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93 Cards in this Set
- Front
- Back
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Acetylcholine (ACh) uses
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NMJ-- muscle contractions
Autonomic ganglia PNS Pre-ganglionic sympathetic CNS- local circuits and projections |
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Synthesis of ACh
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1.Acetyl CoA from mitochondria
2. ChAT in cytoplasm at synapse(particulate form in membranes 3.Choline= rate limiting agent 4. Stimulated by depolarization 5.Newly Synthesized is preferentially released - VAChT= vesicular ACh transporter EX: Vesamicol blocks VAChT SYNTHESIS Acetyl CoA+Choline--USES-- Choline acetyltransferase(ChAT)--FORMS-- Acetylcholine+ CoA |
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High Affinity Choline Transporter
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At nerve terminals
Saturable Inhibited by depolarization 50-85% is utilized for ACh synthesis EG: Hemicholinium-- inhibitor for high affinity transport b/c it doesn't pass the BBB SO increased HR due to less ACh being released |
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Low Affinity Choline Transporter
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At cell body
passive diffusion concentration dependent |
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Birks + Macintosh, 1961
(ACh experiment) |
Perfused the superior cervical ganglia with saline+choline
WITH stimulation= ~no change intracellular (synthesis keeps up with release) ~5x increase output WITH Physostigmine= ~ 2x increase intracellular (AChE inside cell) ~No change in output despite intracellular increase WITH Stimulation+Physostigmine ~2x increase intracellularly ~5x increase output |
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Breakdown of ACh
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1. AChE is in presynaptic cytoplasm
2. AChE on post-synaptic membranes (facing synapse) 3. AChE released at NMJ when muscles contract EX: Physostigmine (Eserine)- blocks AChE which prevents the inactivation of ACh, increasing transmitter's postsynaptic effects BREAKDOWN Acetylcholine+H2O-- USES-- Acetylcholinesterase(AChE)--FORMS-- Choline +Acetic Acid |
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Acetylcholinesterase and Butyrlcholinesterase
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butyrl= lower forms
acetyl= more evolved AChE ~hydrolyzes ACh faster than BCh ~Inhibited by high concentrations of ACh ~found in neural tissue ~very efficient-- 5,000 mol/mol/second ----at NMJ released ACh is gone in 2 seconds BChE ~hydrolyzes BCh faster than ACh ~present in glial cells and non-neural tissue |
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Cholinergic Receptors
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Muscarinic
~ G-protein coupled ~ 5 subtypes with different 2nd messenger systems ----all need increased K+ conductance ----defined by pharmacology ----M5 involved in morphine dependence ~Widely distributed in brain ~Present on smooth muscles and glands ~At heart, agonists decrease HR (loewi) ~Agonists= muscarine, carbachol ~Antagonists= atropine, scopolamine |
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2 Acetylcholine Receptor Subtypes
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Nicotinic
Muscarinic |
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Nicotinic Receptor
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~Respond to agonist nicotine
~Transmitter gated ion channels ---Allow Na+ and Ca++ in ~5 subunits-2 a must each bind agonits ~Present at NMJ ~Present in central reward pathway ~Agonist= nicotine ---cigars and insecticides ~Antagonist= curare, a-bungarotoxin ---useful as muscle relaxants in surgery |
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Important ACh Phenomenon
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Miniature end plate potentials (MEPP)
~1st seen at NMJ ~Spontaneous release of NT ~Does not require depolarization, AP, or Ca++ ~Black widow spider venom increases frequency of MEPP's ----depletes terminals of ACh |
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Anti-cholinesterase
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Physostigmine (Eserine)
~Inhibits AChE- leads to increased ACh activity ~Used to treat glaucoma ----increased stimulation of muscarinic receptors-constricts pupils, allows drainage of aqueous humor, decreases pressure in the eye |
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Organophosphorus Compounds
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~IRREVERSIBLY inhibits AChE
EX: Insecticides: Parathion, Malathion EX: nerve gas: Sarin, DFP, Soman ---Actually oils ---"cure" is to wait for synthesis of new AChE ---better "cure" is atropine and general ACh antagonist, but still need artificial respiration Not TOTALLY irreversible PAM (pyridine-2-aldoxine methiodide) ~Antidote for insecticide poinsoning ~Doesn't pass BBB PB (pyridostigmine bromide) ~Reversible AChE inhibitor ~Protects from irreversible inhibitors |
