NEUROPHARMACOLOGY PSYC 4037
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Date Created: 10/13/15
ANTIDEPRESSANTS Efficacy Clinical trials have large placebo effects At least 20 are refractory to multiple antidepressants Only about 30 have complete remission with a single antidepressant Approximately 23 show a 50 decrease in depressive symptoms within 8 weeks Different classes of antidepressant are roughly equal in efficacy though some evidence SNRIs may be more effective Antidepressant mechanisms PRESYNAPTIC POSTSYNAPTIC SeHT Noradrener ic V neuron g r 3 1A lPa 39 quot PIPZ IP NE gt NE gt NE 39 synthesis x Muptake AR Modulation of cell signaling pathways and cell function 5 HT 5HTRW Serotonergic neuron 02AFl I 539HTR1A1Dn 239 NE HT gt synthesis MAOIs I no Nonselective Hydrazines proniazid socarboxazid no Phenelzine no Nonhydrazine Pargyline no Tranylcypromine no Preferential MAOA inhibitors Clorgyline no Moclobemide yes Brofaromine yes MAOB Inhibitors Selegiline no MAOIs and hypertensive crisis Dangerous elevation of blood pressure MAOIs prevent the breakdown of endogenous and exogenous monoamines tyramnine Causes significant food drug interactions AKA the quotcheese effect Reversible MAOIs have reduced side effect Reversible MAO A inhibitors not available for use in US due to interactions with SSRIs and SNRIs and low financial potential Considered last line medications May be more effective in atypical depression TRICYCLIC ANTIDEPRESSANTS The discovery of CPZ led drug companies to synthesized and screen similar drugs Roland Kuhn tries imipramine in psychiatric patients circa 1955 and discovers its antidepressant effect quotCHIJoRPRoMAzINE j I I IMIPRAMINE Roland Kuhn The Tricyclic Antidepressants tetra cycl ics 1 Imipramine 4lt 00 HZCHacHz 3 Amitriptyline CH CHCHZCHZ r 5 Clomipramine C1 9H 39t CH I 3 r CH3 CH3 1 CHZCHZCHZ 4 CH3 7 Doxepin O H CHCHZCHaiN CH3 j 5 Angapine L am 93 2 Desipraminequot 5quot W CHZCHZCHZ 13 CH3 5 4 Nortrlpiylme H 5 CHCHZGHZ rl1 CH3 6 Trimipramine H CHggHCHZrlu cH3 CH3 8 Protriptyline 5 H CHZCHZCHE div CH O O 10 Mapmtiline IDHZCHZCHZ NHCHa 0 Q Q Amine classification Ammonia NH3 H 39IN H Primary amine Secondary amine Tertiary amine R1 N quotquotquot u 3 39H R R1 H H R2 R1 R2 Tricyclics mechanisms of action Secondary amines eg desipramine Norpramin nortriptylinePamelor have relative selective activity against NE reuptake Tertiary amines amitriptylineElavil imipramineTofranil inhibit NE and 5HT reuptake TCAs also have 0L1 H1 and antimuscarinic actions which contribute to side effects such as hypotentiontachycardia sedation dry mouth blurred vision constipation urinary retention and memory impairment TCA have lower therapeutic index than new drugs Tricyclics have differential effects on NE and 5HT Those that have preferentially strong effect on NE produce greater behavioral activation Those that have preferentially strong effect on 5HT produce greater mood elevation Spectrum of action of antidepressant sub ku rIOEPRESSANYS Prlmamr energizing Primlily mead Maine rhymemucs Thymuiu With psymomcier With bipolar Witt OHM simulating yawnmac Ming compenem component comment MAO Inhibitors De si primine Imipamkno Amitrigtyline l noclvbouzide Chlmimipumme Nomlpryrine l39lm m39 Dibenzwin mmwrimw 7quot 7 39 quotquotquot 9 Mailluce n Prowloryt39ma Secondary amines Dimeihacn39n Donspim Tertiary amines s momma Antidzptesswc alwaan moodvatmating was Fig I SSRIs us VARKET 1987 Fluoxetine Prozac 1992 Sertraline Zoloft 1993 Paroxetine Paxil 1998 Citalopram Celexa 2003 Escitalopram Lexapro First SSRI was zimeldine marketed in Europe banned clue to Association with GuillainBarr Syndrome More about SSRIs 0 Higher therapeutic index than TCAs Used for a variety of clinical symptoms Depression OCD Social anxiety Generalized anxiety Panic disorders PTSD Premenstrual dysphoric syndrome SSRI mechanism of action Increased 5 HT stimulates autoreceptors decreasing serotonin release With prolonged treatment autoreceptors down regulate Postsynaptic receptors thought to remain responsive to serotonin Other late developing effects include decreased expression of SERT activation of CREB and increased expression of BDNF ATE users per year 93 Prescriptions by Antidepressant Class 1 00 90 TCA users I 55W users 5 0 II Other ATD users 70 II MAOI users do quot 5390 40 I 30 20 10 Q V 7 Mei V I L s 7 I L s 1992 19573 1994 i 93995 I 996 i997 1993 I99quot 2000 200i SNRIs US market 1999 Venlefaxine Effexor SN RI 2004 Duloxetine Cymbalta SNRI 2008 Desvenlafaxine Pristiq SNRI 2009 Milnacipran Savella SNRI approved in US only for fibromyalgia Interestingly fibromyalgia is frequently comorbid with psychiatric conditions such as anxiety and stress disorders eg PTSD SNRIS Many of the older TCAs blocked both 5 HT and NE reuptake Newer drugs without the tricyclic structure also block both 5 HT and NE reuptake but with reduced side effect burden All SNRIs are more selective for SERT than NET Ratio selectivity SERT vs NE varies widely from 116 venlafaxine to 16 milnacipran Serotonin receptor antagonists Trazodone Desyrel nefazodone Serzone mirtazapine Remeron mianserin not marketed in US Sedating used to treat insomnia Blockade 5 HT2 family