Neuropharmacology Exam 2 Guide PDF

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NEUROPHARMACOLOGY EXAM 2 QUIZLET PRACTICE https://quizlet.com/_84ehnb?x=1jqt&i=1cffge Neuropharmacology Exam 2 - Chapter 7: Widely Projecting Systems Flashcards

inhibitor for these enzymes so they don’t degrade it all ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Dopamine receptors - 5 types ● Gs -- stimulates adenylyl cyclase ○ Dopamine receptors 1 and 5 ○ Have longer intracellular loop ● Gi -- inhibits adenylyl cyclase https://quizlet.com/_84epw8?x=1jqt&i=1cffge ○ Dopamine receptors 2, 3, 4 Neuropharmacology Exam 2 - Chapter 8: Introduction to the Nervous ○ Have longer C-terminal System Flashcards ● Gq -- stimulates phospholipase C ● Dopamine receptors are targets for antipsychotics https://quizlet.com/_84evvi?x=1jqt&i=1cffge ● Two subtypes of dopamine receptor Neuropharmacology Exam 2 - Chapter 8: Cholinoceptor-Activating and ○ D-1 receptors (short i3, long C-terminal) Cholinesterase-Inhibiting Drugs Flashcards ○ D-2 receptors (long i3, short C-terminal) ● Downregulation of receptors https://quizlet.com/_84f2c1?x=1jqt&i=1cffge ○ If receptors are overstimulated → surface Neuropharmacology Exam 2 - Chapter 8: Adrenoreceptor Drugs Flashcards receptors are endocytosed (and can be recycled) ○ Mainly seen in GPCRs) https://quizlet.com/_84f3vf?x=1jqt&i=1cffge ● Upregulation of receptors Neuropharmacology Exam 2 - Chapter 9: Neuropeptides Flashcards ○ If antagonists are administered https://quizlet.com/_84h38z?x=1jqt&i=1cffge Widely Projecting Systems ● There are excitatory and inhibitory neurons in the brain that work Neuropharmacology Exam 2 - Chapter 10: Neurotrophins Flashcards together ○ BUT some areas are more excitatory or more inhibitory https://quizlet.com/_84haaj?x=1jqt&i=1cffge Neuropharmacology Exam 2 - Pain and Inflammation Flashcards ○ Cerebellum -- purkinje cells → mostly inhibitory ○ Striatum -- part of basal ganglia → exclusively inhibitory CHAPTER 7 - WIDELY PROJECTING SYSTEMS Dopamine projections ● Dopaminergic neurons Monoamines ● Catecholamines ○ Produce dopamine ○ Start from lower part of brain ○ Dopamine ○ Norepinephrine ○ Project to ○ Epinephrine ■ Nucleus accumbens ● Indolamines ■ Frontal cortex ○ Serotonin ■ Striatum ■ Hypothalamus Monoamine transporters ● 12 transmembrane regions. It’s large, compared to 1. Mesolimbic projection ○ Part of limbic system, involved in: ○ GPCR - 4 ○ NMDA and AMPA - 6 ■ Reward system ■ Drug addiction ○ Sodium - 6 ● The big loop is the regulator ○ Increase dopamine levels Intro to Catecholamines ○ Start from ventral tegmental area ● Dopamine, epinephrine, norepinephrine ○ Project to nucleus accumbens ● They all start from the same chemical pathway 2. Nigrostriatal projection ○ Start as tyrosine ○ Important for motor function and movement ● These shut down dopamine synthesis reactions ■ D1 receptors - increase movement ○ Monoamine oxidase (MAO) ■ D2 receptors - decrease movement ○ catechol-O-methyltransferase (COMT) ○ Start from substantia nigra ○ Project to striatum (in basal ganglia) Catecholamine synthesis ● Starts as tyrosine 3. Mesocortical projection ○ Mediate cognitive functions ● There’s a hydroxylase and then a decarboxylase ● *** tyrosine → L-Dopa → dopamine → norepinephrine → ○ Start from ventral tegmental area epinephrine ○ Project to ■ Nucleus accumbens Phenylketonuria (PKU) ● Phenylketonuria - mutation in the enzyme that makes ■ Frontal cortex 4. Tuberohypophyseal projection tyrosine (phenylalanine hydroxylase) → mental retardation ○ Release of dopamine inhibits prolactin secretion ○ Start from hypothalamus ● Phenylalanine accumulates ○ Project to anterior pituitary gland ● Gotta remove Phe from diet ● The function of the last projection is not well-known Degradation of catecholamines ○ Starts from ● Reuptake ● Repackaging dopamine into vesicles ■ Periaqueductal gray ■ Central mesencephalon ● These enzymes are intracellularly present ■ Hypothalamic nuclei ○ MAO (monoamine oxidase) ■ Lateral parabrachial nucleus ○ COMT ○ Projects to thalamus ○ MAOI - prolongs dopamine release by inhibiting MAO ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ○ Selegiline Norepinephrine (NE) ○ When you give L-dopa, you need to also give an

