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PSYC62H3 (280)
Chapter 5

CHAPTER 5.docx

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University of Toronto Scarborough
Suzanne Erb

CHAPTER 5: SYNAPTIC TRANSMISSION, DRUGS & CHEMICAL NEUROANTOMY NEUROTRANSMITTERS & CHEMICAL SIGNALLING IN THE NERVOUS SYSTEM Neurotransmitters commonly viewed as chemicals located in specific regions of neurons, released under specific stimulation, act on specific set of receptors & induce some type of postsynaptic action i.e. change in membrane potential or metabolic activity -include classic transmitters i.e. GLU, GABA, ACh, DA, NE, S-HT + newly characterized substances i.e. anandamide (AN) & adenosine Neurohormone: substances that are synthesized & released from neurons but act as hormones i.e. corticotrophin releasing factor released from hypothalamic neurons & acts at anterior pituitary gland Neuromodulator: any substance that alters neurotransmission in some way -doesn’t show any direct shifts in membrane potential/conductance -same substance can meet definition of neurohormone, neuromodulator & neurotransmitter i.e. DA -most substances that are neurotransmitters also act as neuromodulators -best way to view these terms is to make distinction bw different types of signalling processes -Dale: a given neuron uses the same neurotransmitter at all its synapses & can be identified in terms of which transmitter it uses i.e. dopaminergic neuron -BUT given neuron can co-localize multiple transmitters Monoamines (MA) include: -catecholamines: DA, NE & EPI -indolamine: 5-HT -grouped together bc neurons that utilize monoamines share biochemical features i.e. metabolic pathways & protein expression -contain catechol functional group -share common synthesis & enzymatic breakdown pathways -synthetic pathway for 5-HT resembles catecholamines & monoamine oxidase = metabolizing enzyme -belong to drug classes i.e. stimulants, antiparkinsonian agents, antipsychotics, antidepressants, hallucinogen -ACh (vagusstoff) first neurotransmitter discovered + characterized released by electrical stimulation of vagus nerve -involved in motor control, sleep, emotional & cognitive processes -used to treat parkinsonism & Alzheimer’s disease -Histamine (H) promotes secretion in may tissues (lungs, stomach etc) -drugs that block H receptors =antihistamines=used to treat colds, allergies & stomach ulcers -involved in regulating sleep & wakefulness GLU & asparate (ASP) = excitatory amino acids = ability to induce excitation in neurons -Glutamatergic pathways form much of the basic excitatory wiring of neural circuitry of the brain -excitatory amino acids are very important for neural plasticity & plastic changes in synaptic function regulated by GLU critical for learning & memory =LTP -overstimulation of excitatory amino acid receptors can cause brain damage induced by cerebral strokes or hypoxia bc when GLU neurons die they dump GLU into extracellular space -drugs that block excitatory amino acid transmission act as neuroprotective agents: substances that reduce loss of neurons under various conditions -drugs that block NMDA receptors (subtype of excitatory amino acid receptor) hallucinogenic effects, alter sensory functions & sometimes psychotic side effects; phencyclidine & ketamine GLY = Inhibitory amino acid can act as an excitatory neuromodulator at specific binding at NDMA receptors GLU, ASP & GLY = alpha amino acids; they are in the group of amino acids that normally are the building block units for peptides & proteins GABA = inhibitory neurotransmitter -sedative-hypnotics, anticonvulsants & antianxiety agents i.e. valium act to modify GABAergic transmission -GABAA subtype made up of 5 subunits that can combine in variety of configurations -subunits determines whether receptor has anticonvulsant, anxiolytic, sedative or hypnotic effects AN= endogenous cannabinoid Fatty acid that acts as a neural signalling molecule -THC acts to mimic effects of AN on its receptors Adenosine purine neurotransmitter/neuromodulator -synthesized from cell energy pathways that use AMP-ADP-ATP -NOT stored in vesicles, not released in calcium dependent process -adenosine antagonists = caffeine, theophylline & theobromine Endogenous opiates; morphine & codeine two active ingredients in opium poppy Peptides that are used as neurotransmitters = substance P, oxytocin, vasopressin, cholecystokinin = used as hormones but also central neurotransmitters Neuropeptide Y, vasoactive intestinal peptide, neurotensin & galanin -5 stages involved in chemical neurotransmission: Synthesis: neurotransmitters made from precursor = staring material Storage: Transmitters stored in membranous vesicles, most concentrated in terminals Release: stimulated by influx of calcium into terminal Postsynaptic Action: transmitters bind to receptors & stimulates intrinsic biological activity Inactivation: enzymes break down transmitter or transporters take transmitter back into terminal SYNTHESIS OF NEUROTRANSMITTERS -Enzymatic reactions convert precursor into neurotransmitter depending upon particular transmitter Catecholamines: TyrosineL-DOPADANEEPI T; can be inhibited by a-methyl tyrosine Tyrosine: amino acid precursor TH: Tyrosine hydroxylase-first enzyme in sequence; rate limiting step L-DOPA: drug stimulates synthesis Serotonin: Tryptophan5-HTP5HT TrpH; can be inhibited p-chlorophenylalanine Tryptophan: precursor amino acid TrpH: tryptophan hydroxylase, fist enzyme in sequence; rate limiting step 5-HTTP: drug stimulates synthesis Acetylcholine: Acetyl-coA + Choline  ACh CAT Acetyl-coA: ubiquitous metabolite, involved in energy metabolism Choline: common metabolite, component of phospholipids CAT: choline acetyltransferase, enzyme that forms ACh GABA: GluGABA GAD GABA formed from Glutamate GAD: Glutamic acid decarboxylase, enzyme that forms GABA in neurons Peptides: Peptide neurotransmitters cleaved from larger precursor peptides/proteins i.e. prodynorphindynorphin high-protein meal=5-HT BOTH TOGETHER carbohydrates = tryptophan INCREASES BOTH -protein content can rapidly influence uptake of aromatic amino acids (tryptophan, tyrosine & phenylalanine) -acidic amino acids GLU & ASP don’t have access to the brain from circulation .:. protein ingestion naturally rich in GLU & ASP have no effect on levels of acidic STORAGE OF NEUROTRANSMITTERS -once synthesized most transmitters are stored in vesicles Three major functions of storing neurotransmitter molecules inside vesicles: 1) Storage in vesicles provides a form of protection to the neurotransmitter; interior of the cell contains enzymes that can metabolize the transmitter .:. vesicular storage provides a safe haven for synthesized neurotransmitter 2) Storage of more neurotransmitter than it actually needs which means that a ready supply of transmitter is always available; faster than synthesizing neurotransmitter every time it was excited 3) Subset of vesicles that maintains a pool of neurotransmitter in a kind of pre-release state; close with release sites on terminal membrane & represent readily releasable pool of transmitter molecules Reserpine & tetrabenazine block vesicular storage in monoamine terminals by inhibiting vesicular transporter that pumps transmitter into the vesicle RELEASE OF NEUROTRANSMITTERS -most common mode of release of neurotransmitter release is a calcium-dependent process -when AP arr
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