Neurochemistry Test 1

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Resting membrane potential.
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-70mV
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Agonist
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drug that occupies a receptor and activates it
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Antagonist
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drug that occupies a receptor but does not activate it
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Inverse Agonist
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drug that occupies a receptor and activates it in the reverse
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Acetylcholine is responsible for…
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…all motor transmission in vertebrates
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Acetylcholine is produced in… (2)
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the basal forebrain and the parabrachial nucleus
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ACh in the basal forebrain is primarily involved with…
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…attention and arousal (attentive and aroused when BF is around)
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Ach in the basal forebrain is also involved with…
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learning and memory (Alzheimers?)
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ACh in the parabrachial nucleus is involved with…
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REM sleep (# of cells correlate with REM)
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Acetylcholine is also responsible for…
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Reward and addiction (striatum?) and pain/senses
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Increased or decreased ACh release, duration, receptor activation, etc. is…
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BAD! Very bad. Paralysis and even death can result.
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Acetyl CoA + Choline -> Acetylcholine via which enzyme?
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ChAt (cholineacetyltransferase)
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What is the limiting component of ACh synthesis? Why?
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Choline; it can’t be synthesized
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What enzyme breaks down ACh in the synapse? Why is it speshul?
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Acetylcholinesterase; its *extremely* efficient
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What does ChT do? Why is ChT so important?
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Returns choline to pre-synaptic axon from synapse; choline is the limiting factor in ACh synthesis
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What hinders the work of ChT?
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The blood-brain barrier
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Where can CHt be found that is particularly helpful? What happens?
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On pre-synaptic vessicles; merges with presynaptic axon so CHt is placed where ACh was just released
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What are three possible means to regulate CHt?
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1. exo/endocytosis of CHt 2. another protein may shuttle CHt 3. phosphorylation of CHt to activate or deactivate
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How stable are ACh levels? Why?
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Extremely stable; enzymes responsible for ACh synth and degradation are very efficient
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In terms of ACh, what is the effect of estrogen? What does this mean for aging?
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Increased levels of ChAt, causing increased synthesis of ACh. Less estrogen with again means decreased ChAt, decreased synthesis of ACh.
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What are three inhibitors of acetylcholinesterases?
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1. Alzheimer’s Disease 2. Glaucoma, myasthenia gravis 3. Bioterrorism
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What are the two locations where dopamine is produced?
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the substantia nigra and the ventral tegmental area
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What dopaminergic pathway(s) extends from the substantia nigra? What is the role of this pathway?
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nigrostriatal; movement initiation (Parkinson’s)
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What dopaminergic pathway(s) extend from the ventral tegmental area? What are the roles of these pathways?
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mesolimbic… limbic system (addiction, reward, mood); mesocortical… pre-frontal cortex (decision-making, attention, mood)
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What is the primary location of NE production?
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locus coeruleus
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What is the primary function of NE?
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Fight-or-flight (attention, stimulation, arousal)
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You’re gunna do great.
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🙂
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What is the first reactant of catecholamine synthesis?
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L-Tyrosine
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Which enzyme converts L-Tyrosine to L-DOPA?
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Tyrosine Hydroxylase
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What is the positive cofactor to tyrosine hydroxylase?
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BH4
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What is the rate limiting component of catecholamine synthesis?
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Tyrosine Hydroxylase
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What is the second reactant of catecholamine synthesis?
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L-DOPA
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Which enzyme converts L-DOPA to dopamine?
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DOPA decarboxylase
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In which areas of the brain is DOPA decarboxylase present?
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the substantia nigra and the ventral tegmental area
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Which enzyme converts dopamine to norepinephrine? Where is it located?
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dopamine beta-hydroxylase; the locus coeruleus
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What are the two main benefits of storing NTs in vessicles?
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1. Protect NTs from degradation 2. provide releasable pool of NT
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What does VMAT do?
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the vesicular monoamine transporter packages catecholamines into vesicles from the cytoplasm
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Dopamine membrane transporters can be phosphorylated to ________ enzyme activity. How specific are they?
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decrease; not very specific (they could also uptake NE)
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Dopamine membrane transporters rely on ___ _________ to successfully reuptake DA.
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ion gradients
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Example: cocaine, amphetamines, and ritalin bind to dopamine receptors and consequently _______ dopamine transporters. Therefore, they would be considered dopamine agonists or antagonists?
