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Neurotransmitters. Definition They are chemical messengers which released from neurons to act on adjacent cells which are usually also neurons They are.

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Presentation on theme: "Neurotransmitters. Definition They are chemical messengers which released from neurons to act on adjacent cells which are usually also neurons They are."— Presentation transcript:

1 Neurotransmitters

2 Definition They are chemical messengers which released from neurons to act on adjacent cells which are usually also neurons They are chemical messengers which released from neurons to act on adjacent cells which are usually also neurons Peripherally,adjacent effector's cell may be a muscle or glandular cell Peripherally,adjacent effector's cell may be a muscle or glandular cell

3 Differences Hormones: produced by ductless glands,secreted into circulation, go to distance target cells,to act via specific protein receptors at these cells e.g: Aldosterone,Insulin,ADH,Thyroxin Hormones: produced by ductless glands,secreted into circulation, go to distance target cells,to act via specific protein receptors at these cells e.g: Aldosterone,Insulin,ADH,Thyroxin Autacoids : act on target cells close to their site of release,called local hormones or paracrine secretions e.g: Histamine,prostaglandin Autacoids : act on target cells close to their site of release,called local hormones or paracrine secretions e.g: Histamine,prostaglandin

4 Criteria 1.The substance must be present within the presynaptic neuron 2.The substance must be released in response to presynaptic depolarization, and the release must be Ca2+-dependent 3.Specific receptors for the substance must be present on the postsynaptic cell

5 Major classes of NT Amino Acids Amino Acids Glutamate (excitatory) Glutamate (excitatory) GABA (inhibitory) GABA (inhibitory) Acetylcholine (excitatory) Acetylcholine (excitatory) Monoamine (excitatory) Monoamine (excitatory) Catecholamine: Dopamine, Norepinephrine Catecholamine: Dopamine, Norepinephrine Indolamine: Serotonin Indolamine: Serotonin

6 Neural organization of NT systems Communication (GLT & GABA) Coordination (GLT & GABA) Modulation (Ach, NE, DA,5HT I II III I, II, & III are different CNS areas, e.g. cortex, brainstem, spinal cord

7 1. Amino acids Glutamate (GLT) & ɣ -aminobutyric acid (GABA) Glutamate (GLT) & ɣ -aminobutyric acid (GABA) Main excitatory (GLT) and inhibitory (GABA) NTs in CNS Main excitatory (GLT) and inhibitory (GABA) NTs in CNS Found throughout CNS in long axon and intrinsic neurons Found throughout CNS in long axon and intrinsic neurons Interacts with / modulate activity within other NT systems Interacts with / modulate activity within other NT systems

8 AA synthesis and metabolism Glucose OR glutamine Glutamate (GLT) γ- aminobutyric acid (GABA) Glutamic acid decarboxylase (GAD) Kribs cycle Metabolism Reuptake by presynaptic neuron and glial cells Recycled into glutamate (& GABA)

9 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

10 Glutamate Receptors

11 GLT function & effect Main excitatory NT within CNS Pain perception: Acute: AMPA / kainate (co-transmission substance P) Chronic (neuropathic): NMDA Memory: long-term potentiation (LTP) Epilepsy, excitotoxicity (ischemic episodes)

12 GABA Major inhibitory neurotransmitter in CNS Major inhibitory neurotransmitter in CNS Hyperpolarizes postsynaptic membrane Hyperpolarizes postsynaptic membrane Two types of GABA Receptors: Two types of GABA Receptors: GABA-A GABA-A Cl - channel binding Cl - conductance in presynaptic neurons Cl - channel binding Cl - conductance in presynaptic neurons fast response (1msec) fast response (1msec) Benzodiazepines, barbiturates Benzodiazepines, barbiturates GABA-B GABA-B G-protein coupled receptor G-protein coupled receptor K+ conductance K+ conductance slow response (1sec) slow response (1sec)

13 GABA Receptors

14 GABA functions & effect Main inhibitory NT within CNS Main inhibitory NT within CNS synchronize local neural activity synchronize local neural activity modulation of motor control in basal ganglia modulation of motor control in basal ganglia broad distribution underlies importance of tonic inhibition in CNS broad distribution underlies importance of tonic inhibition in CNS Dysfunction = Epilepsy Dysfunction = Epilepsy

15 2. Acetylcholine (Ach) Earliest discovered neurotransmitter ALL first synapses outside CNS (autonomic ganglia) Terminal NT: parasympathetic NS; skeletal muscle 2 receptor families Muscarinic: metabotropic PNS: parasympathetic NS terminals CNS cortex, hippocampus (HC), striatum Nicotonic: ionotropic (Na+ in) CNS cortex, hippocampus (HC), ventral tegmental area (VTA) PNS: autonomic ganglia, skeletal muscle junctions

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17 ACh synthesis and metabolism choline acetylcholine (ACh) choline [reuptake into presynaptic neuron] + acetate [to blood] Acetylcholinesterase (AChE) Choline acetyltransferase (ChAT)

18 Ach function & effect (brain) 1. 1.Pedunculopontine – lateral dorsal pathway Sleep / wake (REM sleep); motor (ACh DA) 2. 2.Basal forebrain cholinergic pathways Medial septal nucleus HC + amygdala Learning and memory 3. 3.Nucleus basalis of Maynert cortex Attention and memory

19 Ach circuit in brain

20 3. Monoamines Catecholamines Indolamine(s)

21 Dopamine (DA) Found only in CNS (not PNS): widely distributed via pathways ascending from midbrain Can be excitatory or inhibitory [location, receptors,interactions w other NTs] 2 receptor families: D1 (D5) & D2 (D3, D4) D1 striatum; (D5) hippocampus, hypothalamus D2 striatum; substantia nigra (SN) & VTA [autoreceptors] D3 limbic, striatum, cortex; SN [autoreceptors] D4 limbic, frontal cortex

22 DA synthesis and metabolism Tyrosine (amino acid from diet) Dopa Dopamine (DA) DOPAC + HVA Tyrosine hydroxylase Dopa decarboxylase on postsynaptic membrane Monoamine oxidase (MAO) in presynaptic neuron [after reuptake] Catechol-O-methyl transferase (COMT)

23 Wait a minute !! If dopamine is too polar to cross the BBB, how can L-DOPA cross it? If dopamine is too polar to cross the BBB, how can L-DOPA cross it?