receptors is most potent shared action Drugs in this class also act on 0L1 0L2 and H1 receptors which are responsible for hypotension and sedation Contribution of these other actions to antidepressant effect unknown Trazodone known for causing pripism Atypical antidepressants Bupropion Wellbutrin Zyban NE and DA re uptake inhibitor May also stimulate release of NE and DA Nicotinic antagonist No sexual side effects Mild stimulant Extended release approved in 2006 for SAD 2011 Vilazodone Viibryd SSRI amp 5 HT1a partial agonist Atypical antipsychotics Used as adjunctive treatment with antidepressants Aripiprazole Abilify Olanzapine Zyprexa Quietiapine Seroquel All are available as combination with fluoxetine Stimulants Amphetamine Adderall Methylphenidate Ritalin Modafinil Provigil stimulates monoamine release and is histaminergic Stimulant augmentation increasingly used Pharmacokinetics of SSRls Humming Paroxetiue Scnrnlint Cilalop iFLuvoxnming Volume m dislrihmion lt 1246 gt3 8 Pcrccnr pmmn bound 4 v at so 77 Pmk plasma level hours H 278 78 14 z s Pm enr hammz hum 272 20 24725 33 15 Major mcmbnlilc mum s 16 days NM 6611mm N N Standard dose range mg 2rny 10750 5040 1040 507300 Absm39prion 31mm by a M No Yes No Nu m or led smlus A1th mm in the No Yes Yes Yes No gcv39mrnc pancnr Reduced demnce in 1 t rcml patiean 1 or N nOL appLIcublc Cyclic Antidepressant Side Effects Hypo Anti Weight agitation sedation tension Celine rgic gain 3 3 0 FluoXetine O 0 0 0 Pa roxetine O O O O 3 0 3 0 Sert raline O 0 O 0 3 0 3 0 Citalopram O 0 O O 0 3 0 3 0 Bupr opion 3 4 0 O 0 2 0 O O Mirtazapine O 0 4 O O O O 0 O Amitriptyline 0 2 3 3 3 O 2 2 3 From Goodman amp Gillman The Serotonin Syndrome Acute serotonin toxicity usually caused by combinations of drugs that enhance serotonin function 0 15 in overdose prevalence in proper use not known but rare Symptoms Fever Muscle rigidity Tachycardia and hypertension Agitated delirium Seizures coma and death SSRIs and Suicide A link between SSRIs and increased risk of suicide has been suggested since the early 19905 Akathesia is suspected of being responsible for linkage between SSRIs and suicide Main proponent of this view is David Healy Accused drug companies of deliberately trying to conceal the linkage Controversy Whether there is a real link is still hotly debated Critics of Healy say suicides in persons on antidepressants are due to mental disorder not the medication Indeed since the introduction of SSRIs suicide rates in adolescents in US and Europe decreased Adolescent Suicide in the US 3 mm Rates per Imam for Hnmlcldl sulnlde um Flmrm Related Dem a vamn Ann 1519 senma Veus mnznm Fig 1 Suicide rates in Sweden 19692003 Percentages refer to the total suicides uncertain cases 350 ill 5 459 7139 1 403 A a gt Toni 250 NW 200 Uncenmn cases Smacks per loo mm ml39nbmnn S v 3 3 1 395411 1 we e e quot e lt w scssonGBrJPsyc1itly 200715075 Cupyright 2003 The Ruyai CcHege cf Psydwiatrists Nevertheless FDA takes action 2004 The FDA recently required a quotBlack Box warning about increased suicidal ideation in adolescents Since 2000 SSRI prescriptions in children have declined and suicide has increased 1250 1200 115a 1111 E 1050 mm 39 39 95m EDD Suicide Rate since 1993 I Rate per l m Black box warning revised to Include age 24 and below 1St black box warning Children and adolescents I All antibsychotics O Typical antipsycho tics Atypical antipsychotics Prevalence per 1080 patientyears 1992 1993 1994 1995 1996 1997 71998 1999 2000 2001 2002 2003 2004 2005 Year FIGURE 1 Prevalerice of antipsycholic prescriptionsin children and adolescents in geneval practice in the United Kingdom Tolerance and Dependence Tolerance often develops to SSRI side effects eg sedative amp autonomic Tolerance also develops to therapeutic effect called the quotProzac poop out SSRIs produce physical dependence some withdrawal signs Agitation Mania Irritability Sensorymotor za ps Depression relapse Bipolar Disorder Etiology unknown theories tend to propose biological mechanism opposite to depression According to USPHS diagnosis of bipolar disorder increased 40 fold between 1994 and 2003 Mood stabilizers used to treat bipolar disorder Lithium is main drug for serious BPD Proposed Mechanisms of Lithium Direct alteration of neuronal excitability Increased serotonin synthesis and release Inhibition of catecholamine function Alter second messengers Increased dopamine and serotonin sensitive adenylate cyclase Decreased norepinephrine sensitve adenlyate cyclase Inhibition of Inositol salvage ohsuul awwquoqduuoul 01150le pauquan madam H1 J1 Hf Xn hm Mum hm Um asqudsuqck acqudltuLId luapuadapw ZBW uapusdapuy 2m mm mm 37 i A psuqmm n asewquuq 912ququ mammdepw m mapuadapug 43 L 2 n m U quotI A 21 2 39H 4 ssmuquong acexqucoqg Lg mapuadqu 2m uapuadap1 9W 4 div in 4 5J1 lt4 nng r 2 1 4W mm I Z 3 mm was 1 a Inm ggxg 8 WW mam 1 Id 39 Ll BunoAg apmsouloudsoud uo 5139443 Lunmln Anticonvulsants Used To Treat Bipolar Disorder Carbamazepine Tegretol Carbitrol Valproate Depakene Topiramate Topamax Tiagabine Gabitril Gabapentine Neurontin BPD and atypical antipsychotics Olanzapine Zyprexia Quetiapine Seroquel Aaripiprazole Abilify Risperidone Risperdal Ziprasidone