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inhibit; agonists
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Which enzymes break down NE?
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Monoamine oxidase (MAO) and COMT
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Does DA in the striatal pathway get reuptaken or degraded? What about the mesocortical pathway?
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reuptaken; degraded
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Consider the polymorphisms of COMT; what are the three forms and how is DA breakdown rate affected by each?
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1. val/val; increased rate of breakdown 2. val/met 3. met/met; decreased rate of breakdown
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Are men likely to have higher or lower [DA]? [COMT]? Does a COMT isoform help and, if so, which one?
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low [DA], high [COMT]; improve with met/met isoform
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Men tend to have a lower [DA], so they are more likely to be diagnosed with… (2 answers)
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ADHD and Parkinsons
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Are women likely to have higher or lower [DA]? [COMT]? Does a COMT isoform help and, if so, which one?
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high [DA], low [COMT]; no improvement with met/met isoform
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End-product inhibition works best for ______ neurons.
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NE
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Name the two ways in which CA synthesis is regulated. How does each work? How is each relieved?
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1. Local: catechol binds to cofactor BH4… less BH4 for TH to use as its own cofactor, less TH activity. 2. Long-term: catechol binds to Fe3+ site on TH, inhibiting its activity (almost irreversible) Relieved by phosphorylation of N terminal serines
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What is the effect of phosphorylation on TH?
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Increased affinity for BH4; can even overcome end-product inhibition
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Neural stimulation of LC does what to TH activity? How?
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Increases it by increasing its affinity for cofactor BH4 (decreased Km… need less TH for the same effect) and decreasing the affinity for NE (increased Ki… need more NE for the same inhibiting effect).
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NE and seratonin can be released at varicosities; what are the effects of release at varicosities (along the axon) as opposed to at the synapse?
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NT will stay around longer, diffuse more extensively, affect more cells… all because it is further away from the inhibitors and reuptakers at the synapse.
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What are the two actions an autoreceptor will take when excess DA is present?
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Excess DA activates the autoreceptor, which then either a) partially blocks calcium entry into the cell or b) partially inhibits tyrosine hydroxylase
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What are the two firing modes of DA release?
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tonic and bursting
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What happens in the tonic mode of DA release?
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Traditional single spikes, all DA is cleared after each spike
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What happens in the burst mode of DA release?
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Released DA can accumulate in the synapse
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What do DA autoreceptor antagonists do in terms of firing mode?
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Increase firing rate and amount of bursting.
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Which NT has the strongest innervation through the brain?
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Serotonin
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Which regions of the brain is serotonin produced in? Specifically?
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midbrain and hindbrain; raphe nuclei
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What are the two serotonin pathways? What do they innervate? Also, describe their varicosity and please get me a cookie.
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Dorsal; striatum, cortex… varicosities Medial: hippocampus (limbic system), cortex… non-varicose
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Does the activity of serotonin correlate positively or negatively with sleep?
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Negatively; serotonin activity is highest during active wakefulness, and decreases all the way to REM, where it is hardly active at all.
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Name four major functions of 5-HT
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1. General tone of NS (repetitive activities) 2. Stimulate CRH (corticotropin-releasing hormone) release from hypothalamus 3. Negative effects on the ability of light to reset the circadian clock. 4. Decreases food consumption… inhibition of 5-HT stimulate food intake (studies show varying results in human trials)
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What is the first reactant in serotonin synthesis?
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Tryptophan
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What is the limiting component of serotonin synthesis? Why?
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Tryptophan; competes with other “large neutral amino acids” to get across BBB
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What enzyme converts tryptophan to 5-HTP?
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tryptophan hydroxylase
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What enzyme converts 5-HTP to 5-HT?
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aromatic L-amino acid decarboxylase
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Which NT can (eventually) be produced from serotonin?
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melatonin
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SSRIs (selective serotonin receptor inhibitors) target which two mechanisms? For what purpose?
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uptake and degradation of serotonin; increase the amount of serotonin in the synapse
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How can SSRIs backfire?
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They keep so much serotonin in the synapse that autoreceptors are activate
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How does the drug Fenfluramine function with regard to serotonin?
