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focus of today's lecture... the rest of the amino acid derivatives... what are they???
- step 1: DOPAMINE interest
- step 2: HISTAMINE anticipation
- step 3: ACETYLCHOLINE initial commitment
- step 4: NOREPINEPHRINE deep commitment
- step 5: SERATONIN breakup
SHEND ones are amino acid derivatives
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pre-frontal cortex of awake macaque 2007 research showed that synapses are mostly made of which AA?
- glutamate 44,000nM (90% of synapses)
- GABA 4,000nM (9% of synapses)
- dopamine, seratonin and ACH (~1% of synapses)
- we see that the majority of the brain uses glutamate and GABA
- glutamate = green light = excites things = turns things on
- GABA = red light = inhibiting
- these two are the two main things that regulate brain activity
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TODAYS LECTURE DRUG #1 = DOPAMINE (focus) pathways??? how is it involved in the CNS and PNS???
- BRAIN PATHWAYS
- 1. mesocortical/mesolimbic pathway
- - biological drives like hunger and libido
- - primary motivation/wanting... curiosity
- - for attention and focus... you increase dopamine as you get more interested
- - reward motivation/addiction
- - memory
- - pick something up out of curiosity... increase dopamine when you enjoy it... reward yourself and you like it... motivated to eat more... too much dopamine and feel need to have it... get addiction
- 2. nigrostriatal pathway
- - motor coordination via inhibition of antagonistic muscles
- - impt in relaxing antagonistic muscle so we don't get 'fighting' of movements which is seen in parkinson's
- 3. tuberoinfundibular pathway
- - promotes fertility via inhibition of prolactin from anterior putuitary
- - prolactin stimulates milk and inhibits libido and fertility
- - if you just gave birth, you don't want babies yet
- PERIPHERAL INVOLVEMENT
- 4. adrenal gland (medulla)
- - dopamine is the precursor for norepinephrine and epinephrine
- - dopamine may be released during acute stress
- - I.V. dopamine increases HR and BP
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dopamine pathway that's for biological drives like hunger and libido... primary motivation/wanting... attention/focus... reward motivation/addiction... memory???
mesocortical/mesolimbic pathway in brain
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dopamine pathway that's for motor coordination via inhibition of antagonistic muscles.... impt in relaxing antagonistic muscle so you don't get 'fighting' of movements like those seen in PARKINSON's???
nigrostriatal pathway in brain
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dopamine pathway that promotes fertility via inhibition of prolactin from anterior pituitary... prolactin stimulates milk and inhibits libido and fertility... if you just gave birth, you don't want to have babies yet...
tuberoinfundibular pathway in brain
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dopamine involved in this gland because it's the precursor for nerepinephrine and epinephrine... dopamine may be released during acute stress... IV dopamine increases HR and BP
- adrenal gland (medulla)
- dopamine's peripheral involvement
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dopamine transporter #1: REVERSES transporters (dopamine, NE, seratonin)
- AMEPHETAMINES (ADDERAL)/'METH'AMPHETAMINES
- efflux of dopamine/NE/seratonin from neuronal vesicles
- efflux into synapse via reuptake transporters
- increases dopamine/NE/seratonin levels in brain
- basically increases dopamine to increase focus
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dopamine transporter #2: INHIBITS transporters (dopamine, NE, seratonin)
- COCAINE
- inhibition of reuptake transporter
- increases dopamine/NE/seratonin levels in the brain
- if we increase NT, esp dopamine, that's why it's addicting... the more you get, the more you want it and the more you get addicted
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dopamine transporter #3: INHIBITS transporters (dopamine mostly)
- BUPROPRION (WELLBUTRIN, ZYBAN)
- inhibition of reuptake transporter
- increases dopamine levels in the brain
- remember: dopamine is for focus!