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Places that have neurons that release NE ○ Locus coeruleus ○ Lateral tegmental region ● Involved in sleep-wake cycle, arousal ○ Tonic rate while awake ○ Decreases in slow-wave sleep ○ Does not fire in REM sleep ○ Very high firing of locus coeruleus predicts danger NE has alpha receptor ● Gq - Alpha 1 ● Gi - Alpha 2→ on presynaptic neuron, regulates NT release ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Serotonin ● Not a catecholamine but an indolamine ● Derived from amino acids ● Aka 5-hydroxytryptamine Synthesis of serotonin ● Tryptophan → 5-hydroxytryptophan → serotonin → Nacetyl serotonin → melatonin Degradation of serotonin ● MOA-A > MOA-B ● 5-hydroxyindoleacetic acid ● High serotonin levels do not inhibit serotonin synthesis → serotonin builds up ○ Regulation depends on ■ Second messengers involving cAMP ■ Oxygen levels in blood Serotonin receptors - 7 types ● Gs - 4, 6, 7 ● Gi - 5HT receptor ● Gq - 2 ● 5HT is the only ionotropic receptor, the rest are GPCRs ● Serotonin receptors are targets of antidepressants ● Antimigrane drugs work on 5HT receptors ● Blocking serotonin reuptake transporter → increase serotonin ○ SSRIs (serotonin reuptake inhibitor) ○ SNRIs (serotonin-norepinephrine reuptake inhibitor) Specific clinical uses of manipulating receptors (3 of 7) ● 5HT1 “slow inhibition” ○ Through G proteins ○ Reduces adenylyl cyclase activity ○ On pre- and post- synaptic ● 5HT2 “slow excitation” ○ Through G proteins ○ Increase K+ and Ca2+ influx ● 5HT “fast excitation” ○ Ion-coupled to Na+ ○ Some modulation of Ca2+ channels ○ Trigger vomiting Serotonin pathways in the brain ● Can also be released non-synaptically ● Actual pathways all emerge from the same set of neurons in the Raphe region of the brainstem 1. Caudal pathway ○ To medulla and spinal cord ○ Mainly 5HT1 receptors ○ Contraction of ■ Muscles! ■ Uterus → muscle cramps ■ Blood vessel walls → increase blood pressure ○ Stimulates release of endorphins that then inhibit pain messages 2. Middle pathway ○ To: ■ Cortex along with NE axons ■ Basal ganglia along with DA and Ach axons

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○ Mainly 5HT2 receptors ○ Induces positive mood ○ Uses SSRIs as antidepressants Rostral pathway ○ To: ■ Raphe nuclei within ● Autoreceptors ● 5HT1 do self-inhibition ■ Sensory cortex ● Sensory cortex -- particularly visual perception ● Hallucinogens ● 5HT2 receptors ■ Limbic system ● Pleasure and anxiety ● 5HT1 receptors ■ Hypothalamus and thalamus ● Thermoregulation ● 5HT1 receptors ■ Suprachiasmatic nucleus ● Sleep/wakefulness ● 5HT1 receptors

CHAPTER 8 - INTRODUCTION TO AUTONOMIC NERVOUS SYSTEM Autonomic nervous system

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General functions ○ 1- regulation of heart ○ 2- regulation of secretory glands ○ 3- regulation of smooth muscles Parasympathetic functions ● Helps conserve energy! ● Slow heart rate ● Increase gastric secretion ● Empty bladder ● Empty bowel ● Focus eye for near vision ● Constrict pupil ● Bronchoconstriction ●

