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Dr S Theegala Introduction Synapse Receptors Neurotransmitters Neurotransmitter pathways Receptor mechanisms Receptor location Neurotransmitter transporters Dopamine Noradrenaline Serotonin Acetylcholine Glutamate GABA Questions – MCQs and EMIs Introduction •Discovery of effective psychotropic medication – 1950 • Chlorpromazine – as an antihistamine •MAO inhibitors - Discovered in the efforts to find antitubercular drug •Psychotropic drugs exerts their effects by altering specific chemical processes involved in neuronal communication •Research efforts led to discovery of Neurotransmitter substances Neuroreceptors Neurochemical pathways Synapse •Synaptic unit – ‘The functional building block of nervous system’ •Term ‘synapse’ – Charles Sherrington in 1897 •Types of synapses Axodendritic Axoaxonic Axosomatic •Communication between two neurons involves a combination of bioelectrical and chemical processes Receptors •Neurotransmission •Release of a neurotransmitter •Subsequent activation of a receptor •Activation of postsynaptic receptor •Excitation/ inhibition •Direct effect – ion channel •Indirect effect •Fast transmission opening of ion channels •Slow transmission G protein stimulation or inhibition of an enzyme - or of second messenger Neurotransmitters Experiment by Otto lewi in 1921 offered first evidence of chemically mediated neurotransmission •Amines Ach, DA, NA, 5-HT •Aminoacids Histamine, Glutamate, GABA •Peptides Enkephalin , endorphin, substance p , Vasopressin , CCK ,NT, TRH,NPY, CRF and Orexins •Other Endocannabinoids Neurotransmitter pathways •Long Ascending and descending axonal pathways derived from discrete neuronal cell groups located within specific brain nuclei DA, NA,5-HT and Ach •Long and short axonal- derived from neuronal cell bodies widely distributed through out the brain Glutamate and GABA •Short intraregional pathways within cerebral cortex , striatum ,etc Somatostain neurons in the cerebral cortex Receptor mechanisms •Directly coupled to an ion channel – ligand- gated ion channel/ionotropic receptors Fast transmission NMDA, GABA A, 5HT3 and nicotinic Ach receptors •G- protein receptors When transmitter or agonist binds – either activate or inhibit second messenger systems 1. Adenylate cyclase/cyclic adenosine monophosphate (CAMP) 2. Phospholipase C/Inositol triphosphate / Diacyglycerol DA, NA, 5-HT (except 5HT3), muscarinic Ach, Adrenoceptors and GABA B Receptor location •Post synaptic •Terminal auto receptor •Somatodendritic auto receptor •Presynaptic heteroceptors Neurotransmitter transporters • Most neurotransmitters are removed from synaptic cleft by transporters • Terminates neurotransmitters action on post and presynaptic receptors • Are single protein chains that cross neuronal membrane • Are actually cotransporters transporting Na ions into the cell • They are second major target for psychotropic drugs Dopamine •Neuronal cell bodies Substantia nigra Ventral tegmental area Tuberoinfundibular •Synthesized from tyrosine •Metabolized by MAO (B) and COMT •Inhibitory auto receptor feedback regulation by presynaptic D2 and D3 receptors •5 receptors D1 like – D1 and D5 D2 like – D2, D3 and D4 D1 , D2 – more wide distribution (striatal, mesolimbic and hypothalamic) D3 and D4 more localized Noradrenalin •Principal location of NA containing neurons locus cerulus - axons projecting to limbic areas and spinal cord Lateral tegmental area – projections to forebrain regions •Cortical projections – arousal and alert state •Limbic projections - drive , motivation , mood and response to stress •Synthesized from tyrosine •Metabolized by MAO(A) and COMT Alpha 1 and 2 – post synaptic sites Alpha 2 also on noradrenergic terminals – acts as auto receptors Alpha 1 – excitatory; Alpha 2 – inhibitory Beta 1,2 and 3 – stimulatory Beta antagonists – reduction of performance anxiety Serotonin •Cell bodies – midbrain and brain stem raphe nuclei Ascending pathways - fore brain regions (hippocampus, striatum, amygdalae, hypothalamus and cerebral cortex) o5- HT has a modulatory role in aspects of behaviour including mood, emotion, sleep , wakefulness and regulation of circadian functions , control of feeding and sexual