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1 Synapses and Neurotransmitters

2 Communication Between Neurons Synapse: A specialized site of contact, and transmission of information between a neuron and an effector cell Anterior Motor Neuron Figure 45-5

3 Communication Between Neurons Electrical synapse Chemical synapse

4 Communication Between Chemical synapse Neurons Neurotransmitter: is a messenger of neurologic information from one cell to another.

5 Action of Neurotransmitter on Postsynaptic Neuron postsynaptic membrane contains receptor proteins for the transmitter released from the presynaptic terminal. The effect of neurotransmitter on the post synaptic neuron depend on the type of the receptor

6 Action of Neurotransmitter on Postsynaptic Neuron Two types of receptors Ion channels receptors Second messenger receptors

7 Ion Channels receptors transmitters that open sodium channels excite the postsynaptic neuron. transmitters that open chloride channels inhibit the postsynaptic neuron. transmitters that open potassium channels inhibit the postsynaptic neuron.

8 Seconded messenger receptors (as example G-protein) 1. Opening specific ion channels Ion Channel 2. Activation of camp or cgmp 3. Activation of one or more intracellular enzymes 4. Activation of gene transcription.

9 Agonists and Antagonists

10 Agonists and Antagonists

11 Neurotransmitters Synthesis : esp. rate-limiting enzyme and/or substrate Clearance and inactivation Location and pathway Dysfunction and CNS pathology

12 Neurotransmitters More than 50 chemical substances does function as synaptic transmitters. small molecules which act as rapidly acting transmitters. acetylcholine, norepinephrine, dopamine, serotonin, GABA, glycine, glutamate, NO. neuropeptides. endorphins, enkephalins, VIP, ect. hypothalamic releasing hormones. TRH, LHRH, ect. pituitary peptides. ACTH, prolactin, vasopressin, ect.

13 Fast Neurotransmitteres

14 Glutamate (L-glutamic acid) Main excitatory neurotransmitter in the mammalian CNS 95% of excitatory synapses in the brain are glutamatergic Precursor for the GABA (major inhibitory neurotransmitter)

15 Enzymatic Pathways Involved in the Metabolism of Glutamate Glutamate Gluck et al, Am J Psychiatry 2002; 159;

16 Fast synaptic transmission Slow synaptic transmission

17 presynaptic Kainate Ca ++ NMDA postsynaptic Na + AMPA Kainate Kainate 95% of excitatory synapses in the brain are glutamatergic

18 mglur III mglur II Glutamate synapses glutamine (gln) Glia Glutamine synthetase glutamate (glu) gln glu EAAT1/2 Postsynaptic neuron EAAT3 gln glutaminase mglur I glu mglur I ketoglutarate Presynaptic neuron TCA glu (-) glu KA R glu NMDA R AMPA R KA R Zarate et al. Psychopharmacol Bull 2002;36:35-83

19 Glutamate and CNS disorders 1) Stroke Ischemia no ATP increase Glutamate Over activation NMDA R & AMPA R increase Ca+ cell death 2) dysfunction of glutamatergic transmission may also involve in schizophrenia-like symptoms, cognitive dysfunction, Depression and memory impairment

20 GABA Main inhibitory neurotransmitter in the mammalian CNS

21 GABA Main inhibitory neurotransmitter in the mammalian CNS Ionotropic GABA A Heterooligomeric protein complex that consists of several binding sites coupled to an integral Cl - channel Metabotropic GABA B G - protein coupled receptor, seven transmembrane domain protein

22 GABA-A- ionotropic receptor An integral chloride channel activated by competitive agonists: GABA and muscimol Blocked by convulsant bicuculine (competitive antagonist) and picrotoxin (noncompetitive antagonist) Allosterically modulated by benzodiazepines and barbiturates, which potentiate the effect of GABA

23 GABA A and ethanol Ethanol facilitates GABA ability to activate the receptor and prolongs the time that the Cl - channel remains open

24 GABA Synthesis Glutamate GAD GABA GABA is formed by the α-decarboxylation of glutamate in the reaction catalyzed by GAD (glutamic acid decarboxylase)

25 GABA Degradation GABA GABA-T succinic semialdehyde GABA is catabolized into the succinic semialdehade in the reaction catalyzed by GABA-T (GABA-Transaminase)