Geodon Addiction Dependence and Tolerance Theoretical Constructs Addiction De nition Repetitive compulsive obsessive deleterious harmful drug self administration for nonmedical purposes Cornpulsive drug seeking behavior Obsession and preoccupation with drug use Addiction is not dependence Dependence A state physical or psychological produced by drug exposure that is revealed by physical or psychological abnormalities upon abstinence Addiction can occur in the absence of dependence and Vise versa you can be addicted but not dependent cocaine and dependent but not addicted caffeine Addiction is not tolerance Tolerance Reduction of potency ef cacy or duration of a drug effect due to prior exposure L OMAmmo Dose mg REEPDI39I se Tolerance to different effects of a drug may vary Margin of Initial drug 1 f 39 E V39 use gt TDIEWEIHCE Related Concepts Acute tolerance tachyphylaxis Cross tolerance Reverse tolerance sensitization Homeostasis Homeostatic opponent process model of dependence amp tolerance Drug effect only Non tolerantnon dependent individual MCI Llow I Norlrnal High Body Temperature Drug effect plus opponent process Tolerant individual I I ltDmgeffect I gt Opponent process Opponent process only Dependent individual I l l l l Opponent process Relation between tolerance and dependence A dependent person is tolerant A tolerant person is not necessarily dependent because there ar elots of ways to produce tolerance that don t initiate dependence There are mechanisms that produce tolerance Without initiating opponent processes Types of tolerance Metabolic pharmacokinetic eX enzyme induction Not getting drug to brain be enzymes are breaking it down Takes rnore drug to produce effect Horneostatic pharmacodynamic eX receptor downregulation drug gets to brain tissue not breaking it down correctly Behavioral context speci c Learning Habituation learning not to respond to stimulus Operant conditioning Classical conditioning Demonstration of context speci c tolerance Mar150 msz t H 39 f 397 1 J J I y 72ifamp a fery 6 0005 fa N 5m e uira Me f 76560 It i uti ur fo m Classical Conditioning m m Food Automatically salivatian 39 Fullnwed by ellcits I Conditioned Uncondiuoned unconditioned slimmus c5 stimulus UCS response ucn Aflar some number of repenuans Salivalion Conditioned Condlllaned skimulus 5 response CR 3 Classical conditioning Classical Conditioning Explanation of Behavioral Tolerance One explanation Drug UCS body responds to drug no learning needed Drug effect UCR Opponent process CR Environmental cues CS 0 Another explanation Enuge kctGJCS Opponent process UCR Opponent process CR iEnVnonnmnu cuesCS Conditioned Withdrawal Reduced levels of drug in the bmly mm D deln in ubtaining the subsan L U5 4 Euvnumneum stimuli L39nndmmied wilhdrawni asmciaicd With priu sympmms inc uding craving CF Unculklilianed withdrawal sv I mp mus UR withdrawal rendiom C5 Models of addiction Moral Social Psychological Pharmacologic Dependence Negative Reinforcement Model of Addiction Negative reinforcement response that terminates an aversive stimulus or state is strengthened Aversive State 1165130105e Consequence Withdrawal Drug selfadministration Termmatlon of Withdrawal reinforcement Problems With Dependence Model of Addiction There are addictive drugs that produce little apparent physical dependence Does not account for initiation of drug use Addiction persists long after detoxi cation Positive Reinforcement Model Positive reinforcement de nition ApproachWithdrawal TABLE 42 Drugs That Act as Reinforcers in the Operant conditioning WWW Central stimulmts Comma Amphclaxni n e Mexhylpheninlm Ritalin 1 ubing leaduw Lo indwelling 3mm 501 Camme Opi xlcs Morphine Mcllmdonc Cubu iv Ns dcprcsmnls Pcmoharbilal Amoharhimi Chlordmnpmide Librium Elhyi alcohol Category Speci c drug httpWingsbuffaloeduaruIVS Afacilitieshtm TABLE I PnIhninnry rmulll on hrrlml39c ratio ml by intravenous selfadm inisfran39on 0 drug in MI unity Mquot quot quot 115 nunw lm 11 212138 OglETQXm ditww1 Shmp 1513011350 kg 4 2400 1600 6400 m In ism2 M 114 kg 000 1100 800 3200 101 LID 11111011101153 kg I50 300 100 1600 11m 150 10221M10 kg no 000 1100 1600 200 150 11023 M 32 kg 3100 1100 1100 3300 121 so ll1111L3kg m 000 1100 1100 1000 0 Finch number show the maximal number of lever pressquot for on dnu of drug 2 lt E lt E rd llriLIIvl mq mq z Iq le 222258 uwummfur Cumulative mortality 100 90 70 10 r1 I V LLLAA LLLL1 LLALLLA AL 5 1o 15 20 2530 Days of Unlimited Access Neural Substrate of Reward Median forebrain bundle NUCIGUS accumbens Ventral fegmental area Frontal cortex v 39 o Problems With the Positive Reinforcement Model Operant responding for drugs could be motivated by Withdrawal avoidance Conditioned place preference Drug addiction has serious aversive consequences Another Problem 0 As addiction progress ill l oslln e rmnlm cemvnt tettpttotia addicts like the drug less and less but want the drug more and more Incentivemotivation sensitization models Attempts at abslmonw t ftr the drugdue ttt l Compulsive t t a sunm et ntlu ballcn 39 system Relapse 1 Figure 811 The incentivesensitization model of 39 n An opponent process model BF Arm many stimula ons Stimulus Underl npp Lvunl