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dopamine receptor family type #1: D-1 like (D1, D5)
- agonism: dopamine
- learning and memory
remember: agonist = green light, antagonist = red light
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dopamine receptor family type #2: D-2 like (D2, D3, D4)
- agonism: dopamine
- negative feedback control (autoreceptors that inhibit it)
- antagonistic muscle control regulates muscle movement
- inhibits prolactin release
- antagonism: several drugs
- motor problems... loss of control of antagonistic muscles
- reproduction problems... loss of libido and fertility
not: these can be presynaptic or postsynaptic receptors
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TODAYS LECTURE DRUG #2 = HISTAMINE (anticipation) pathways??? how is it involved in the CNS and PNS???
- CNS
- - histaminergic neurons
- - release associated with wakefulness (if you're anticipating something, you're more awake)
- PERIPHERY INVOLVEMENT
- 1. hyperdefense
- - released by WBCs in connective tissue
- - causes WBC recruitment and get itching & inflammation
- - indication that something's coming to get you... usually a false anticipation during a lot histamine release... ex. poison ivy and allergies
- 2. eating
- - released by enterochromaffin-like cells (ECL cells) in stomach
- - causes release of stomach acid
- - happens in anticipation of eating... start creation of more stomach acids
- 3. arousal
- - causes vessel dilation in penis and erection
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histamine receptor #1: H1 receptor
- H1 agonism: histamine
- - vessel dilation/permeability, itching, bronchoconstriction, wakefulness
- H1 antagonism: "antihistamine" meds for allergies
- - OTC: loratadine (claritin)... low sedation bec of low entry to CNS
- - OTC: cetirizine (zyrtec)... med sedation bec of med entry to CNS
- - OTC: diphenhydramine (benadryl)... high sedation bec of high entry to CNS
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what determines H1 receptor antagonist ("antihistamine" meds) sedation effects?
- differences seen on side effects of sedation and drowsiness
- determined by the ability to cross the blood brain barrier
- basically, by its ability to cross the brain
- in the examples given... benadryl is good at getting in the brain while claritin has low sedation
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histamine receptor #2: H2 receptor
- H2 agonism: histamine
- - release HCl from parietal cells in stomach, cause ERECTION
- H2 antagonism: heartburn meds
- - cimetidine (tagamet) and ranitidine (zantac)
- - very high doses may result in erectile dysfunction
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histamine receptor #3: H3 receptors
- H3 agonism: histamine inhibits release of histamine (autoreceptor)
- what types of receptors is a histamine autoreceptor? answer = H3!!!
- this is so we don't release too much histamine
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histamine receptor #4: H4 receptors
- H4 agonism: histamine increases WBC chemotaxis
- chemotaxis means chemical movement
- WBC moves towards histamine gradient
- this is how WBC knows you've had some kind of reaction
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TODAYS LECTURE DRUG #3 = ACETYLCHOLINE (initial commitment) pathways??? how is it involved in the CNS and PNS???
- BRAIN
- 1. agonism of nicotinic receptors: ACh, nicotine
- - initial wakefulness, sustaining attention
- - stimulates dopamine release; that's why we can get cigarette addiction
- 2. agonism of muscarinic receptors: ACh
- - short term memory formation
- PERIPHERAL INVOLVEMENT
- agonism of nicotinic receptors: ACh
- a. stimulation of skeletal muscle contractions!!!!!!!
- - remember... need dopamine (interest) to get motor coordination, then need initial commitment = stimulation of skeletal muscle contraction
- b. stimulation of parasympathetic responses (rest and digest)
- - release ACh onto muscarinic receptors of several organs
- c. stimulation of sympathetic responses (fight or flight)
- - releases ACh onto muscarinic receptors of sweat glands (exception)
- - release of norepi/epi from adrenal medulla
- - release of NE onto adrenergic receptors of several organs
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how does ACh affect parasympathetic pathways: salivary gland? heart? airways? GI tract? urinary bladder?