When to take drugs that inhibit these functions ○ Atropine - prevents constriction of pupil ○ Surgery ○ COPD Sympathetic functions ● Overall homeostatic objectives ○ 1- Maintenance of blood flow to the brain ○ 2- Redistribution of blood flow during exercise ● Both parasympathetic and sympathetic, there is a ganglion ○ 3- Compensation for blood loss (from vasoconstriction) between two neurons ● Specific functions ○ Ach is the neurotransmitter here ○ Regulate cardiovascular system ○ Receptor is a pentameric nicotinic receptor ■ Increase cardiac output ● Parasympathetic ■ Vasoconstriction ○ Long pregang, short postgang ○ Fight-or-flight response ○ Ach and muscarinic receptor at the end ○ Thermoregulation ○ Craniosacral outflow ■ Sweat to cool body ● Sympathetic ■ Dilate vessels to increase heat loss ○ Short pregang, long postgang ■ Piloerection to decrease heat loss ○ NE and adrenergic receptor at the end How ANS regulates physiological processes ■ Exception: sweat glands release Ach ● Innervation by both sympathetic and parasympathetic ○ Thoracolumbar outflow ○ Opposite effects ● Other info on the NTs ■ E.g. heart rate ○ Adrenal medulla releases epinephrine (Epi) into the ○ Complementary effects blood ■ E.g. male reproductive system ○ Motor neurons release Ach on skeletal muscles ● Innervation by one division Adrenal glands ○ E.g. blood vessels are innervated exclusively by ● Secrestes Epi and NE when stimulated by the SNS sympathetic nerves ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ● Feedback ○ E.g. baroreceptor reflex

Receptors Cholinergic receptors Receptors activated by Ach

- includes nicotinic and muscarinic receptors ● Nicotinic receptors ○ 5 subunits (pentameric) ■ 2 alpha ■ 2 beta ■ 1 something else ○ Ionotropic ○ At neuromuscular junction and CNS ○ Responses to nicotinic cholinergic stimulation ■ Depolarizing, let Na and K inside ■ Causes muscle contraction ■ Always excitatory (EPSPs) ■ Conductance and therefore potency depends on subunit composition ■ Related to reward system ○ NicotinicN receptors ■ On CNS and adrenal medulla ■ Do CNS excitation and release of adrenaline ○ NicotinicM receptors ■ On skeletal muscles, neuromuscular ■ Do skeletal muscle contraction ■ Blocked by tubocurarine ○ NicotinicG receptors ■ On autonomic ganglia ■ Do ganglionic transmission ● Muscarinic receptors ○ On all organs innervated by the PNS ○ GPCR ○ 2 subtypes, 5 receptor types (M1-M5) ■ Linked to Gi ● → Inhibition of adenylyl cyclase ● → Opening of K channels ● Hyperpolarization ● Reduced contraction of heart muscles ■ Linked to Gq ● These look like parasympathetic effects ● → Formation of IP3 → release of ● ** antagonists for these receptors would have no effect bc there is intracellular Ca2+ nothing to block ● → Formation of DAG → ○ You need an agonist to have an antagonist activation of PKC ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ● Depolarization Adrenergic receptors ● In glands and smooth muscles ■ M1 ● Gq-protein ● increased IP3 ● decreasing K+ permeability ● ganglia ■ M2 ● Gi-protein ● decreased cAMP ● activation of K+ channels or inhibition of Ca2+ channels ● heart ■ M3 ● Gq-protein ● Glands ● On all organs regulated by the SNS (except sweat glands) ● increased IP3 and Ca2+ ● Alpha receptors are not selective ● vascular endothelium ● NE is selective, does not want to activate B2 receptors ● Nitric Oxide (NO) ● Alpha 1 receptors ○ Gq coupled ○ Postsynaptic Functions of peripheral cholinergic receptor subtypes ○ Activates phospholipase C ○ Physiological effects: mainly constriction ■ Vasoconstriction → increase bp ● Can block receptor to treat hypertension ■ Bronchoconstriction ??

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■ Contraction of GI and GU sphincters ■ Smooth muscle contraction, like in uterus ■ Pupil dilation Alpha 2 receptors ○ Gi coupled ○ Presynaptic ○ Usually autoreceptors ○ Inhibits adenylyl cyclase → Inhibits NT release ○ Physiological effects: mainly reducing constriction ■ Negative feedback mechanism ■ Reduce vasoconstriction → decreased bp ○ If you block this → more NT in synapse → system more active ■ BUT if you try to block alpha receptors without being specific about which one, you might accidentally inactivate the system Beta 1 receptors ○ Gs coupled ○ Postsynaptic ○ Activates adenylyl cyclase ○ Physiological effects: mainly in heart ■ Increases conduction velocity (dromotropic) ■ Increases heart rate (chronotropic) ■ Increases contractility (inotropic) Beta 2 receptors ○ Gs coupled ○ postsynaptic ○ Activates adenylyl cyclase and Na+/K+ pump ○ Physiological effects: in smooth muscle and gland cells ■ Vasodilation ■ Bronchodilation ■ GI relaxation ■ Uterine relaxation ■ Gluconeogenesis, lipolysis, gluconeogenesis, and insulin release ■ Opposite effects of alpha 1 receptors! In general, adrenergic stimulation can have both excitatory and inhibitory effects ○ Responses vary due to different receptor proteins