Ti me TI mu Figure 812 The origlnal opponentprocess model of motivation After Soomon1977 Another opponent process model A luimlmsponw HI Sensitiwd respunsc Hudnnic scale 9 g E 1 2 r a 3 an m Time Neuropharmacology Caveat The mechanism of action of most drugs is not know with certainty Different sources often give conflicting mechanisms And most drugs have multiple mechanisms Preview Drug Mechanisms of Action Drug serve as m precursor Precursor Drug inhib39 synthesis H Drug prevems storage or m asides Drug stimulates alllorecepton inmbits leiease of NT Enzvme V Neuronansnutter D blocks cepmrs increases release of NT 10 Drug inhibit NT degradation 1 Drug blocks ruupmke rug b ucks Poslsy39naplic pustsmap c receptors ecepmr Puslsynap c ren ACETYLCHOLINE Acetylcholine Synthesis Acetyl coenzyme A acetyl CoA in the presence of choline is transformed by choline acetyltransferase ChAT into acetylcholine Choline comes from dietary fat and liver synthesis l m A l cue HOCH2CH2NCH33 W CHaciocHZCliZMCl lalg 50A inelyl 00A Choline ace lggg f ase ACh Vesicular sequestration of ACh Acetylcimline Like all classic NT vesicular sequestration is done by vacuolar type H ATPase dependent V ATPase antiporter VACHT Acetylcholine Inactivation Acetylcholine is inactivated through catabolism by acetylcholinesterase AChE AChE is found in axon terminal and bound to postsynaptic membrane 0 Choline metabolite is transported back into presynaptic neuron H7 0 ll CH3COCHZCH2NCH33 CH3070H HOCHQCHZMCHQG Acelylcholineslerase ACh Acetic acld Choline Distribution of ACh Brain Autonomic nervous system Somatic nervous system Cholinergic Pathways nremduml and pad unculoponnm chmentzv Hm 1m dammem pom Caudalurpumwun and nu em amumech unmin nmrmmum 1M Supenur Cingulate conmum Dee X 4 nude thlbulm39 Locus mum OLEaLkoly bulb mam I eligu m39 m mq Hon bub tantia Rth mum mem hypothahmus Pontme w renam mrmd uu Mvdm epmm Nuduug mum and magnum and mmmnm mm nude mnommam Basal forebrain acetylcholine system Autonomic Nervous System gympamgng Pavzsympalhehc Preganghomc neurons Acexy chmme Aom Gangm Aueyclvuvue ACH Fnsxgangumm neuvons Aceychnhne ACh gt oz Norepmephme NB I I I I mm i0 Epmephnne j Key i0 A 7 a pha reuepior a 7 new recepmr M V muscanmc receplnr Amenm N mcoumc receptor meduHa ACh Autonomic NS Summary Parasympathetic pre and post ganglionic fibers Sympathetic preganglionic some postganglionic ie sweat glands Functions of ACh Brain Cognitive function Learning and memory Sleep cycles 0 Autonomic NS NT of parasympathetic nervous system NT of sympathetic nervous system Somatic NS NT of neuromuscular junction Two types of Ach receptors Nicotinic Ionotropic Nat secondarily Muscarinic Metabatropic 5 subtypes M1M3M5 M2M4 G Acetylcholine receptors Chniine CHAT Aculyi CDA Ca qu39PIC pathan presynammm PLC or adenylyi cyclase Postsynapiin ceii KK Activates Inwardly rectifying Kt channels Secund messengers CAME iPai DAG or Cpliiiiar responses 4 Distribution of Ach Receptors Brain Both nicotinic and muscarinic receptors are distributed widely through out the brain muscarinic prdominate Brain nicotinic receptors are primarily quotpre junctional causing release of other NTs eg DA responsible for rewarding effects of nicotine NeuromuscularJunction Nicotinic Autonomic nervous system Ganglionic synapses are primarily nicotinic Synapses on postganglionic parasympathetic effectors are muscarinic Autonomic Nervous System gympamgng Pavzsympalhehc Preganghomc neurons Acexy chmme Aom Gangm Aueyclvuvue ACH Fnsxgangumm neuvons Aceychnhne ACh gt oz Norepmephme NB I I I I mm i0 Epmephnne j Key i0 A 7 a pha reuepior a 7 new recepmr M V muscanmc receplnr Amenm N mcoumc receptor meduHa The Monoamine Neurotransmitters Monoamines Serotonin Indolamine Catecholamines Dopamine Norepinephrine Epinephrine Adrenaline TH E CATECHOLAIVIIN ES Hrth I ran 112 HD Ci it l lf Anjing I l39LlE EUH gmmp Biosynthetic pathway httphigheredmcgraw hillcomolcwebCgipluginpopcgiitswf5 35 535 lsitesdllfreeOO7243731 61 20070 bio10swfFeedback20lnhibition200f ZOBiochemical20Pathways Characteristics of catecholamines Formed through successive enzymatic modification of the amino acid tyrosine Tyrosine hydroxylase 1 the rate limiting enzyme 2is normally saturated Final synthesis occurs in axon terminal Synthesis is regulated by end product inhibition Different catecholamines occur in distinct neurons because the enzymes that form them from a common precursor are localized to different cells Secondary active transport reuptake the principal means of inactivation Vesicular monoamine transporter Two isoforms exist VMATZ is present in central nervous system 0 VMATZ is non specific transporting catecholamines and serotonin Characteristics of catecholamine reupta ke There are three monoamine membrane transporters DAT NET and SERT These have greater specificity than vesicular transporters Membrane transporters are NaC39 dependent symporters Monoamine vesicular and mnmhmnp francnnrf A Mmja m m 1 DAT NEEBERT I I O I I I i I I I Manammas 39 Sodium symporters DAT NET and SERT belong to a superfamily of intrinsic proteins with 12 transmembrane domans Includes transporters for GABA and glycine Extracellular space lransmemorane 39 l i al