Neurochemical Transmission – Flashcards
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Parts of the standard neuron
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Inputs, dendrites, soma, myelinated axon, nodes, terminal, synapse
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Where are the neurotransmitters held?
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In the synaptic terminal
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What is exocytosis dependent on and why?
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Ca2+ concentration - calcium ions cause vesicles to fuse with the presynaptic membrane
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Mechanism of exocytosis
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Vesicles dock with specialized proteins attached to the inner surface of the presynaptic membrane. Proteins within the vesicular membrane interact with complementary proteins in the presynaptic membrane to form a pore, thus enabling release of the vesicle's contents into the synapse. The whole process is very well orchestrated.
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SNARE Complex
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Process by which priming/fusion and endocytosis/recycling occurs. Polypeptide chains and proteins interact to fuse vesicle to plasma membrane
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Botulinum toxin (Botox)
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Cleaves SNAP-25 (chain on membrane) to prevent vesicle fusion and endocytosis - acts by interfering with the docking process
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Tetanus toxin
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Cleaves synaprobrevin in inhibiotry (GABA glycine) interneurons in the spinal cord - as a result of the inhibition of neurotransmitter release there is over activation of the alpha motor neurons (constant contraction)
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Defining features of a neurotransmitter (5)
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1. Synthesized by the neuron 2. Present in terminal 3. Released from terminal in pharmacologically identifiable form 4. Has reproducible effects at a postsynaptic site 5. There is an identifiable mechanism of termination
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Different types of neurotransmitters
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Biogenic amines, amino acids, and peptides
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Which are the best characterized (most studied) neurotransmitters?
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Biogenic amines
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Which are the most abundant (in quantity, not variety) neurotransmitters?
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Amino acids
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Which are the most numerous?
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Peptides
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Name the biogenic amines
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Dopamine, Norepinephrine, Epinephrine, Serotonin, Acetylcholine
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Name the amino acids
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Glutamate (primary excitatory), GABA (primary inhibitory), Glycine, Aspartate
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Name the peptides
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Somatostatin, *substance P*, cholecystokinin (CCK), neuropeptide Y (NP-Y), *oxytocin*, vasopressin, *enkephalins*, *endorphins*, vasoactive intestinal polypeptide (VIP), *prolactin*, gonadotropin releasing hormone (GnRH), *thyroid releasing hormone (TRH)*, etc.
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Name the four dopamine pathways
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Nigrostriatal, mesolimbic, mesocortical, tuberoinfundibular
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Describe the nigrostriatal pathway of dopamine.
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Substantia nigra to striatum (caudate-putamen) Associated with extrapyramidal motor system (EPS) and movement *What is compromised in Parkinson's *Travels up and branches out*
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Describe the mesolimbic pathway of dopamine.
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Ventral segmental area to limbic structures (nucleus accumbens, hippocampus, amygdala, anterior cingulate cortex) - arousal (feelings of euphoria), memory, motivational behavior *travels forward, small branching and then loops up to limbic*
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Describe the mesocortical pathway of dopamine.
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Ventral segmental area to cerebral cortex (particularly the *prefrontal cortex*) -cognition, executive functioning, stress *travels forward into prefrontal cortex*
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Describe the tuberoinfundibulnar pathway of dopamine.
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Arcuate nucleus of *hypothalamus* to pituitary - prolactin secretion (dopamine inhibition of prolactin release)
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What is associated with dopamine depletion?
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*Parkinson's disease* -cut section of the midbrain where a portion of the substantia nigra is visible. -normal contains darker, melanin concentrated areas -PD has diminished substantia nigra (no coloring)
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Where do projections of norepinephrine originate from?
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*Locus Coeruleus* Lies in the pons just beneath the floor of the fourth ventricle. Neurons projecting from it innervate widespread regions of the BRAIN AND SPINAL CORD
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Locus Coeruleus and norepinephrine
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-Important homeostatic control center for the body -Projections produce excitation and arousal -Receives inputs from limbic structures (amygdala, cingulate cortex), allowing emotions to trigger noradrenergic responses -Plays a role in attention and memory function
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Norepinephrine pathway
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Originates in locus coeruleus and loops once around, branching out towards hypo, hippo, thal, amy, cereb, spinal cord
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Distribution of serotonin
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90% in gut, 10% in brain
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What role does serotonin play in the gut?