CHAPTER 8 - CHOLINOCEPTOR-ACTIVATING AND ■ Do sweat tests - pilocarpine makes you CHOLINESTERASE-INHIBITING DRUGS sweat → can detect changes in ion Choline esters concentration ● Ex. Varenicline - for nicotinic receptors ● Acetylcholine ○ Ach is the starting molecule, and you can add ○ Competitively inhibits Ach ○ Used to stop addiction to nicotine, brings down modifications to make it more stable or more selective dopamine level for different receptors ● Ex. Methacholine - challenge test for asthma ○ Ex. adding a carbonate group increases resistance to cholinesterase activity ○ Parasympathetic agonist → contracts lungs ● Methacholine ○ Will not dramatically affect healthy person ● Ex. Carbachol - help with glaucoma ● Carbamic acid ● Carbachol ● Ex. Cevimeline - help with dry mouth from radiation therapy Indirect acting ● Bethanechol Pharmacological effects of muscarinic agonists ○ Inhibit acetylcholinesterase → prolong action of Ach at ● These seem like parasympathetic effects neuroeffector junction ○ Types of cholinesterase ● Eye ○ Pupillary constriction ■ Acetylcholinesterase (AChe) ○ Rapid and specific Ach hydrolysis in ○ Facilitation of aqueous humor outflow to decrease intraocular pressure cholinergic synapses ● Cardiovascular ■ Butyrylcholinesterase (CuCHe), aka ○ Sinoatrial node Pseudocholinesterase ■ Decreased heart rate ○ Non specific; in plasma and tissues ○ Atria ○ Cholinesterase inhibitors ■ Decrease in contractile strength ■ Inhibiting cholinesterases → increases Ach ○ Atrioventricular node concentration and duration of effects ■ Decrease in conduction velocity ■ Causes fasciculations (increase in skeletal muscle ○ Ventricles contractions) ■ Small decrease in contractile strength ■ Ex. neostigmine - intermediate-acting ■ Decrease of CO ■ Ex. carbamates - reversible ○ Arteries and veins ■ Ex. physostigmine - used in insecticide ■ Dilation via NO → hypotension ■ Irreversible bc they phosphorylate the enzyme ● GI ○ Contraction of smooth muscles ■ Ex. edrophonium - short-acting ■ Cholinesterase inhibitors used for Alzheimer’s ● Exocrine glands ○ Sweating ● Need to pass BBB ○ Lacrimation ○ Cholinesterase inhibitor effects ○ Salivation ■ Cardiovascular effects on heart Ach effects on the body ● Negative chronotropic, dromotropic, and ● Heart inotropic actions ○ Ach causes parasympathetic and vagus nerve ■ Autonomic “SLUD” syndrome activation ● Salivation ○ Reduces heart rate ● Lacrimation ● Urination ○ Longer intervals between APs ○ Inhibits Ca2+ channels ● Defecation ● Blood ■ Muscle twitch ○ Drop in bp ○ Clinical use of cholinesterase inhibitors (anticholinesterases) ○ Relaxation of blood vessels ■ Reversal of nicotinic receptor neuromuscular blocking ○ Very transient effect bc Ach is quickly destroyed agents PARASYMPATHOMIMETICS (cholinomimetics) ● Like when you’re done with surgery ● Drugs that facilitate or mimic some or all of the actions of the ■ Management of myasthenia parasympathetic nervous system ■ Treatment of glaucoma ■ Antimuscarinic drug intoxication ● Two ways to activate the system: Direct acting PARASYMPATHOLYTICS (anticholinergics) ● Drugs that reduce or inhibit some or all of the actions of the ● Bind to and activate muscarinic or nicotinic receptors ● Ex. Bethanechol parasympathetic nervous system ○ More resistant to hydrolysis by AChE ● Two ways to inhibit the system ○ AND more specific/selective for muscarinic receptors Muscarinic receptor antagonists ○ Used to treat ● Effects of muscarinic antagonists ■ Postoperative ileus ○ Inhibition of secretions ■ Congenital megacolon ○ Blockade of vagally mediated bradycardia ■ Urinary retention ○ Mydriasis ○ Add betamethol to make it selective for muscarinic ○ Inhibition of GI motility ○ Relaxation of smooth muscle (bronchia, biliary and receptors ○ Carbamic acid makes it resistant to AChE urinary tracts) ● Ex. Pilocarpine - partial agonist ○ Helps with motion sickness ○ Used to: ○ :( → lose near vision ■ Constrict pupil and manage glaucoma ■ Ciliary muscles cannot contract ■ Treat xerostomia ■ Lens cannot accommodate for near vision