lS rquot nn SI l23456 1l31112 K U H u x U I 39F Entrace lularmam clm39f fo acid chain Eel membrane Catecholamine Synthesis Phenyfafa nine hdn1xWage Phewlalanime 7 7777 Tymsine Tetrahyd rob i mpteri n Qu i HUHDi C d 1 l1 ydl39oljlimpntEri r1 Hyperphenylalaninemias Disorders in which there is excessive plasma phenylalanine Phenylketonuria is defined by plasma phenylalanine levels gt 165 mgdl Phenylalanine is an quotessentialquot amino acid Maternal PKU Catecholamine biosynthesis COOH 1 GHFCHiN H2 Tyrosine HO Raev mmng step It Tyrosine hydroxylase EOOH HO CHFCHNHz DOPA HO J Aromatlc ammo acid decarboxylase HO CHFCHFN H2 H0 Dopamme 1 OH 1 Ho cwmrmz Ho Norepinephrine Phenylemanolamine Nmemyl Iransierase IDH HO CH CHNH CHa Ho Epinephrine Catecholamine metabolism 0 Two enzymes Monoamine oxidase MAO mitochondrial MAO A breaks down NE DA and 5 HT MAO B preferential for DA Catechol O methyl transerfase COMT cytosolic 0 Principal catabolic products Dopamine Homovanillic acid HVA Dihydroxyphenylacetic acid DOPAC MethoxytyramineMT Norepinephrine 3 methoxy 4 hydroxy phenylglycol MHPG Vanillymandelic acid VMA Regulation of catecholamine release and synthesis by autoreceptors Dopamine neurons Release modulating axon terminals Synthesis modulating axon terminals Impulse modulating somatodendritic Release modulating autoreceptors appear to be present on all dopamine neurons Synthesis and impulse modulating autoreceptor show regional variation 0 NE neurons Release modulation well established Little information on other types of modulation Brain Dopamine Pathways w Nigrostriatal pathway Mesolimbic pathway Dopamine tubero infundibular pathway H V thhalamu 4 I i39 339 3 we TFiH l39 l39 Bromocriptine 1 Anterior pituitary Suckling re ex I 1 Dopamine 1 k ania gonists 39CU 4 Prolactin releasing inhibiting factor P reiaclin Fr Mainary glands Some Dopamine Functions Movement RewardPleasure Working memorycognition Prolactin secretion Dopamine Receptors 0 All are metabotropic D1 family D1 D5 D2 family D2 D3 D4 Dopamine receptors transduction Q UT 1 UT DZ K agonist agomst D1 receptor Adenylyl D2 receptor 7 u cyclase Dopamine Neuropharmacology Block tyrosine hydroxlyase MAO Inhibitors Metrosine AM PT N Ive Methyldopa MAOA Stimulate DA synthesis moclobemide Ldopa v MAO MAOB selective y UUI A selegiline Block vesicular transporter COMT Reserpine COMT Inhlbltor Methylphenidate MDMA ecstasy tolcapone Dopamme transporter N A m Block DAreuptake Stimulate DAreIease Vesxcular amlne Autoreceptor agonist Low dose apomorphine Coca ne Amphetamine Methylphenidate MDMA ecstasy D2 agonists Bromocriptin e Apomorphine D2 antagonists 250le Chlorpromazine Hal operidol EXI39IEEIIIIII39 0 o e AMPH 0 P39m39m 0 o 39 o 39 cottanspurtedlons c o a 39 O n I 0 CI 0 AMFH humans ImnnIIulir Ni nh AT Nlznnirlus p s hmmim Ind SVNIA assnslaiun marshy pronoun DAT manna Intracellular Synaptic vesicle Norepinephrine Pathways I llppnmmpus 511mm humn w Mimi mHicMus Olmclnry bulb Cmtex Crrebellum A6 Lac coerule A l wnpm uer Medan nblongnm Hypulhalamus Some Central Adrenergic Functions Consciousness Central arousal Attention Vigilance Sympathetic arousal Activity Motivation EmotionMood Norepinephrine Receptor Subtypes 0 Two adrenergic receptor types Alpha Alpha1lP3DAG Alpha2 Inhibits adenylyl cyclase autoreceptors and postsynaptic receptors Beta Betal stimulate adnenylyl cyclase Beta2 stimulate adenylyl cyclase Central Adrenergic Receptors Alphal Low CNS concentration cerebral cortex hippocampus brain stem primarily peripheral Alpha2 Found in cerebral cortex caudal brain stem spinal chord diencephalon basal ganglia cerebellum hippocampus Betal Found in cerebral cortex basal ganglia cerebellum hippocampus Beta2 hippocampus cerebellar cortex 90 of cerebellar adrenergic receptors Norepinephrine Neuropharmacology MAO Inhibitors L39dopa i V 7 Nonselective Drug serve 1 NT W 39s ro az PMquot 039 Drugs that block MAO W Metrosine 7 V E Drug inhibit NT P mm Moclobemide Methyldopa mm 7 Enzyme s Ding stimulates aulureceptols inhibits Clonidine Reserpine leiease of NT Dfiug grevmils SUMage Neurotransml er in N1 in vesicles V MAQA a Drug blacks Fusar39c ac39d 1 aumremptors Idazoxan increases release of NT 4 Dzug stimulates releasc Amphetamine NT Methylphenidate Phentefm39 9 Dl39ug inhibits release of Ephedrine NT r 7 MDMA Drug stimulates AIbuter9I i wsisynapic NE I t Ephedrine e 90 We NT DemMina DeSIpramine Drug biuiks Pnslsynaptic elmVine n postsy naptk rect39pmra recepmr v Polsllsynapm cl Phentolamine DANE nonselective Propranolol SNRIs Cocaine Atenolol Cymbalta Methylphenidate Effexor Amphetamine Pristiq MDMA Autonomic Nervous System gympamgng Pavzsympalhehc Preganghomc neurons Acexy chmme Aom Gangm Aueyclvuvue ACH Fnsxgangumm neuvons Aceychnhne ACh gt oz Norepmephme NB I I I I mm i0 Epmephnne j Key i0 A 7 a pha reuepior a 7 new recepmr M V muscanmc receplnr Amenm N mcoumc receptor meduHa a1 a2 31 32 Peripheral adrenergic receptor functions Smooth muscle Vascular Contraction Intestinal Relaxation Axon terminal auto receptors Reduce NE release amp post synaptic Heart Stimulate Smooth muscle Vascular Relaxation Bronchial Relaxation Intestinal Relaxation Adrenergic Agonists Classification Drug Medical