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regulates intestinal motility (antidepressants containing serotonin can also cause diarrhea)
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What role does serotonin play in the brain?
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Role in mood, depression, obsessions/compulsions, social interactions/agressiveness
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What does serotonin regulate?
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The release of dopamine and other neurotransmitters to affect appetite, diurnal rhythms
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Serotonin pathway
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Originates in the rostral and caudal *raphe nuclei* and branches into multiple loops that branch throughout the brain -- projects widely throughout the brain
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Dopamine are norephinephrine are ___.
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catecholamines (benzene ring with two hydroxyl groups on neighboring carbons) *Norepinephrine is synthesized from dopamine by dopamine beta-hydroxylase)
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Serotonin is a(n) ____.
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Indolamine (six and five carbon rings with a N in the 5 carbon ring)
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Serotonin biosynthesis
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Synthesized from tryptophan -- further reactions can synthesize melatonin (pineal gland) and degradation produces 5-hydroxyindoleacetic acid
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What is the primary neurotransmitter of alpha motor neurons?
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Acetylcholine
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What role does acetylcholine play in the brain?
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wakefulness, attention, learning, and memory
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What disorders have decreased levels of acetylcholine in the brain?
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Alzheimer's disease, Parkinson's disease, Down's syndrome, and even with normal aging
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What word is associated with neurons and their innervation of acetylcholine?
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Cholinergic
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What is the rate limiting step for acetylcholine biosynthesis?
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Choline availability (Uptake at the synapse)
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Acetylcholine Biosynthesis
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Acetyl-CoA and Choline
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Sources of choline
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Food (egg yolk, veggies, etc.), ACh, phospholipids
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Main difference between glutamine and glutamate
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Glutamine can cross the blood-brain barrier and glutamate cannot (charged)
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What is glutamate?
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The primary excitatory neurotransmitter in the brain.
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What is GABA?
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The primary inhibitory neurotransmitter in the brain.
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What other set of reactions is involved in the synthesis of glutamate and GABA?
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The Krebs cycle (produces alpha-ketoglutarate)
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2 ways to form glutamate
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Glutamine + oxidase (glutaminase) OR alpha-ketoglutarate + GABA-T (transaminase)
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Glutamate
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Rapidly removed from the extracellular fluid astrocytes and then converted to glutamine for release and re-uptake by neurons
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What are the two types of neurotransmitter receptors?
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Ionotropic receptors and metabotropic receptors
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Describe ionotropic receptors
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Work by opening ion channels; receptor regulated channels open or close depending on whether or not a ligand is bound to the receptor
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Examples of inotropic receptors
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AMPA receptor NMDA receptor GABAa receptor Nicotinic ACh receptor
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AMPA receptor
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a glutamate receptor Na+ channel
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NMDA receptor
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a glutamate receptor Ca2+ channel
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GABAa receptor
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# of different binding sites Cl- receptor
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Nicotinic ACh receptor
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Na+ channel
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Describe metabotropic receptors
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Don't form a pore/ion channels; G-protein coupled receptors, span membrane
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How do metabotropic receptors work?
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Neurotransmitter binds with receptor Receptor activates G-protein G-protein subunit breaks away, triggering production of secondary messenger Second messenger opens ion channel To nucleus and other parts of the cell
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What do G-proteins do?
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When activated, triggers secondary receptors - either on membrane or inside cells
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Examples of metabotropic receptors
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Muscarinic ACh receptors (respond to ACh) GABAb receptors Beta-Adrenergic receptors Dopamine receptors Serotonin receptors mGlu receptors
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Beta-Adrenergic receptors
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Norepinephrine
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In metabotropic receptors, each neurotransmitter has ___.
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multiple receptors/types for the same neurotransmitter
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Atrophine
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ACh muscarinic receptor inhibitor
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How does atrophine work?