- increases salivary gland
- decreases heart rate
- decreases airways (don't need as much O2, keep out microbes)
- increases GI system
- increases urinary bladder (good time to peeeee)
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how does ACh affect sympathetic pathways: heart? airways? sweat glands? stomach? adrenal medulla? colon?
- increases heart rate
- increases breathing (to get more O2)
- increases sweating (to maintain body temp, to cool off)
- decreases stomach activity
- in adrenal medulla... sits on top of kidneys and increases sources of adrenaline and noradrenaline
- decreases colon activity
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TODAYS LECTURE DRUG #4 = NOREPINEPHRINE/NORADRENALINE (deep commitment) pathways? how is it involved in the CNS and PNS???
basically for sympathetic: fight or flight
- BRAIN (epinephrine in CNS not understood)
- - increased wakefulness, alertness
- - attention, memory, learning
- - strong attention and wakefulness leads to memory which leads to learning
- - this is what makes you the most awake
- PERIPHERAL INVOLVEMENT
- - ACh --> NE directly onto organs
- - ACh --> adrenal medulla --> NE, E into blood
- - increased mobilization of fuels from storage
- - increased breathing
- - increasing HR, SV, BP
- - increased circulation to skeletal muscles
- - increased sweating
- - ACh stimulates release of NA onto organs then onto blood
- - it's all we need for flight or fight response
- - increases more blood flow to cause more oxygen and nutrients to increase heart rate, stroke volume and BP
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norepinephrine transporter #1: REVERSES transporters (dopamine, NE, seratonin)
- AMPHETAMINES (ADDERAL)/'METH'AMPHETAMINES
- efflux of dopamine/NE/seratonin from neuronal vesicles
- efflux into synapse via reuptake transporters
- increases dopamine/NE/seratonin levels in brain
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norephinephrine transporter #2: INHIBITS transporters (dopamine, NE, seratonin)
- COCAINE
- inhibition of reuptake transporter
- increases dopamine/NE/seratonin levels in brain
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norepinephrine transporter #3: INHIBITS transporters (NE, seratonin)
- AMITRIPTYLINE (anti-depression)
- inhibition of reuptake transporter
- increases NE/seratonin levels in the brain
- not for dopamine!
- anti-depression because it increases attention, BUT seratonin is the significant effect to get this antidepressant effect
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norepinephrine transporter #4: INHIBITS transporters (NE only)
- ATOMOXETINE (STRATERRA) (anti-ADHD)
- inhibition of reuptake transporter
- increases NE levels in brain
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adregenergic receptor (for both NE and E) #1: ALPHA-1 RECEPTORS (blood vessels)
- agonism: NE, E, drugs --> vasoconstriction
- drug: phenylephrine (sudafed PE)... decongestant
- antagonism: drugs --> vasodilation
- drug: prazosin (minipress)... hypertesion
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adregenergic receptor (for both NE and E) #2: ALPHA-2 RECEPTORS (brain, adrenal gland)
- agonism (autoreceptor): NE, E, drugs --> decreased NE release
- drug: clonidine (catapres)... hypertension
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adrenergic receptor (for both NE and E) #3: BETA-1 RECEPTORS (heart)
- agonism: NE, E, drugs --> heart stimulation
- drug: dobutamine... heart failure
- antagonism: drugs --> heart inhibition
- drug: metoprolol (lopressor)... hypertension
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adrenergic receptor (for both NE and E) #4: BETA-2 RECEPTORS (lungs)
- agonism: NE, E, drugs --> airway relaxation, bronchorelaxation, bronchodilation
- drug: albuterol (proventil)... asthma
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adrenergic receptor (for both NE and E) #5: BETA-3 RECEPTORS (adipocytes)
- agonism: NE, E --> lipolysis from fat cells
- NE and E mobilizes fuel so it causes breakdown of trig and fat from fat cells to use as fuel
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things to remember or how to memorize adrenergic receptors
- that they're differentiated by which part of the body they affect
- learn sympathetic response so you can "guess" or "estimate" the effect
- adrenergic receptor on blood and give NE or E --> vasoconstrict when stimulated and vasodilate when inhibited
- autoreceptor is the alpha-2 receptor!!! this is to monitor the release of NE and E
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TODAYS LECTURE DRUG #5 = SERATONIN (breakup, cessation) pathways??? how is it involved in the CNS and PNS???