26

27 Acetylcholine Choline + Acetyl CoA ChAT Acetyl choline + CoA

28 Acetylcholine synapse

29 Acetylcholine receptors

30 Acetylcholine receptors

31 Drugs acting at cholinergic terminal

32 Acetylcholine Pathway Nucleus basalis

33 Acetylcholine Pathway arousal and reward enhancement of sensory perceptions sustaining attention Nucleus basalis

34 Acetylcholine Pathway arousal and reward enhancement of sensory perceptions sustaining attention Nucleus basalis Alzheimer s disease loss of cholinergic cells in nucleus basalis

35 Neuromodulators

36 Biogenic Amines

37 The biosynthetic pathway for the catecholamine neurotransmitters 08/20/2008 Lerant: Catecholamines

38 Biogenic Amines Synapses MAO : Monoamine Oxidase

39 Dopamine

40 Dopamine receptors G protein-coupled receptors D1 excite D2 inhibit Mainly presynabtic (Autoreceptor) D3 inhibit D4 inhibit D5 excite

41 3. Dopaminergic (DA) synapse 08/20/2008 Lerant: Catecholamines

42 Dopamine Pathways

43 DOPAMINERGIC PATHWAYS Striatum Nucl. accumbens Prefrontal CTX Nigrostriatal pathway Mesolimbic pathway Mesocortical pathway Substrantia nigra of midbrain Ventral tegmental area of midbrain Lerant: Catecholamines 2008

44 Striatum DOPAMINERGIC PATHWAYS Degeneration of nigro-striatal DA system Nucl. accumbens Prefrontal CTX and Decreased DAergic trans-mission in the basal ganglia will lead to Parkinson Disease Nigrostriatal pathway Mesolimbic pathway Mesocortical pathway Substrantia nigra of midbrain Ventral tegmental area of midbrain Lerant: Catecholamines 2008

45 DOPAMINERGIC PATHWAYS Striatum PLEASURE, REWARD AND BEHAVIOR REINFORCING PATHWAY Nigrostriatal pathway Nucl. accumbens Mesolimbic pathway Prefrontal CTX Mesocortical pathway Substrantia nigra of midbrain Ventral tegmental area of midbrain Lerant: Catecholamines 2008 PLEASURE, REWARD AND BEHAVIOR REINFORCING PATHWAY

46 DOPAMINERGIC PATHWAYS Striatum PLEASURE, REWARD AND BEHAVIOR REINFORCING PATHWAY Nigrostriatal pathway Nucl. accumbens Mesolimbic pathway Prefrontal CTX natural Mesocortical pathway drug-induced Substrantia nigra of midbrain Ventral tegmental area of midbrain cocaine Lerant: Catecholamines 2008

47 DOPAMINERGIC PATHWAYS Striatum PLEASURE, REWARD AND BEHAVIOR REINFORCING PATHWAY Nigrostriatal pathway Nucl. accumbens Mesolimbic pathway Prefrontal CTX natural Mesocortical pathway drug-induced Hyperactivity Substrantia of nigra mesolimbic pathway: of midbrain - positive symptoms of schizophrenia (hallucinations, etc) Ventral tegmental area of midbrain cocaine Lerant: Catecholamines 2008

48 DOPAMINERGIC PATHWAYS PATHWAY INVOLVED IN MOTIVATION TO Striatum EXPLORE THE ENVIRONMENT: CURIOSITY, INTEREST, COGNITIVE FLEXIBILITY, DRIVE FOR SOCIAL ENGAGEMENT. Nucl. accumbens Relative hypofunction in schizophrenia: Primary mesocortical dopamine deficiency will increase the NEGATIVE SYMPTOMS like Cognitive blunting, social isolation, apathy, anhedonia Prefrontal CTX Nigrostriatal pathway Mesolimbic pathway Mesocortical pathway Substrantia nigra of midbrain Ventral tegmental area of midbrain Lerant: Catecholamines 2008