Use AlphaBeta Nonselective Agonistreleaser ephed ne Cardiac stimulant used to treat asthma in past Alphal Phenylephrine Nasal decongestant Pseudoephedrine maintain bp during Oxymetazoline aneStheSIa Alpha2 clonidine Treat hypertension and autonomic symptoms of opiate withdrawal decreases sympathetic outflow Beta nonselective isoproterenol Treat asthma cardiac stimulant Betal selective dobutamine Cardiac stimulant Beta2 selective albuterol Treat asthma Adrenergic Antagonists Classification Drug Medical Use Alpha Nonselective phentolamine Control hypertension in pheochromocytoma Alphal prazosin Treat hypertension Night terrors Alpha2 yohimbine Male impotence Aphrodisiac Beta nonselective propranolol Treat hypertension cardiac arrhythmias angina Anxiety SIB Betal Atenolol Treat hypertension Beta2 SEROTONIN 5HYDROXYTRYPTAMINE 5HT Serotonin Pathways CacheHum Nencorlex 01 bu factory lb Jquot M A Aquot H mm 39 39 k Six laila 5PM Lubercle C 39 Hypothalanws pom w mm Subgtlantla u m Sepm mm Raphe nuclei Some Serotonin Functions EmotionMood Anxiety Aggression Sleep Dominance hierarchies Appetite and food consumption Memory Serotonin Synthesis iTryptophan COOH i CH1 7 CH NH J N H quotmmquot Rate limitin hydroxylase Q L 5 l1ydmxytrypmphan 157111391 CUOH H0 Qj CHI 7 CH 7 NH2 N H Av 0mm mmiuo acid ducmhuxylabe Sr ydmxylryptamine 57m serotonin Melatonin H0 cm 7 c1127 NH I I I 5hydroxylndole acetic aCId i 5 d MAO HIAA Characteristics of serotonin Tryptophan hydroxylase not saturated Final synthesis occurs in axon terminal Synthesis may not be regulated by end product inhibition Inactivated by reuptake 5 HT membrane transporter same molecular family as DA and NE transporters and has same requirements Synthesis release and impulse inhibition autoreceptors Serotonin receptors There are at least 1 dozen serotonin receptors belonging 7 different families 5 HT 1 7 All except the 5 HT3 are metabotropic 5 HT1 receptors linked to Gi transducer 5 HT1 autoreceptors on axon terminals soma and dentrites release synthesis and impulse modulating 5 HT2 receptors linked to Gq transducer 5 HT3 depolarzing expressed in area postrema 5 HT47 positively or negatively linked to adenylyl cyclase Serotonin Neuropharmacology Tryptophan Drug serves as NT rsor F can Nonselective Drugs that block MAO pronaizid MAOA selective Moclobemide Precursor Parachlorophenylalanine D TH NT mgmwhl PCPA ltynthcsis s Dzugstimulntes auloreceptols inhibtts 1 1 ea or M Autoreceptor 5HT1A v anta onlst a Drug blocks mumKepler Busnrone m creases release of NT Enzyme Reserpine v m revenls stora e D P ES 5quot Neurotransmitter of NT In vestcl Fenfluramine MDMA ecstacy 4 Dxug stimulates release of NT Drug inhibits release of NT r a LSD 5HT2AAgonist Drug stimulates pastsynaphc receptors MDMA I Degrade D39 Mka I 39t t It 39 quot p i wipti r3233quot mm pussynapm 5mm SSRIS39 mquot SNRIs TraZOdone Prozac fluoxetine Cymbalta I I 5HT3 Antagonist Paxil paroxetine exor Atyglcal antlgsychotlcs Zofran antiemetic Zooft semanne Pristiq ClOZaplne Celexa citalo ram p SequUel Lexapro escitalopram oxalate Amino Acids Alpha whim Side chain HEN CL C OO I I H Mpha Alpha carhmylir P 39 l n 3911 dtml L Eli 11p amd grmlp Vesicular sequestration Vesicular transporters are energized by vacuolar type H ATPase VATPase VATPase is highly conserved in evolution V ATPase pumps proton ions into synaptic vesicles creating pH and electrochemical gradients that provide energy for transporting NTs into synaptic vesicles Vesicular transporters move NTs into synaptic vesicles against their concentration gradient in exchange for transport of two protons out of the vesicle Amino Acid Neurotransmitters Excitatory Inhibitory ammaaminobutyri Glutamate Acid GABA Aspartate Glycine Characteristics of amino acids Glutamate and GABA most abundant NTs in brain In contrast to classical NTs glutamate and GABA are found in all areas ofthe brain Many glutamate and GABA neurons are interneurons Vesicular sequestration by V ATPase dependent antiporters Glutamate and GABA are inactivated through reuptake and uptake by glial cells Astrocytes cells as well as neurons have high affinity transporters Glutamate Facts Glutamate multiple physiological rolls protein synthesis neurotransmitter Most important rapid excitatory neurotransmitter Primary NT of all primary sensory neurons Often co released with a neuropeptides eg substance P in nociceptive neurons Plays role in synaptic plasticity involved in learning and memory Involved in excitotoxicity Gultamate and GABA Synthesis zlumm np 0 x 1 x 7m 7UIP7CH37f 7VH H10 A ATP GluLa minasE Glutamate O D L 0 IHy 7 lt H 704 7 CH 7 c 7 o7 Clutarnic acid decarboxyxase GAD yaminnbutyric acid GABA U H M44 7 m1 7L39H37CH1 7 g 7 or CO Glutamate vesicular transporters Sequestration by V ATPase dependent antiporter Greater dependence on electrochemical gradient than monoamine vesicular transporters Vesicular transporters have relatively low affinity for Glutamate Relatively high cytoplasmic concentration of Gutamate High specificity for Glutamate Glutamate membrane transporters 0 Different from other membrane transporters Transporters have 8 membrane spanning domains Transport relies on co transport of Na and