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Selective Lesioning of basal Forebrain Cholinergic Neurons in Mice
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192IgG-saporin
Morris water maze used to test effects Decreases learning, memory, and attention |
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Myasthenia Garvis
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Disorder
Characterized by weak muscles Due to abnormal and decreased nicotinic receptors ~Autoimmune disorder- immune system attacks nicotinic receptors Treatment? ~Short-term with anti-cholinesterases ~Neostigmine and pyridostigmine don't cross BBB |
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Effects of Cholinergic Drugs on Behavior
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MICE- nicotine increases rate of operant responding but at high rates of responding, nicotine decreases responding
SMOKERS fall into 2 categories ~Low arousal smokers ~High arousal smokers |
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ACh in Alzheimer's Disease
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Muscarinic antagonists induce loss of recent memory
AD patients show decreased ACh, ChAT, and high affinity choline uptake AD patients have decreased number of cholinergic neurons projecting to cortex In some(not all) AD patients see decreased muscarinic and nicotinic receptors AD patients also show ~Decreased somatostatin, neuropeptide Y ~Increased NMDA receptors ~Decreased locus ceruleus neurons Little success in treating AD with choline, physostigmine, or muscarinic agonists |
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Is ACh a Hormone?
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(Remember Loewi's heart experiment... but his stim was WRONG)
ACh made by non-neuronal tissue in lungs Foreshadowing for catecholamines |
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Drugs to Know for ACh
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Muscarine
Atropine Hemicholinium Physostigmine Nicotine Curar Black Widow Spider Venom Vesamicol |
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Nicotine
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basic
works with ACh small and large leaf plant Originally came from S.A mainly England loved it Spain held the rights to it before anyone else did look at notebook for further history.. probly not on exam tho. |
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Oral Nicotine Administration
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not popular
pKa of 8.8 with pH of stomach being 4.4 (I think) It won't leave the stomach b/c it's 25 million ionized to 1, unionized |
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Transdermal Nicotine Administration
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chew or snuff
pKa of 8.8 still with blood pH of 7.4 3 ionized to 1 unionized so it will enter blood pipe and cigar tobacco are easier to use this way b/c they are air cured |
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Inhalation of Nicotine
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FASTEST
faster than an IV lungs to blood to heart to brain. similar U/I level to snuff or chew. |
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PNS and Nicotine
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increases HR
Increases BP w/ increased norepinepherine Vasoconstricter Inhibits stomach excretion Natural laxative |
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CNS and Nicotine
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Nicotine receptors on norepinepherine and dopamine neurons
-Located in ventral tagmentum to nucleus accumbance which triggers dopamine release Stimulant Increases brain activity Increases activity in area posthems-- can induce vomitting because there is no BBB (but build tolerance to this) Increases release of Serotonin (5-HT) in raphe cortex nicotine withdrawals occur in hours nAChR receptors- 1 of 2 subtypes of ACh receptors EG: mecamylemine--direct antagonist on nAChR receptors |
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Nesbitt's Paradox of Nicotine
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Effects in CNS don't match what ppl feel
you feel you calm down when you smoke but the CNS activity increases.. 98% of depressed people smoke |
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Biotransformation of Nicotine
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70-80% by Cyptochrome P450 subtype Cytochrome P450 2A6 (CYP 2A6) into metabolite cotinine in liver
genetic difference in some ppl in amounts of CYP 2A6 EX: Methoxsalen inhibits breakdown of nicotine in liver |
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Who smokes?