■ Tachycardia in heart Examples of muscarinic antagonists (based on function) ■ Cycloplegia and pupillary dilation in eye ○ Surgery ■ Dry mouth from salivary glands ■ Atropine - preanesthetic ■ Relaxation of intestinal muscle and ■ Glycopyrrolate - reduces respiratory and GI constipation in GI tract secretions ■ Difficulty emptying bladder ○ For motion sickness Neuromuscular-blocking drugs ■ Scopolamine - CNS ● Skeletal muscle relaxants ○ Respiratory ● Work at the neuromuscular junction ■ Ipratropium and tiotropium - an inhalation ● Non-depolarizing: neuromuscular nicotinic receptor competitive drug for asthma and COPD antagonists ○ GI ○ Ex. D-Tubocurarine (d-TC) ■ Pirenzepine and glycopyrrolate - treats ■ Competitive nondepolarizing block irritable bowel syndrome, sometimes peptic ■ Competitive antagonist that blocks nicotinic ulcer cholinergic receptors ○ Cardiovascular ■ Clinical uses ■ Attenuate response of reflex vagal discharge ● Reduce muscle movement in accompanying myocardial infarction surgery ○ Urinary ● Allow small amounts of anesthesia ■ Treatment of urinary urgency and ● Allow artificial support of respiration incontinence ○ Ex. Pancuronium ○ Parkinson’s disease ■ Drugs - diphenhydramine, benztropine, ■ Inhibition of NE reuptake → increase in procyclidine heart rate and MAP ■ Long acting ■ Treat by blocking muscarinic receptors ○ Cholinergic poisoning - insecticides ■ More potent than curare ○ Ex. Atracurium ● Side effects of muscarinic antagonists ■ Less potent than pancuronium ○ Dry mouth ■ Short acting ○ Tachycardia (increased heart rate) ● Ex. Succinylcholine ○ Increased intraocular pressure ○ Depolarizing block ○ Difficulty in micturition ○ Constipation due to GI atony ○ Initially activate nicotinic receptors in skeletal ○ High dose toxicity: “hot, red, dry, and mad” muscles → muscle contractions ○ But no sweating bc you’re blocking muscarinic ○ Later → they quickly cause paralysis through receptors sustained depolarization and subsequent Ganglionic blocking drugs depolarization blockade ● Block nicotinic cholinergic receptors in autonomic ganglia either Botulinum toxin: Botox by: ● Blocks cholinergic transmission at both striatal and smooth muscle synapses ○ Competitive antagonism or ○ Blockade of ion channel ○ Cleaves parts of SNARE proteins (SNAP-25, ● Basically does the opposite of the autonomic tone VAMP2, syntaxin) → prevent the release of Ach ● _________________________________________________ ● Initially used to help with face spasms → later used it to ● Background on autonomic tone reduce wrinkles → the different types have a ton of ○ In most organ systems, both divisions exert a different uses tonic action → effectors have intermediate activity ○ Three possibilities ■ Opposing effects ● E.g. respiratory smooth muscle, heart ■ Complimentary effects ● E.g. skeletal muscle, vasculature ■ No interaction ● Somethings only have control by either sympathetic innervation or parasympathetic innervation ● E.g. upper respiratory, spleen, sweat glands, piloerector muscles, and most blood vessels are controlled by sympathetic ● E.g. GI, cardiac, and iris muscles are controlled by parasympathetic ● _________________________________________________ ● Ganglionic blockers - nicotinic cholinergic receptor antagonists ○ Effects are opposite of the autonomic tone ○ Effects on organs with sympathetic tone ■ Vasodilation in arterioles and veins ■ Decreased sweating ○ Effects on organs with parasympathetic tone ●

CHAPTER 8 - ADRENOCEPTOR DRUGS ● Sympathetic neurotransmission is called “adrenergic” ● Norepinephrine (NE) is released by the most postganglionic sympathetic nerve fiber ● Epinephrine (Epi) is released by the adrenal medulla Types of adrenoceptors and their effects

Direct-acting catecholamines

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● See above for more info on adrenergic receptors Where the different receptors are

Synaptic neurotransmission ● We can modify permeability ● We can modify action of COMT and MAO ● We can modify specificity for subtypes ○ Isoproterenol is more selective for beta ○ NE is more selective ...