.

Dopamine Pathways & Function:

Dopamine Pathways & Function Mesolimbic/ mesocortical pathways Cell bodies in midbrain and whose fibres project to parts of the limbic system, especially the nucleus accumbens and the amygdaloid nucleus and to the frontal cortex . Focus and orient frontal lobes to pay attention Emotion and drug-induced reward systems Mesocorticol dopamine deficiency - ADHD Mesolimbic dopamine deficiency -Schizophrenia

Dopamine Pathways & Function:

Dopamine Pathways & Function Tuberohypophyseal system Group of short neurons running from the ventral hypothalamus to the median eminence and pituitary gland Regulate secretions of pituitary gland Prolactin release (inhibited) Growth hormone release (stimulated)

Dopamine Pathway:

Dopamine Pathway

Dopamine Receptors:

Dopamine Receptors There are five dopamine receptor subtypes. Dopamine receptors.pdf D 1 and D 5 receptors are linked to stimulation of adenylyl cyclase – excitatory frontal lobe D 2 , D 3 and D 4 receptors are linked to inhibition of adenylyl cyclase - inhibitory subcortical areas Most known functions of dopamine mediated mainly by receptors of the D 2 family - schizophrenia

Dopamine Drugs:

Dopamine Drugs

Pharmacological Treatment of Parkinson’s Disease:

Pharmacological Treatment of Parkinson’s Disease Goals: = restore dopamine receptor function. Several types of drugs: Levodopa Dopamine Receptor Agonists Monoamine Oxidase Inhibitors (MAOIs). Catechol- O- Methyltransferase (COMT) inhibitors. Amantidine.

Vomiting:

Vomiting Dopaminergic neurons have a role in the production of nausea and vomiting. N early all dopamine receptor agonists (e.g. bromocriptine ) and other drugs that increase dopamine release in the brain (e.g. levodopa) cause nausea and vomiting as side effects, Dopamine antagonists (e.g. phenothiazines , metoclopramide) have antiemetic activity. D2 receptors occur in the area of the medulla (chemoreceptor trigger zone) associated with the initiation of vomiting and are assumed to mediate this effect.

Serotonin:

Serotonin

Serotonin (5-HT):

Serotonin (5-HT) Lysergic acid diethylamide (LSD) , a drug known to be a powerful hallucinogen acted as a 5-HT antagonist on peripheral tissues, and suggested that its central effects might also be related to this action . 5HT 2A 5-HT is mainly found in 99% in gut, but1 % in brain important. Selective serotonin reuptake inhibitors constitute an important group of antidepressant drugs.

5-HT Synthesis:

5-HT Synthesis 5-HT synthesis resembles noradrenaline. Except precursor is Tryptophan not Tyrosine Availability of tryptophan is the main factor regulating synthesis

5-Hydroxytryptamine pathways :

5-Hydroxytryptamine pathways

Serotonin Pathways:

Serotonin Pathways 5-HT neurons are concentrated in the midline raphe nuclei in the pons and medulla, Projecting diffusely to the cortex Limbic system H ypothalamus Spinal cord S imilar to the noradrenergic projections.

5-HT Functions:

5-HT Functions Functions associated with 5-HT pathways mainly vegetative functions Social engagement Mood and emotion Appetite Sleep/wakefulness Control of sensory pathways, including nociception Body temperature control Vomiting

Serotonin imbalance:

Serotonin imbalance Depression Anxiety Obsessions and Compulsions Pain Sensitivity Aggression Sleep Disorders

5-HT receptor selective drugs:

5-HT receptor selective drugs Serotonin reuptake inhibitors (SSRIs)- fluoxetine , used as antidepressants 5-HT 1D receptor agonists, - sumatriptan - treat migraine 5-HT 1A receptor agonist used in treating anxiety - buspirone & vitamin D 5-HT 3 receptor antagonists, - ondansetron - antiemetic agents 5-HT 2A/2C receptor antagonists Antipsychotic drugs - clozapine

PowerPoint Presentation:

5-HT 3 receptor antagonist :Ondansetron Chemotherapy induce vomiting 5-HT 4 receptor antagonist :Metoclopramide Gastrokinetic and anti emetic 5-HT reuptake inhibitors ( SSRI ) Fluoxetine :Depression and OCD

Acetylcholine:

Acetylcholine

Acetylcholine Synthesis:

Acetylcholine Synthesis Synthesis, storage and release of acetylcholine (ACh) in the central nervous system (CNS) are essentially the same as in the periphery

Acetylcholine pathways:

Acetylcholine pathways ACh is widely distributed in the CNS, important pathways being: Magnocellular forebrain nuclei which send a diffuse projection Degeneration – Alzheimer’s Dementia Septohippocampal projection S hort interneurons in the striatum and nucleus accumbens .

Acetylcholine pathways:

Acetylcholine pathways

Acetylcholine Receptors:

Acetylcholine Receptors Acetylcholine has mainly excitatory effects Nicotinic (ionotropic) Muscarinic (G-protein-coupled – some muscarinic ACh receptors (mAChRs) are inhibitory. The mAChRs in the brain are predominantly of the M1 class

Acetylcholine Function:

Acetylcholine Function Muscarinic receptors appear to mediate the main behavioural effects associated with ACh, Arousal Learning Short-term memory Reward Muscarinic antagonists (e.g. scopolamine) cause amnesia.

Acetylcholine Drugs:

Acetylcholine Drugs Acetylcholinesterase Inhibitor: Alzheimers disease Tacrine Donepezil Galantamine Rivastigmine . Muscarinic Cholinergic Receptor Antagonists : Trihexyphenidyl and Benztropine

Histamine:

Histamine Histaminergic neuron origin Projections Roles 1)arousal 2)body temp 3) sleep Antihistminics :H 1 receptor blocker sedation as side effect

References:

References Rang et al (2007) Rang & Dale’s Pharmacology 6 th Ed. Jay Lombard DO – Neurotransmitters & Behaviour