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30% of population
smokers tend to drink alcohol(depressant) and caffeine(stimulant) decreases anxiety- it's anxiolytic in smokers and causes anxiety in non-smokers smokers have less MAO (monoamine oxidase inhibitor) breakdown of dopamine, serotonine, norepinepherine, so it does make them happier. |
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Learning and Memory with Nicotine
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Improves learning and memory
Nicotine to Alzheimer's patients have increased cognitive function --- most likely due to overall CNS increased activity and maybe not just due to nicotine |
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Withdrawals from Nicotine
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happens in 1-2 hours
short term- depression long term- mood improves hr decreases gain weight inhibited ability to focus and pay attention anger mecamylamine induces nicotine withdrawls |
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Serotinin
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5-hydroxytryptamine
5-HT SERum- components of blood with TONic effects of constricting smooth muscle |
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Serotonin Synthesis
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Tryptophan--USES--tryptophan hydroxylase(TH)--MAKES--5-hydroxytroptophan(5-HTP)--USES--Aromatic Amino Acid(AAA) decarboylase-- MAKES--5-hydroxytryptamine(5-HT; serotonin)
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Regulation of Serotonin Synthesis
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little to no end production linhibition
activity dependent phosphorylation of tryptophan hydroxylase EG: PCPA irreversibly inhibits tryptophan hydroxylase -- 1 to 2 doses reduces 5-HT by 80-90% for 2 weeks 5-HT reuptake mechanism --concentration dependent LOOK AT PICTURE IN SLIDES |
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Breakdown of Serotonin
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Serotonin(5HT)--- USES--monoamine oxidase inhibitor(MAO)--MAKES-- 5-hydroxyindoleacetic acid (5-HIAA)
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CNS Distribution of Serotonin
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Raphe nucleus
--fine axons- more sensitive to MDMA --Beaded axons Pineal body --50x concentration of 5-HT in brain -- circadian rhythm-10x at noon vs midnight --converted to melatonin --released into blood (w/peptides) |
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5-HT 1A Receptors
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Many, not all are autoreceptors
--decrease cAMP and hyperpolarize the neuron --5-HT normally decreases appetite and eating 5-HT 1A agonists increase it --Agonists also reduce anxiety EG: buspirone- Buspar |
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5-HT 2 Receptors
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Type 2
--sexual function --5-HT 2A --Phosphoinositide 2nd messenger system --agonist= hallucinations --antagonists and schizophrenia Type 3 --GI function |
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Function of 5-HT
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Pacemaker pattern and diffuse projections and afferents suggest homeostatic function
5-HT levels correlate well with arousal Food intake Sleep Depression SEE TABLE IN SLIDES |
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Serotonin and Depression
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Reserpine (high BP)- leads to behavioral depression and sedation
--used to treat hypertension, mania, excited schz-- w/ serious side effects --NT levels decreased for many days, but behavioral effects last ony 48-72 hrs --behavioral effects not sen with 5-HT selective drugs, so likely due to NE or DA system Common element of anti-depressant drugs is increased 5-HT activity LOOK AT TABLE IN NOTES |
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Serotonin and LSD
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LSD is 5-HT agonist at some receptors (5-HT 2A) but antagonist at others- net effect is decreased raphe activity
BUT --lesions of raphe do not cause LSD like symptoms --stim of raphe does slightly --LSD has effect in raphe lesioned rats |
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Serotonin and Sleep
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Lesions of raphe lead to wakefulness
Depleting brain 5-HT levels leads to insomnia as 5-HT levels recover, so do sleep patterns Large, intraventricular doses of 5,6-DHT causes insomnia In cats, giving 5-HTP alleviates insomnia BUT --long term treatment that decreases brain 5-HT show return of sleep (almost normal despite 90% 5-HT depletion) SO sleep is important and control is complicated |
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Drugs to Know for Serotonin
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Resperine
--blocks ventricular monoamine transporter (VMAT) --causes leakage of vessicles, depletes 5-HT (and NE and DA) LSD --primarily 5-HT agonist Fenfluramine --anoretic, facilitates 5-HT release 5,7-DHT --serotonergic neurotoxin, doesn't cross BBB MDMA --selective serotinergic neurotoxin PCPA --irreversibly inhibits tryptohphan hydroxylase (TH) |
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Depression
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Bipolar
Unipolar Age of onset of depression is getting earlier and earlier |
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Bipolar Depression
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1% of population
Onset between 20-30 years Monozygotic twins=80% concordance Dizygotic twins=10-20% concordance |
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Unipolar Depression
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5-25% of population