counter transport of K 1 negatively charged glutamate molecule is imported with 3 Na and one proton in exchange for export of 1 K Leads to net influx of 2 positive charges for each cycle generating a large inward force on glutamate Glutamate Reuptake CIutAmine r transmitters i ASkDCY e 1 Q Nerve Three isoforms of mm glutamate membrane transporters EAAT lT3 EAAT 1 amp 2 on astrocytes EAATS on 3 neurons Glutamate recep tors Glutamate receptors 0 lonotropic AM PA aamino3hydroxyl5methyl4 isoxazole propionat Kinate NMDA Nmethyl D aspartate mGIuR Metabotropic glutamate receptors Multiple isoforms Autoreceptors evidence for release and impulse modulation Can regulate ion channels causing EPSPs and IPSPs Targets for new drugs to treat Parkinson s syndrome and schizophrenia Glutamate Ionotropic Receptors pentameric pentameric tetrameric AMPA Kainate NM DA a NAT Outside celll E i iilifj t j i i 1 Inside cell 391 139 that A T Selatirndsmessenger f metinns Q Coincidence detector NMDA Glutamate and Longterm Potentiation 5 AdditiDna AMPA receptols ne NMDA 2 Calclum won emers 3 Linking proteins inserted in mem m receptor acuva esCaM I allachtoCaMr H 1 Outside Q E lt C i WWWmm AMHQJWJJJJJH Inside Calif F SD95 r 4 AMPA receptors dehvered j Postsynaptic density protein m membrane in vesmes 2 Glutamate excitotoxicity Cell death due to prolonged depolarization due to exposure to glutamate and certain drugs eg Kainate NMDA Kills nerve cells but spares quotfibers of passage May be responsible for cell death in ischemia and various diseases GABA Facts GABA s only function is neurotransmitter The most important rapid inhibitory neurotransmitter Many are interneurons Plays role in everything movement fine muscle control and coordination cognition sleep pain sedation and antixiety effects of drugs etc Gultamate and GABA Synthesis mummm o 7 L o w 1 NH 7 CH 7 cw l7 7 LSH 7 r 7 wt H10 7 pr Glutaminase Glutamate o o L 0 H vm 7ltH7CH1 7CH1 7 C 7 o7 Glutamic add i dmboxymlmm Glutamate decarboxylase 39y aminubutyric acid GABA H NH 7Fl77LHliLH C 707 GABA transporters Vesicular Sequestration by V ATPase dependent antiporter Greater dependence on electrochemical gradient than monoamine vesicular transporters Transporter has relatively low affinity for GABA Relatively high cytoplasmic concentrations of GABA Accumulates both glycine and GABA Membrane 3 isoforms have been identified GAT13 GATl neurons GAT3 astrocytes GAT2 choroid plexus GABA presynaptic pharmacology Glmammc transpurter minimal Tiagabine Gabitril Blocks GAT1 Anticonvulsant Allyglycine blocks GAD causes seizures GAT3 Vigabatrin Sabril Block release Tetanospasmin GABA transporter f CABA race p Lars Postsynaplic cell GABA Presynaptic Pharmacology cont Gabapentin Neurontin Mechanism of action unknown Anticonvulsant GHB is a GABA precursor through one pathway may result in overproduction of GABA may also serve as a GABA agonist High dose especially walcohol CNS depressant Lethality due primarily to respiratory arrest Low doses Stimulant aphrodisiac empathogenesis entactogen Xyrem sodium oxybate used to prevent cataplexy GABA receptors GABAA Ionotropic Regulate CI39 channels GABAB Metabotropic G protein coupled Autoreceptors GABA Receptor subtype GABAA GABAB Class Ionotropic Meta botropic Activation effect Inhibition Inhibition Ion Channels TCI39 conductance GI lCa conductance TK conductance Agonists Muscimol Baclofen Antagonists Bicuculline Picrotoxin Metrazol Phaclofen Potentiators allosteric modulators Benzodiazepines Ba rbitu rates Ganaxolone The GABA A Receptor 7 in 39 FG 7 Fax outside Picrotuxin Site membrane inside CI Glycine Facts Inhibitory neurotransmitter in lower parts of CNS Tetanospasmin the poison produced by the tetanus bacterium blocks release of glycine and GABA The glycine receptor is inontropic control Cl39 ion channels Strychnine is a glycine antagonist and a nicotinic antagonist Peptide Neurotransmitters Peptide Bond eeeeeeeee nd Polypeptide H H2 H Rd 1 W I I 1 H l O H Ln r 1 Lu H H O H R o H H Peptide Neurotransmitters Pep des Opioid Nonopioid Endorphins Substance P Enkephalins Neurotensin Dynorphins Oxytocin Endomorphins Etc Characteristics of peptide NTs Unlike other NTs peptides are synthesized in the soma not the axon terminal Peptides are inactivated by extracellular proteases peptidases To keep up with demand peptides must be synthesize de novo and transported to the terminal Storage vesicles dense core vesicles for peptides are larger stain differently and have a different distribution in the axon terminal than quotclassicquot NTs The number of quotneuroactivequot peptides continues to grow eg hypocretinorexin orphaninnociceptin Synthesis of neuroactive peptides Neuroactive peptides are derived from large precursor molecules propeptides transcribed and translated in the soma Propeptides are packaged in vesicles from endoplasmic reticulum These vesicles are transported to the Golgi apparatus where they are processed into smaller neuroactive peptides by proteases Golgi apparatus then packages neuroactive peptides into synaptic vesicles that are transported to axon terminal Proopiomrelanoco in rvLNISH a vhviSH E MSH Elam A H v39 Y t V ACTH atLPN H END ll J Y B LPH