24 Answer ! L-DOPA is transported across the BBB by an amino acid transport system (same one used for tyrosine and phenylalanine) L-DOPA is transported across the BBB by an amino acid transport system (same one used for tyrosine and phenylalanine)

25 DA function & effect Nigrostriatal pathway Motor function Mesolimbic and Mesocortical pathways Pleasure & Reward, reinforcement, motivation Attentional and behavioural control Endocrine regulation (Prolactin) Psychosis Schizophrenia, hallucinatory drugs

26 DA circuit in brain

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29 Reward circuitry Prefrontal cortex dopamine nucleus accumbens dopamine VTA dopamine

30 Reward Pathway ?

31 Norepinephrine (NE) Found in both PNS (sympathetic NS), and widely distributed in CNS 3 receptor families (all metabotropic): Alpha-1: excitatory postsynaptic (Ca2+ flow) Alpha-2: inhibitory presynaptic [autoreceptor] (K+, Ca2+) Beta: excitatory presynaptic [autoreceptors] & postsynaptic Synthesized from DA in NE axon terminals; metabolized (after reuptake) by MAO / COMT

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33 NE in PNS: Autonomic (sympathetic) NS Sympathetic NS terminals and adrenal medulla Fight-or-flight response

34 NE pathways in brain 2 major groups of NE neurons ascending from pontine locus coeruleus (LC) and lateral tegmental nuclei (LTN) some overlap, together innervate whole brain

35 NE function & effect Arousal: LC sleep/wake state Arousal attention Tonic NE activity in LC = vigilant attention Scanning, high behavioural flexibility Phasic NE activity in LC = focused attention Selective attention, response inhibition Also involved in nociception, memory, and control of autonomic & endocrine function

36 Serotonin (5-HT) 5-hydroxytryptamine Found in both PNS and CNS CNS contains < 2% total 5-HT in body Outside CNS: broad range physiological functions 7 (!) receptor subtypes (ionotropic and metabotropic) Not clearly associated with specific brain regions Some functional specificity (with overlap)

37 Serotonin Receptors 5-HT 1A CNS: neuronal inhibition, behavioral effects (sleep, feeding, thermoregulation, anxiety) 5-HT 1A CNS: neuronal inhibition, behavioral effects (sleep, feeding, thermoregulation, anxiety) 5-HT 1B CNS: presynaptic inhibition, behavioral effects; vascular: pulmonary vasoconstriction ergotamine 5-HT 1B CNS: presynaptic inhibition, behavioral effects; vascular: pulmonary vasoconstriction ergotamine 5-HT 1D CNS: locomotion; vascular: cerebral vasoconstriction 5-HT 1D CNS: locomotion; vascular: cerebral vasoconstriction 5-HT 2A CNS: neuronal excitation, behavioral effects; smooth muscle: contraction, vasoconstriction / dilatation; platelets: aggregation α-methyl-5-HT 5-HT 2A CNS: neuronal excitation, behavioral effects; smooth muscle: contraction, vasoconstriction / dilatation; platelets: aggregation α-methyl-5-HT 5-HT 2B stomach: contraction α-methyl-5-HT 5-HT 2B stomach: contraction α-methyl-5-HT 5-HT 2C CNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSD 5-HT 2C CNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSD 5-HT 3 CNS, PNS: neuronal excitation, anxiety, emesis 5-HT 3 CNS, PNS: neuronal excitation, anxiety, emesis 5-HT 4 GIT, CNS: neuronal excitation, gastrointestinal motility 5-HT 4 GIT, CNS: neuronal excitation, gastrointestinal motility 5-Ht 5 CNS: unknown 5-Ht 5 CNS: unknown 5-Ht 6 CNS: unknown 5-Ht 6 CNS: unknown 5-HT 7 CNS, GIT, blood vessels: unknown 5-HT 7 CNS, GIT, blood vessels: unknown

38 5-HT synthesis and metabolism Tryptophan (amino acid from diet) 5-hydroxytryptophan Serotonin (5-HT) 5-HIAA Tryptophan hydroxylase L-aromatic acid decarboxylase Monoamine oxidase (MAO) in presynaptic neuron [after reuptake] Aldehyde dehydrogenase

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40 5-HT functions: body Coordinate physiological functioning Physiological regulation Thermoregulation, appetite and digestion, cardiovascular activity, sexual functioning, pain perception Circadian rhythms Sleep/wake cycle: precursor of melatonin (pineal gland)

41 5-HT functions: mind Affect regulation and cognitive function Learned helplessness Anticipatory anxiety Inhibit pain sensation 5-HT contributes to (declarative) memory, particularly for emotional stimuli

42 Summary Neural signaling occurs via electrical impulse down the axon, causing NT release Amino acids glutamate and GABA are the major excitatory and inhibitory NTs in the CNS, modulating activity via long-axon and intrinsic neurons Ach, DA, NE, and 5-HT systems originate in subcortical nuclei and project along organized pathways to modulate brain activity; although interactive, each is associated with certain functions and neuromodulatory disorders

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