10% of 1st degree relatives More common in women Monozygotic twins=60% concordance Dizygotic twins=30% concordance |
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Past Treatment for Depression
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Opiates
--short lived improvement --addiction leads to increased depression Alcohol --short lived --long term use increases depression --some alcoholics are self-medicating an underlying depression |
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Mono Amine Oxidase (MAO) Inhibitors
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Iproniazid
--first used as a TB treatment --reversed effects of reserprine in rats --1956, Nathan Kline saw dramatic improvement in depressed patients with iproniazid Earliest MAO --irreversible --EG: selegeline MAO-A vs MAO-B --newer class of reversible inhibitors of MAO-A (RIMA's) |
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MAO-I Side Effects
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Enhances effects of NE agonists
--EG: nasal sprays, cold medicine, amphetamine, cocaine Tyramine effect --increases BP Inhibits Cytochrome P450 --prologs activity of barbituates, alcohol, opiates, aspirin, ect.. Was very intense dietary restrictions for patients taking MAO-I's LOOK AT CHART IN SLIDES |
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Tricyclic Antidepressants (TCA's)
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1955-Imipramine synthesized as a more stable form of chloropramazine(anti-psychotic drug)
Competitive inhibitors of NE and 5-HT reuptake mechanisms --EG: Amitriptyline Serotonin specific reuptake inhibitors (SSRI's) are typical TCA's LOOK AT PICTURE IN SLIDES |
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TCA Side Effects
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Greatest morbidity and mortality of commonly prescribed centrally acting drugs
--TI=10-15 Antagonists at muscarine, histamine, adrenergic, and serotonin receptors Leads to low BP, sedation, dry mouth, constipation, sexual dysfunction (sexual dysfunction in 40-70% of patients) --these side effects cause low compliance, estimated 75% of patients receive sub-therapeutic dose |
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TCA Toxicity
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"Hot as a hare, blind as a stone, mad as a hatter, and dry as a bone"
Treatment? --muscarinic antagonist (visostigmine) inhibits AChE |
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SSRI's for Depression
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Atypical TCA's
Fewer side effects= improved compliance! EG: Fluoxetine (Prozac) |
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SSRI Side Effects
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Anxiety, Restlessness, nausea, headache, nervousness, insomnia, sexual dysfunction
Serotonin syndrome --disorientation, agitation, confusion, fever Physical withdrawal effects |
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Dual Acting (SNRI's) for Depression
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Inhibit reuptake of both NE and 5-HT
EX: Mirtazapine (Remeron) Milnacipran (Ixel) Venlafaxine (Effexor) Duloxetine (Cymbalta) |
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Direct 5-HT1A Agonists for Depression
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Buspirone (BuSpar)
Ipsapirone Gepirone (Ariaz) |
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The Lag Time Problem with Antidepressants
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Chemical effects of antidepressants occurs in minutes, but clinical effects can take weeks
Possibly due to downregulation of receptors in response to drugs --chronic treatment with antidepressants leads to decreased alpha(a)-2 receptors and 5-HT autoreceptors Receptor downregulation used to screen antidepressant drug candidates IN PICTURE IN SLIDES Use a graph to measure the amount in arbitrary units over the amount of days comparing the level of drug in the blood (eg Imipramine) compared to the mood level or the inhibition of amine uptake compared to reduction of serotonin and beta receptors |
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The Monoamine Hypothesis in Depression
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Lowered levels of NE and/or 5-HT cause depression
Different kinds of depression are shown by varying levels of 5-HT and NE Catecholamine hypothesis --resperine(depletes NE, DA, and 5-HT) casues depression and amphetamine(increases NE and DA) elevates mood --drugs that elevate DA levels cause euphoria, but don't help with depression --BUT, no consistent changes in NE metabolites or noradrenergic receptors in depressed patients (noradrenergic receptors are stimulated by NE) NE may be underlying cause in only some patients |
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The Biogenic Amine Hypothesis in Depression
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Lowered levels of NE and/or 5-HT cause depression
The 5-HT (indole amine) hypothesis --Reserpine also depletes 5-HT --Reduced levels of 5-HIAA and incresed levels of 5-HT2 receptors in suicide victims --PCPA depletes 5-HT and makes depressed patients worse --Tryptophan is reduced in many depressed patients --effective antidepressant drugs act on 5-HT system |
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Monoamine Oxidase (MOA) Evidence in Depression
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Only inhibitors of MAO-A are effective antidepressants and MAO-A preferentially oxidizes 5-HT vs NE
Ne and DA can be catabolized by either MAO or catechol-O-methyl transferase(COMT), but 5-HT is only catabolized by MAO (catabolize- the breakdown of a molecule into smaller units that release energy) |
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NE or 5-HT in Depression?