Proenkephalin metENE ieuENK H Prodynorphin w 39 V 7 4 quot quot a Nonendnrphin D i N A DENB 7j B Neoendorphin Orphanin nociceptin Does not display opioid activity eg analgesia Has no affinity for opioid receptors Opioids do not bind to the nociceptin receptor Actions not antagonized by opioid antagonists Blocks the antinociceptive effect of morphine s elevated under experimental chronic pain May be involved in hyperalgesia Release of peptides Release is Ca dependent Does not require quotactive zone Dense core vesicles not recycled Peptides usually co released with other neurotransmitters Release requires high stimulation frequencies action potentials Catabolism of released peptides often produces active metabolites Opioid Receptors Receptor Subtype H mm 5 delta K kappa Functions Supraspinal and spinal analgesia sedation inhibition of respiration slowed gastrointestinal transit modulation of hormone and neo rotransmitter release Supraspinal and spinal analgesia modulation of hormone and neu rotransmitter release Supraspinal and spinal analgesia psychotomimetic effects slowed gastrointestinal transit Endogenous Opioid Peptide Affinity Endorphins gt en kephalins gt dynorphins Enkephalins gt en dorphins and dynorphins Dynorphins gt gt endorphins and enkepl ialins Opioid receptor transduction Opioid receptors are G protein coupled All three receptor subtypes inhibit adenylyl cyclase Effects of activation of opioid receptors inhibit neuronal excitability by indirectly increasing K and decreasing Ca conductance Classification of narcotics Opiates occur naturally in opium Morphine Codeine Semisynthetic Opioids Morphine derived Heroin HydromorphoneDilaudid Thebaine derived Oxycodone Oxycontin Precodan BuprenorphineSuboxone Synthetic Opioids MethadoneDolophine MeperidineDemerol PentazocineTalwin FentanylDuragesic Mepetidx ne niany Paventeral only Parenteral only Oxycodoneg 6 Hapow ae 7 Pentazo ci n e Narcotic Antagonists Naloxnne Narcan HO Naltrexnne Urexan I3 Dphardt c 2003 Clinical uses of opioid antagonists Naloxone reverse respiratory depression sedation hypotension in narcotic overdose and reverse psychotomimetic effect of pentazocine Naltrexone treatment of narcotic and alcohol addiction Treatment of self injurious behavior Suboxone Buprenorphine plus naloxone Used to treat narcotic addiction Naloxone is intended to prevent iv injection Buprenorphine is a partial mu agonist and a kappa antagonist Opioid Effect Log Dnse Fw lll Agonist Mattmadame Partial Agonist Buprenmphine Antagonist N a oxone Other Neurotransmitters Other Neurotransmitters Histamine Nitric oxide Anandamide Other Neurotransmitters Endocannabinoids Lipid neurotransmittersneuromodulators Synthesized from arachidonic acid Anandamide and 2arachidonoyl glycerol Endogenous ligands at cannabinoid THCreceptors Anandamide not stored in synaptic vesicles Synthesized on demand Whether anandamide is inactivated by reuptake or glial uptake is subject of debate catabolism by fatty acide amide hydrolase CBl CBZ receptors in CNS and PNS respectively Gprotein coupled CBl receptors are presynaptic released by postsynaptic neuron CBl receptors mediate appetite mood pain sense STM rewarding effects of opiates Anandamide Drugs THC CBl agonist Rimonabant CBl antagonist MAFP inhibits fatty acid amide hydrolase AM1172 blocks anandamide reuptake Has been suggested that Acetaminophen inhibits anamide reuptake and degradation and is a C81 agonist Other Neurotransmitters Nitric oxide Soluble Gas not sequester in vesicles Formed from tha amino acid arginine by the enzyme nitric oxide synthase Retrograde transmitter Appears to be involved in tolerance and sensitization Activates cGMP system Nitric oxide sensitive guanylyl cyclase cGMP causes dilation of blood vessels in penis and erection Viagra sildenafil prevents break down of cGMP by blocking cGMP phosphodiesterase Other Neurotransmitters Histamine CNS Histamine neurons located exclusively in hypothalamus but axons project to all areas of brain Active solely during waking Maintain wakefulness and attention Antihistamines diphenhydramine H1 blocker developed in 19305 Modafinil Provigil Nuvigil proposed histaminergic though mechanism of action remains elusive More about modafinil Approved for narcolepsy and quotshift work sleep disorder Increases alertness enhances concentration enhance performance on wide range of cognitive tasks brightens mood Appears to lack adverse properties of classic stimulants is not addictive is not sympathomimetic not a psychotomimetic s currently being studied in ADHD and depression Widespread use as a nootropic Outrageously expensive up to 18 per pill Limitless httpwwwiamroguecomimitlessfullsiteindexhtml httpwwwncbinlmnihgovpmcarticlesPMC3197159 httptechcrunchcom2008O715how manvofour startupexecutivesarehoppeduponprovigiI Neuromodulator Adenosine Nucleoside sugar plus a purine or pyrimidine base Mediates response to cell damage due to inflammation or ischemia Dilates blood vessels Adenosine receptors are metabotropic Open K channels and produce inhibition General behavioral depressant Plays a role in sleep and wakefulness Caffeine is an adenosine antagonist
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