- CNS
- - seratonergic neurons
- - release associated with positive mood, confidence, dominance, cessation of appetite, cessation of arousal
- PERIPHERAL INVOLVEMENT
- 1. GI tract
- - 85% of body's seratonin; from enterochromaffin cells
- - food: triggers seratonin release and gut motility, vomiting
- - dysregulation: irritable bowel syndrome.. prob with seratonin!
- - seratonin keeps food from moving! irritants cause a large release of seraton... get fast GI tract... diarrhea!!!
- 2. blood vessels
- - vessel damage: stimulates seratonin release by platelets to:
- a. seratonin stimulates vasoconstriction!!!
- b. seratonin stimulates fibroblast proliferation
- - fibroblast = repair, secretes collagen
- - excess plasma seratonin can result in fibrosis (excess collagen) of heart valves
- - fibrosis = excess collagen, hard to move things!
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what are the 3 things that can reabsorb seratonin?
- we don't want seratonin loose in CSF or plasma
- the 3 things that absorb seratonin: (1) transporters influx serationin into neurons, (2) neuronal vesicles, (3) circulating platelets
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reversal of transporters
- - efflux of seratonin from neuronal vesicles or circulating platelets
- - increases seratonin levels in the brain and plasma
- - basically causes excess seratonin in brain and blood
- drugs that do this:
- 1. MDMA (ecstasy): positive mood
- 2. fenfluramine: loss of appetite
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inhibition of reuptake transporter
- increases seratonin levels in brain, but not plasma!!!
- antagonism (SSRI): increases seratonin, used for depression, OCD
- drug example of SSRI antagonism: paroxetine (paxil)... antidepressant
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describe why using SSRIs like paroxetine (paxil) has a therapeutic lag??? why patients who are under these antidepressants don't see effects for weeks???
the autoreceptors must first desensitize before the concentration of extracellular seratonin in the synapse can become elevated appreciably
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seratonin receptor 5-HT-1 type #1: 5-HT1A agonism
- 1. decreased release of glutamate to cause less anxiety
- - remember... too much glutamate makes you anxious!!!
- - top 200 drug: buspirone... anxiolytic
- 2. decreased release of substance P to cause less pain
- - see seratonin end pain
- 3. decreased release of ACh to get less traumatic memories
- 4. increased prolactin and oxycotin.... less nursing and milk production.. prolactin and oxytocin released after orgasm to shut off libido
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seratonin receptor 5-HT-1 type #2: 5-HT1B/1D agonism
- decreased release of dopamine to allow prolactin production
- vasoconstriction in CNS
- top 200 drug: sumatripan... anti migraines
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seratonin receptor 5-HT-1 type #3: 5-HT2
- 1. 5-HT2A agonism
- - in CNS general excitation... agonism is LSD and mushrooms to cause hallucinogens... antagonist is olanzapine (zyprexa) for anti-psychotic
- - in PNS, hemostasis via vasoconstriction and platelet aggregation
- 2. 5-HT2B agonism: increases proliferation of fibroblasts
- 3. 5-HT2C agonism: decreases appetite
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seratonin receptor 5-HT-1 type #4: 5-HT3
- stimulates vomiting via receptors on vagus nerve in GI tract and receptors on brain that are accessible to circulating seratonin
- sends a signal to brain to vomit
- antagonism: ondansetron... anit emetic
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seratonin receptor 5-HT-1 type #5: 5-HT4
stimulates peristaltic contraction in GI tract
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