behaviours , body temperature , perception and emesis. Descending pathways oDorsal horn of spinal cord (inhibition of pain transmission) oVentral horn (regulate motor neuron input) Serotonin (contd.) •Synthesized from tryptophan •Metabolized by MAO •14 known 5 HT receptors •All are G- protein coupled except 5 -HT3 5- HT 1A – important target in the action of antidepressants 5- HT 2A – sensory perception 5- HT 2c- when activated reduce food intake, induce anxiety/panic 5- HT3 – antagonists have antiemetic action - regulates DA release in nucleus accumbens 5 –HT 6 - Modulate memory and attention 5-HT7 may be important in depression and circadian functions Acetylcholine •Acetylcholine - More diffuse distribution in the brain •Cholinergic nuclei – basal forebrain and pons •Nucleus basalis of meynert - cortex •Lateral septum – hippocampus (memory dysfunction ) •Synthesized from – choline •Nicotinic receptors - ion channel Two basic types – muscle – found in neuromuscular junction Neuronal – brain •Muscarinic receptor - M1 – M5 all in brain G protein coupled GABA •Widely distributed in the brain •Highest densities – basal ganglia, hypothalamus, amygdalae and other limbic areas •Formed from glutamate •GABA – ligand gated ion channel (Cl-) Benzodiazepines, barbiturates, Zopiclone and alcohol A •GABA B- G protein linked •Significance of them not well understood - important in absence seizures, cognitive performance and regulation of amine release. Glutamate •Excitatory amino acid •Cell bodies - widely distributed in the brain •Synthesized from glucose or from glutamine •Role of glutamate transmission in psychosis (antagonists at glutamate receptors) •Glutamate Receptors ligand- gated ion channels oNMDA; AMPA; Kinate receptors G- protein linked metabotropic channels omGluR1-8 Which of the following statements regarding transporters is true? A. Amphetamines do not gain entry to nerve terminals via transporters B. Inhibitors of GABA transport do not have anticonvulsant activity C. Neurotransmitter transporters are electrogenic D. There are five types of GABA transporters E. Transporters do not terminate neurotransmitter action on post and pre-synaptic receptors. Answer: C Which of the following statements regarding orexins is true? A. They do not have an effect on schizophrenia B. They do not have an effect on response to stress C. They do not have an effect on circadian rhythm D. They are not important in regulation of feeding E. The ox1 and ox2 are highly expressed on cortex Answer: A Which of the following statements is true? A. Anandamide is endogenous against of CB1 and CB2 receptors B. CB1 receptors are found in brain and are potential targets for immune system C. CB2 receptors are associated with treatment of pain and various mood disorders D. CCK receptor antagonists are successful anti panic medications E. Neurotensin has been postulated as a possible target for treating mood disorders. Answer: A Which of the following is ligand gated receptor? A. 5-HT 1A B. Muscarinic acetylcholine C. D2 D. GABA B E. NMDA Answer: E Which of the following is G protein coupled receptor? A. 5-HT 3 B. Nicotinic acetylcholine C. GABA A D. GABA B E. NMDA Answer: D A neurotransmitter released from a neuron regulates its own release by interacting with A. Presynaptic hetero receptors B. Post synaptic receptors C. Terminal auto receptors D. Somatodendritic auto receptors E. Terminal hetero receptors Answer: C A neurotransmitter released from a neuron affects neuronal firing by interacting with A. Presynaptic hetero receptors B. Post synaptic receptors C. Terminal auto receptors D. Somatodendritic auto receptors E. Terminal hetero receptors Answer: D EMI 1 Theme: Neurotransmitters and its precursors Options: A. Acetyl Co A B. Tyrosine C. Tryptophan D. Glutamine E. Glutamate F. Glycine G. Glucose H. Glucosamine I. Homovanillic acid Choose one suitable precursor for the following neurotransmitters 1. Serotonin 2. Noradrenalin 3. GABA EMI 2 Theme: Serotonin receptors Options: a. 5 HT 1 b. 5 HT 2 c. 5 HT 3 d. 5 HT 4 e. 5 HT 5 f. 5 HT 6 g. 5 HT 7 Choose one suitable receptor for the following actions 1. Nausea and emesis 2. Circadian rhythm and thermoregulation 3. Adaptive response to stress Thank you