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Counteracts the effects of the parasympathetic (rest/digest) nervous system, thereby causing: pupil dilation, increased heart rate, reduced salivation and other secretions (sympathetic type actions/responses)
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Glutmate receptors
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AMPA Receptor and NMDA Receptor
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How do AMPA receptors work?
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Glutamate binds, pore opens, Na+ enters, depolarization effect
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How do NMDA receptors work?
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Glutamate still needs to bind, blocked by Mg2+, depolarization causes Mg2+ block to release, channel opens, Ca2+ enters (Ca2+ is an activator)
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Difference between a sedative and a hypnotic
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Sedative: enough depression of CNS, calming effect but doesn't put someone to sleep Hypnotic: depresses CNS to the point where someone is put to sleep (OD problem)
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How are receptors grouped into families?
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pharmacological properties or structure/genes that code for them
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2 types of acetylcholine receptors
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Muscarinic receptors and Nicotinic receptors
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Muscarinic ACh receptors
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-Located at postganglionic, parasympathetic neurons and CNS -Can be excitatory or inhibitory -Blocked by atrophine -7-transmembrane with G-protein coupled to cAMP (M2 and M4) or IP3 (M1, M2, M3) -100-250 msec latency -pharmacological effects are effected by muscarine
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Nicotinic receptors
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-Located at autonomic ganglion cells (NN) and neuromuscular junction (NM) -Excitatory -Blocked by curare -Ligand-gated ion channel, with 5 subunits traversing membrane around the channel -5 msec latency -pharmacological effects are effected by nicotine
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Receptor levels are (dynamic/static)
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DYNAMIC, levels go up or down depending on neural activity, drug exposure, and age
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Neuropsychopharmacology
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Treatment for tobacco dependence: effect on brain nicotinic acetylcholine receptor density Patients that are addicted to cigarettes underwent therapy; the more receptors, the more addicted; after therapy, number of receptors decreased, showing that the levels can be changed
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What are the two mechanisms of termination?
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Uptake and degradation
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What are some drugs that act by blocking reuptake of neurotransmitters?
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*SSRIs* (fluoxetine, paroxetine, setraline, etc.) *Tricyclic antidepressants* (TCAs; desipramine, clomipramine) *Cocaine* *Tiagabine*
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Reuptake of which neurotransmitter is blocked by SSRIs?
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Serotonin
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Reuptake of which neurotransmitter is blocked by Tricyclic antidepressants?
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norepinephrine and in some cases serotonin
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Reuptake of which neurotransmitter is blocked by cocaine?
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Dopamine
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Reuptake of which neurotransmitter is blocked by Tiagabine?
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GABA
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What are degradative enzymes?
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MAO
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How does MAO work?
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Breaks down monoamines (dopamine, serotonin, norepinephrine) into aldehydes
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What are the preferred substrates of MAOA?
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noradrenaline, 5-HT, dopamine
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What are the preferred substrates of MAOB?
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B-phenylethylamine, benzylamine, dopamine
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What inhibits MAOA?
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clorgylene
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What inhibitis MAOB?
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deprenyl
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What enzymes catalyze the degradation of catecholamines?
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Catechol-O-methyltransferase (COMT) - catalyzes the transfer of a methyl group from S-adenosyl methionine to m-hydroxyl group of catecholamines
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What enzymes catalyze the degradation of acetylcholine?
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Acetylcholinesterase (AChE) - catalyzes breakup of acetylcholine to choline and acetic acid
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What drugs act by blocking degradation?
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MAOIs (clorgyline, deprenyl, iproniazid), Carbidopa, ChEIs (physostigmine, tacrine, donepezil, galatamine, rivastigmine)
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How do MAOIs work?
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Inhibits monoamine oxidase (MAO)
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How does carbidopa work?
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Inhibits DOPA decarboxylase (in periphery so L-DOPA isn't converted and can cross into the brain to be transformed there)
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How do ChEIs work?
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Inhibit acetylcholinesterase (AChE)