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Fenfluramine blcoks uptake of serotonin into vesicles and forces SERT (serotonin transporter) to run in reverse, pumping serotonin from the pre-synaptic neuron into the synapse without regulation
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What effect does phosphorylation have on SERT?
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decreases SERT activity in absence of high [SER]… the effects of phosphorylation are prevented if substrate (5-HT) is occupying the transporter so SERT isn’t turned off when 5-HT needs to be reuptaken
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Low 5-HT levels lead to __________ (increased or decreased) levels of SERT and SERT activity
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decreased
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What are three methods of regulation for 5-HT release?
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1. Tryptophan availability 2. Firing rate of neuron (pretty constant) 3. Autoreceptors (somatodendritic and terminal)
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In terms of serotonin regulation, what are the two different kinds of autoreceptors and how are they different?
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1. Somatodendritic: away from terminal, ‘activity modulating’, raise threshold to make AP more difficult 2. Terminal: at synapse, ‘release modulating’, directly reduces probability of serotonin release at synapse
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What are the two excitatory NTs?
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glutamate (85%), aspartate
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What are the two inhibitory NTs?
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glycine and GABA
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What is the main role of glutamate? What are two other roles?
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Learning (long term potentiation); purposeful movement, quality of stimuli, processing and understanding sensations, language, “thought”
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What two metabolic processes does the synthesis of glutamate utilize?
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glycolysis and the TCA cycle
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________ -> glutamate
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alpha-ketoglutarate
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What other NT can be (eventually) synthesized from glutamate? Via what enzyme?
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GABA (GAD)
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Why is it important that glutamate be recycled?
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So glucose supply is not depleted.
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Glutamate can be recycled by either the presynaptic neuron or a nearby astrocyte. If glutamate is uptaken by the astrocyte, what must happen before it can be returned to the glutamatergic neuron?
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It must be made into glutamine (via glutamine synthase) and then transferred before it can be made back into glutamate.
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If synaptic glutamate is uptaken by a an astrocyte, what are its two possible destinations?
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1. The original glutamatergic neuron to be reused (must be made into glutamine first) 2. A nearby GABAergic neuron, where it can be made into GABA (must be made into glutamine before it can be sent to the GABAergic neuron)
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Where is glutamine synthase (GS) expressed?
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In astrocytes (glia).
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What protein must glutamatergic neurons express? Why?
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vesicular glutamate transporter (VGLUT); allows cell to store glutamate in vesicles so it isn’t used in metabolic pathways
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glutamate, serotonin, and monoamine transporters are driven by…
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a proton gradient and the use of ATP
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How many VGLUT isoforms are there? Which ones are absolutely vital? What is special about VGLUT3?
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Three; VGLUT1 and VGLUT2; VGLUT3 is expressed in neurons using monoamines, GABA, and Ach… suggesting co-release
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Glutamate has also been found to be released by _________, which also appear to have all three isoforms of __________.
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astrocytes; VGLUT
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Experiments suggest that glutamate can be released by astrocytes; describe the two scenarios that support this finding.
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Get rid of Ca2+ or Na+ channels and you see decreased glutamate release from astrocytes too
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What is the transporter that moves glutamate into glutamatergic neurons or astrocytes?
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excitatory amino acid transporter 2 (EAAT2)
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New evidence suggests that glutamate may be a co-transmitter with ___________. This is supported by the overlap of proteins _______ and ____________, suggesting some vesicles contain both.
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dopamine; TH and VGLUT2
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Where are GABAnergic synapses located in respect to the post-synaptic neuron? Why is this significant?
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synapse at the cell body or axon hillock; stronger influence on neuron
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Which enzyme is responsible for synthesizing GABA from glutamate?
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glutamic acid decarboxylase (GAD)
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Which enzyme degrades GABA?
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GABA-T
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What are the two versions of GAD? Where is each located and how do they differ in terms of function?
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GAD65: localized on vesicles; mostly synthesizes vesicular GABA GAD 67: found in cytosol; synthesizes non-vesicular GABA
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What are the results of GAD65 knockout? GAD67?
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GAD65: increased seizure susceptibility, impaired experience-dependent plasticity GAD67: normal brain activity, but development of a cleft palate
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In which two disorders is GAD67 reduced?
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schizophrenia and bipolar disorder
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Which protein is responsible for vesicular uptake of GABA?