49 Norepinephrine

50 Norepinephrine receptors α family Current Nomenclature of Adrenergic Receptor Subtypes Β family

51 Subtype Differentiation β1- The dominant receptor in heart and adipose tissue equally sensitive to epinephrine and norepinephrine. β2- Responsible for relaxation of vascular, uterine, and airway smooth muscle. Less sensitive to NE as compared to E. β3- Insensitive to commonly used β adrenergic receptor antagonists. Previously referred to as the atypical β adrenergic receptor. (The Biochemical Basis of Neuropharmacology, 2003) α1- Postsynaptic. 1A and 1B subtypes defined by their differential affinity for agents such as WB4101 & phentolamine. No 1C subtype. α2- Postsynaptic & presynaptic. First thought to be exclusively presynaptic. 2A & 2B subtypes differentiated by their affinity for agents such as prazosin & oxymetazoline. Helpful rule of thumb- A drug needs to be at least ten-fold selective for one subtype over the other subtypes to be considered a useful subtype selective agent.

52 Noradrenergic (NE) synapse 08/20/2008 Lerant: Catecholamines

53 Norepinephrine Pathway

54 Norepinephrine Pathway LC noradrenergic system is highly responsive external stimuli attention Learning/memory and seep/wake cycle Anxiety and stress response In FRONTAL CORTEX: Mood regulation Hypofunction of pathway Depression

55 NE: Locus Ceruleus FRONTAL CTX β1 postsynaptic receptor In FRONTAL CORTEX: Mood regulation. Hypofunction of pathway: Depression α2 postsynaptic receptor In FRONTAL CORTEX: Attention, working memory, information processing.

56 Serotonin

57 Serotonin synthesis

58 Serotonin Pathway

59 Serotonin Receptors

60 Serotonin Pathway Almost 17 type of receptor Wide spread

61 Serotonin Pathway Almost 17 type of receptor Wide spread mood, sleep, sexuality, impulsivity, aggression, stress, drug abuse

62 Serotonin Pathway Almost 17 type of receptor Wide spread Serotonin system dysfunction involve in : Depression, Schizophrenia, OCD, Eating Disorders, Autism

63 Antipsychotics Clozapine Risperidone Olanzapine Anxiolytics Buspirone Gepirone Antiemetics Ondansetron Granisetron Anti-migraine Sumatriptan Potent antagonist actions at 5-HT 2A receptors, in addition to D 2 antagonism Partial 5-HT 1A agonists Effective for treating GAD, OCD 5-HT 3 antagonist used for Minimizing chemotherapyinduce nausea 5-HT 1 agonist, exerts some Selectivity on 5-HT 1D receptors

64 Selective Serotonin Reuptake Inhibitors

65 dopamine neuron dopamine Substantia nigra 5HT2A receptor serotonin 5HT2A receptor serotonin neuron Raphe

66 Newer Antidepressants and Mood Stabilizers I. Serotonin-Norepinephrine reuptake inhibitor Venlafaxine, Milnacipran, Duloxetine DRI SRI SNRI NRI

67 II. Serotonin Receptor Antagonist/Reuptake Inhibitor (SARIs) Nefazodone, Trazodone SARI (nefazodone) actions at 5HT synapses NRI SRI Nefazodone 5HT2 5HT1A 5HT2A

68 Nitric Oxide

69 Nitric Oxide NH 2 COOH NH Arginine C NH 2 NH Nitric Oxide Synthase (NADPH, THB) NO Citrulline NO is a diffusible bioactive gas produced from arginine by nitric oxide synthase NOS-1 (nnos) Constitutive Neuronal Ca ++ -dependent NOS-2 (inos) Inducible Mostly Glial Ca ++ -independent Pro-inflammatory NOS-3 (enos) Constitutive/Inducible Vascular endothelium Ca ++ -dependent

70 Nitric Oxide (NO) NO is a diffusible bioactive gas produced from arginine by nitric oxide synthase NO is widely distributed in brain and peripheral tissues NO is not stored and synthesis is regulated by the enzyme activity

71 Nitric Oxide Regulation of blood flow - Neuron-derived NO plays a major role in the regulation of blood flow, vasodilation and increased blood flow At the cellular level, NO can changes intracellular metabolic functions that modify neuronal excitability and influence neurotransmitter release In the brain, NO acts as a neuromodulator to control behavioral activity, influence memory formation, and intensify responses to painful stimuli May be responsible for glutamate induced neurotoxicity

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