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There are at least 2 types of depression
NE and 5-HT modulate each other Patients that are suicidal should probably have antidepressants that focus on 5-HT levels --violent suicide attempts are usually due to 5-HT levels Dual acting drugs are better because they take care of 5-HT and NE --EG in monkeys- lower 5-HT levels jump more risky distances and pick fights they know they will lose --EG in humans- people who engage in extreme sports usually have lower levels of 5-HT levels |
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Circadian Rhythm and Depression
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Melatonin synthesis uses tryptophan that then can't be used to synthesize 5-HT
Melatonin inhibits 5-HT activity directly High levels of melatonin during the day induce depression Short days lead to longer periods of high melatonin levels and can lead to seasonal affective disorder (SAD) Super charasmatic nucleus in hypothalamus sends signal to pineal gland and uses serotonin to make meletonin --light inhibits this --melatonin levels are highest at night when asleep PICTURE IN SLIDES |
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Circadian Rhythm
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Sleep/ wake cycle
Body temp Hormones |
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Sleep and Depression
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Depressed people have abnormal sleep cycles
--longer to get to sleep --less time in deep sleep --earlier REM sleep Sleep deprivation reduces symptoms of depression in 59% of patients Partial sleep deprivation (sleep shifting) helps depression and reduces during lag time Most antidepressant drugs alter sleep cycles |
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Other Uses for Antidepressants
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Prozac is effective in OCD
SSRI's often used in eating disorders Some antidepressants used in ADD and ADHD |
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Drugs to Know for Depression
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Iproniazid
Amitriptyline Fluoxetine (Prozac) Venlafaxine (Effexor) Selegeline Buspirone (BuSpar) |
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Muscarine
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ACh
stim muscarinic cholinergic receptors |
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Atropine
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ACh
muscarine antagonist blocks muscarinic receptors counteracts effects of poisoning with cholinergic agonist |
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Hemicholinium (HC-3)
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ACh
blocks choline transporter |
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Physostigmine (Eserine)
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ACh
blocks AChE |
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Nicotine
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ACh
stimulant by reducing MAO |
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Curare
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ACh
blocks nAChR (nicotinic acetlycholine receptor) |
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Black Widow Venom
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ACh
neurotoxin Increases the release of ACh |
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Vesamicol
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ACh
blocks vesicular ACh transporter |
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Reserpine
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Serotonin
blocks VMAT and causes leakage in vessicle, depleting 5-HT |
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LSD
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Serotonin
5-HT agonist |
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Fenflouramine
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Serotonin
Stimulates 5-HT release |
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5-7-DHT
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Serotonin
neurotoxin that selectively lesions 5-HT neurons in axons and nerve terminals but not to cell bodies in raphe nuclei |
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MDMA
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Serotonin
neurotoxin that selectively kills 5-HT neurons |
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PCPA
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Serotonin
Irreversibly inhibits tryptohpan hydroxylase by 80-90% and lasts for 2 weeks till more TH is synthesized |
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Methoxsalen
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Nicotine
Inhibits enzyme CYP 2A6 |
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Mecamylemine
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Nicotine
induces nicotine withdrawal |
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Iproniazid
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Antidepressant
MAO inhibitor Used initially for TB helped with depression |
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Amitriptyline
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Antidepressant
Tricyclic Increases 5-HT |
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Fluoxetine (Prozac)
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Antidepressant
SSRI |
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Venlafaxine (Effexor)
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Antidepressant
SNRI dual acting on NE and 5-HT |
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Selegeline
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Antidepressant
Irreversibly blocks MAO |
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Buspirone (BuSpar)
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Antidepressant
5-HT agonist |
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Mushrooms (Psilocin)
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Hallucinogenic
5-HT agonist psilocybine is biotransformed into psilocin |
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Peyote (Mescaline)
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Hallucinogenic
5-HT2A agonist makes you VERY ill |
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Dimethyltryptamine (DMT)
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Hallucinogenic
DMT doesn't get metabolized due to beta carbolines 5-HT agonist |
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PCP
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Hallucinogenic
NMDA antagonist used as anethetic |
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Ketamine
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Hallucinogenic
non-competetive NMDA antagonist replaced PCP floating feeling person awake and speaking but has amnesia of event |
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Dextromethorphan (DM)
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Hallucinogenic
cough syrup |
