Synapses and Neurotransmitters Loai.physiology@yahoo.com
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
Communication Between Neurons Electrical synapse Chemical synapse
Communication Between Chemical synapse Neurons Neurotransmitter: is a messenger of neurologic information from one cell to another.
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
Action of Neurotransmitter on Postsynaptic Neuron Two types of receptors Ion channels receptors Second messenger receptors
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.
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.
Agonists and Antagonists
Agonists and Antagonists
Neurotransmitters Synthesis : esp. rate-limiting enzyme and/or substrate Clearance and inactivation Location and pathway Dysfunction and CNS pathology
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.
Fast Neurotransmitteres
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)
Enzymatic Pathways Involved in the Metabolism of Glutamate Glutamate Gluck et al, Am J Psychiatry 2002; 159;1165-1173
Fast synaptic transmission Slow synaptic transmission
presynaptic Kainate Ca ++ NMDA postsynaptic Na + AMPA Kainate Kainate 95% of excitatory synapses in the brain are glutamatergic
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
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
GABA Main inhibitory neurotransmitter in the mammalian CNS
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
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
GABA A and ethanol Ethanol facilitates GABA ability to activate the receptor and prolongs the time that the Cl - channel remains open
GABA Synthesis Glutamate GAD GABA GABA is formed by the α-decarboxylation of glutamate in the reaction catalyzed by GAD (glutamic acid decarboxylase)
GABA Degradation GABA GABA-T succinic semialdehyde GABA is catabolized into the succinic semialdehade in the reaction catalyzed by GABA-T (GABA-Transaminase)
Acetylcholine Choline + Acetyl CoA ChAT Acetyl choline + CoA
Acetylcholine synapse
Acetylcholine receptors
Acetylcholine receptors
Drugs acting at cholinergic terminal
Acetylcholine Pathway Nucleus basalis
Acetylcholine Pathway arousal and reward enhancement of sensory perceptions sustaining attention Nucleus basalis
Acetylcholine Pathway arousal and reward enhancement of sensory perceptions sustaining attention Nucleus basalis Alzheimer s disease loss of cholinergic cells in nucleus basalis
Neuromodulators
Biogenic Amines
The biosynthetic pathway for the catecholamine neurotransmitters 08/20/2008 Lerant: Catecholamines 2008 37
Biogenic Amines Synapses MAO : Monoamine Oxidase
Dopamine
Dopamine receptors G protein-coupled receptors D1 excite D2 inhibit Mainly presynabtic (Autoreceptor) D3 inhibit D4 inhibit D5 excite
3. Dopaminergic (DA) synapse 08/20/2008 Lerant: Catecholamines 2008 41
Dopamine Pathways
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
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
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
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
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
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
Norepinephrine
Norepinephrine receptors α family Current Nomenclature of Adrenergic Receptor Subtypes Β family
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.
Noradrenergic (NE) synapse 08/20/2008 Lerant: Catecholamines 2008 52
Norepinephrine Pathway
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
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.
Serotonin
Serotonin synthesis
Serotonin Pathway
Serotonin Receptors
Serotonin Pathway Almost 17 type of receptor Wide spread
Serotonin Pathway Almost 17 type of receptor Wide spread mood, sleep, sexuality, impulsivity, aggression, stress, drug abuse
Serotonin Pathway Almost 17 type of receptor Wide spread Serotonin system dysfunction involve in : Depression, Schizophrenia, OCD, Eating Disorders, Autism
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
Selective Serotonin Reuptake Inhibitors
dopamine neuron dopamine Substantia nigra 5HT2A receptor serotonin 5HT2A receptor serotonin neuron 11-18 Raphe
Newer Antidepressants and Mood Stabilizers I. Serotonin-Norepinephrine reuptake inhibitor Venlafaxine, Milnacipran, Duloxetine DRI SRI SNRI NRI
II. Serotonin Receptor Antagonist/Reuptake Inhibitor (SARIs) Nefazodone, Trazodone SARI (nefazodone) actions at 5HT synapses NRI SRI Nefazodone 5HT2 5HT1A 5HT2A
Nitric Oxide
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
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
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