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VIAAT
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Which protein is responsible for the reuptake of GABA into the pre-synaptic neuron?
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GAT
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Which two ions are transported into the pre-synaptic neuron along with GABA by GAT?
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2NA+ and Cl-
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In the case of a seizure, the protein ____ can pump _____ out of the cell, which is accompanied by two positively charged _______ ions, helping to inhibit further neuronal stimulation.
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GAT; GABA; Na+
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Which NT can be either excitatory or inhibitory (depending on the situation)?
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glycine
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Either _______ or _______ can serve as the cofactor at glutamate receptors.
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glycine; serine
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After synthesis and packaging, neuropeptides are stored in ____________.
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large dense-core vesicles
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What genetic process gives rise to unique transcripts, leading to unique peptides?
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alternative splicing
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What is often the rate limiting component of peptide synthesis?
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endoproteolytic cleavage
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The availability of _________ enzymes determines which peptides are produced.
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cleavage
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How are neuropeptides inactivated in the synapse?
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They are not O_O
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During low activity, neurons tend to release traditional neurotransmitters. During high and long-lasting activity, neurons tend to release ____________ which have (short/long)-term results.
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neuropeptides; long
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Name the five alternative transmitters.
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purines, gases, fatty acid metabolites, neurotrophic factors, and D-amino acids
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ATP is a co-transmitter with and is co-released with ________. However, most ATP is released from _______________ terminals.
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Acetylcholine; non-adrenergic, non-cholinergic (NANC)
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ATP is very (long/short)-lived and is broken down into _________, another purine transmitter.
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short; adenosine
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ATP is released in response to… (3 things)
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hypoxia, mechanical stress, injury
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Adenosine is released by _________ cells and increases ______ _______ by _________ _________. It also decreases cell ______ ______ by reducing cellular oxygen requirements.
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stressed; oxygen delivery; dilating vessels; energy usage
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_________ builds up during wakefulness and accumulates to the point where it helps stabilize the (inhibition/excitation) of pro-sleep neurons.
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adenosine; inhibition
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The adenosine transporter is unique in that it is _____________.
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Bidirectional
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__________ inhibits the adenosine transporter. If inhibited, the concentration of adenosine is (increased/decreased), leading to sleep, anti-convulsant effects, and decreased neuronal firing rate.
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ethanol, increased
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Presynaptic adenosine receptors (not ____-receptors) can affect the release of other NTs, such as (inhibiting/augmenting) _________ release.
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auto; inhibiting; glutamate
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Activation of glutamate receptors also leads to _______ production in the post-synaptic neuron, which will feed back to the pre-synaptic neuron and (inhibit/augment) glutamate release.
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NO, augment
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The gas transmitter NO is synthesized by which enzyme?
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Nitric oxide synthase (NOS)
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In addition to its effects on glutamate, NO can also inhibit the reuptake of which NT?
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dopamine
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Loss of NOS abolishes ______ ________.
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long-term potentiation
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The gas transmitter CO is synthesized by which enzyme?
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heme oxygenase
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What induces the synthesis of NO and CO?
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Ca/Cam activation of the appropriate enzyme
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Experiments suggest what sort of relationship between NO and CO?
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additive… they both contribute to the NANC current
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The phospholipase __________ cleaves membrane phospholipids so that they can go signal either the pre- or post-synaptic neuron.
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cPLA2
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Describe endocannabinoids in terms of production and storage.
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Endocannabinoids are not stored; they must be produced and released on demand
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Give an example of an endocannabinoid. Where does it act? What does it do and how?
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anandamide; on pre-synaptic neuron; it acts on the CB1 receptor and reduces excitation, affecting long-term potentiation
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Which phospholipase produces anandamide?
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PLD
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Neurosteroids are released from _________ and affect which two NTs?
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astrocytes; GABA and glutamate
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D-serine is produced exclusively in __________.
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astrocytes
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It may be that _________ is actually the co-factor at glutamate receptors.
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D-serine
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Which enzyme converts the L-serine to D-serine?
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serine racemase
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The target of neurotrophins may shift from _____ ______ to ________ as animals age.
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target-derived; autocrine
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Knockout of neurotrophic factors or their receptors causes….
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DEATH
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Neurotrophins have three important developmental roles; what are they?
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1. process survival 2. neuronal survival 3. synaptic pruning

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