181lec6 - Psych 181: Dr. Anagnostaras Lec 6: Psychomotor...

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Unformatted text preview: Psych 181: Dr. Anagnostaras Lec 6: Psychomotor stimulants CH3 N O C O CH3 O Cocaine CH2 C O CH CH3 NH2 Amphetamine Psychomotor stimulants Large class of diverse compounds q Stimulate alertness, arousal (“psycho-”) q Stimulate motor activity (“-motor”) Major ones: q Amphetamines q Cocaine and related compounds Amphetamines History and basic pharmacology q β-phenylethylamine derivatives q sympathomimetic amines Naturally-occurring compounds q cathinone CH 2 q ephedrine CH 2 NH 2 Phenylethylamine (PEA) Naturally-occuring compounds Cathinone q active agent in Khat (shrub) q Legal in Israel, Kenya, & Oman q chewed q synthetic version (meth-cathinone) O C CH CH 3 NH 2 Cathinone Ephedrine Ephedrine q from Ma Huang (herbal tea) q isolated in 1920’s q bronchodilator for asthma q pseudoephedrine is an isomer of ephedrine q structure similar to epinephrine OH CH CH CH 3 NH CH 3 Ephedrine Neosynephrine amphetamine phenylalanine ephedrine pseudoephedrine “faces of Meth” project Amphetamine History q synthetic synthetic q identified identified in search for substitute for ephedrine (Alles, 1927) ephedrine q structurally-related to catecholamines q 1932, Benzedrine inhaler q widespread adoption q peak use in early 1970’s (“speed”) q new West Coast popularity ("tweakin") Forms of amphetamine Amphetamine (racemic) q mixture mixture of d- and l- isomers isomers q Benzedrine®, Adderall® q bennies, speed CH2 CH CH3 Amphetamine NH d-Amphetamine q dextroamphetamine q Dexedrine®, Vyvanse*® q dexies, hearts, speed Forms of amphetamine l-Amphetamine q q levoamphetamine less potent dl-methylamphetamine Methedrine®, Desoxyn® meth, crystal, crank, speed most potent l-methamph = "desoxyephedrine" l-methamph CH2 CH NH CH3 Methamphetamine q q q q q CH3 Methamphetamine Ice, Crank, Crystal Meth US News & World Report (1995) Text Ice, Crank, Crystal Meth Pure d-methylamphetamine HCl Pure (can be smoked because of purity) Traditional synthesis q q amalgam method > not very pure dl-methamphetamine amalgam dl 1981 main ingredient made illegal Synthesis from ephedrine or pseudoephedrine q q pure d-methylamphetamine HCl pure Since renewal of the patriot act sales of precursors restricted Used to be made mostly in small labs Now primarily made by Mexican syndicates q q “Ice” or “Crystal” Smoked vs. Oral Amphetamine Blood level (ng/ml) Hours Amphetamine-related drugs methylphenidate q Ritalin® q attention deficit disorder fenfluramine q Redux® q anorectic phenmetrazine q Preludin® q anorectic subitramine q Meridia® q anorectic O CH C O CH 3 N Methylphenidate Psyc 181: Lec 6 Cont’d (#18)Medical uses of amphetamine q Obesity (anorexic effects) once major use - no longer q q q q Narcolepsy Attention deficit hyperactivity disorder (about Attention 1/3 of prescriptions) 1/3 Therapeutic dosing much lower than doses Therapeutic taken by addicts taken 2/10 7 pm Ledden Auditorium Major effects - amphetamine Humans Autonomic functions q increase blood pressure q increase body temperature q bronchodilation q (sympathomimetic effects) Effects on CNS Analeptic (awakening) Anorexia Psychomotor stimulant effects q decreased q arousal q elevated q euphoria q sense fatigue, increased alertness mood of power/confidence Effects: non-human animals Autonomic effects q same as humans Psychomotor stimulant effects q complex dose-effect relations q low doses - locomotor hyperactivity q higher doses - stereotyped behavior Reinforcing effects q self-administration and place preference Effects of repeated administration Tolerance q most autonomic effects q anorectic effects Sensitization q psychomotor stimulant effects q rewarding effects q psychotomimetic effects psychotomimetic (amphetamine psychosis) (amphetamine Sensitization Sensitization to the Sensitization psychomotor stimulant effects of amphetamine effects q q Rats given 2.0 mg/kg of Rats d-amphetamine once per day for 10 days day Measure amount of druginduced rotational induced behavior each day behavior Days Cocaine Source and history q q q q q Naturally-occuring alkaloid in leaves of shrub Naturally-occuring Erythroxylon coca Erythroxylon first reported use by Europeans - 1499 active agent extracted in 1859 by Niemann widely used in late 1800’s, early 1900’s local anaesthetic effects - 1884 procaine (1905) Cocaine - production Cocaine - history of use Forms of cocaine Raw leaves q chew q alkaloid content low (0.6 - 1.8 %) q not stable Coca paste q initial extraction q smoked q around 80% cocaine Forms of cocaine Cocaine HCl q purified & converted to HCl salt q crystalline form, water soluble q pure if not diluted q snorted or i.v. Cocaine free base extract (volatile solvents) smoked Crack free base made with baking free soda & ammonia - not cheaper crackles when heated crackles Effects of cocaine Very similar to amphetamine (generalize in drug discrimination), but Very some major differences: some Duration of action Cardiovascular effects q danger of CVA much higher these sensitize Lidocaine, novacaine, benzocaine are related drugs Convulsive properties q Local anaesthetic effects q Psychostimulant actions Mechanisms of action q Primary actions on monoamine neurotransmission q Monoamines (compounds with one amine group,- NH2) q q q q Epinephrine (E) Norepinephrine (NE) Dopamine (DA) Serotonin (5-HT) Psychostimulant actions Catecholamines (CA; catecholaminergic) Catecholamines (CA; (compounds with catechol nucleus and amine) q Epinephrine (adrenergic) q Norepinephrine (noradrenergic) q Dopamine (dopaminergic) HO R HO Indolealkylamines (indole and amine) (indole q Serotonin Catechol (serotonergic) Indole N Catecholamine Catecholamine Synthesis Synthesis ΧΗ2 ΧΗ ΝΗ2 ΗΟ ΗΟ ΗΟ Τψροσινε Τψροσινε ηψδροξψλασε ΧΗ2 ΧΗ ΝΗ2 ΧΟΟΗ ΧΟΟΗ ∆ΟΠΑ ΗΟ ΗΟ ΧΗ2 ΧΗ2 ΝΗ2 Αµινο αχιδ δεχαρβοξψλασε Tyrosine DOPA DA TH AADC HO HO ∆οπαµινε Dopamine β− ηψδροξψλασε OH CH CH2 NH2 Norepinephrine Phenylethanol amine N-methylOH transferase HO CH CH2 NH CH3 8.1 HO Epinephrine 8.3 DA DA synapse 8.1 Synthesis & storage Tyrosine DOPA DA AADC DA MAO DOPAC T H MAO= monoamine oxidase H+ DA Dopamine Metabolism H+ DA Vesicular monoamine transporter Synaptic vesicle Inactivation & degradation DA Presynaptic membrane DA COMT MAO DA transporter DA D2 presynaptic autoreceptor 3-MT MAO 8.17 DOPAC COMT DOPAC DA D1ÐD5 postsynaptic receptor DA 3-MT HVA Synaptic cleft Postsynaptic membrane HVA COMT Receptors HVA NE NE synapse 8.2 Synthesis & storage NE MAO DHPG or DHMA Inactivation & degradation DA DBH DA NE Tyrosine T H DOPA DA AADC Vesicular monoamine transporter DA NE NE synapse 8.2 Inactivation & degradation α 2−αδρενεργιχ αυτορεχεπτορ ΝΕ τρανσπορτερ ΝΕ ΝΕ Text ∆Α ΝΕ DHPG MHPG α ορ β −αδρενεργιχ ποστσψναπτιχ ρεχεπτορ Receptors ΧΟΜΤ Distribution of NE Hippocampus Cortex Olfactory bulb Dorsal bundle A11 A7 Cerebellum Locus coeruleus A6 A4 A5 A2 A1 A3 Basal ganglia 8.30 Ventral Medulla Hypothalamus bundle oblongata Descending spinal tracts Distribution of NE Locus coeruleus Distribution of DA Caudateputamen A8 Substantia nigra A9 pars Nigrostriatal Nucleus accumbens compacta Medial forebrain bundle Caudateputamen Mesolimbic A10 Nucleus accumbens 8.19 Olfactory tubercule Ventral tegmental area Serotonin (5-hydroxytryptamine) Receptors 5-HT 1-4 5-HT 1-4 Synthesis & storage 5-HT MAO 5-HIAA Inactivation & degradation Tryptophan 5-HTP 5-HT AADC Try H Raphe 9.1 Primary neurochemical effects Increase synaptic concentrations of Increase monoamines (DA, NE, E & 5-HT) monoamines 1. 2 13.03 700 600 500 400 Increase in DA 1. 0 0.75 mg/infusion 0.50 mg/infusion 0.25 mg/infusion 0.00 mg/infusion 13.20 0. 8 Coc 0. 6 300 200 AMPH 0. 4 0. 2 100 240 0 80 160 Time (min) 0 Ð40 0 40 80 120 Time (min) 160 200 Primary site of action HVA Monoamine Monoamine transporter transporter (both amphetamine and cocaine) q Extracellular DOPAC DOPAC 8.13 actions on DA, NE & 5-HT transporters Dopamine transporter Monoamine Vesicular oxidase long-term store Tyrosine Cytoplasmic DA Releasable DA DOPA Extracellular DA Actions of cocaine Cocaine and amphetamine have Cocaine different actions on monoamine transporters transporters Cocaine Blocks transporter q prevents reuptake q requires calcium DA DA transporter Amphetamine DA Cocaine 8.1 Actions of cocaine Human PET Scans Normal Cocaine Actions of cocaine Time course of cocaine uptake into brain (11C)cocaine_ Fowler et al. (2001) Actions of cocaine Time course to peak cocaine after i.v. administration mirrors times course of subjective effects Fowler et al. (2001) Actions of cocaine Fowler et al. (2001) Actions of amphetamine Release q calcium independent q not blocked by reserpine q blocked by TH blocked Amphetamine inhibition inhibition DA q requires transporter DA transporter (blocked by (blocked reuptake blockers) reuptake DA Cocaine 8.1 Locus of action Autonomic effects q sympathetic nervous system Psychomotor and rewarding effects q brain monoamine systems q DA, NE and/or 5-HT? q DA primary locus Role of DA Evidence that DA mediates the psychomotor Evidence stimulant and rewarding effects of psychostimulants psychostimulants Pharmacological studies Lesion studies Neurochemical studies Correlational studies Molecular biology studies q q q q q Pharmacological studies Pharmacological Amphetamine self-administration Response rate (% control) 400 Pimozide 0.0625 0.125 0.25 0.5 Phentolamine 2.5 5 10 Propranolol 2.5 mg/kg 5 10 300 200 100 13.11 0 2 4 6 8 10 2 468 Time (hr) 10 2 4 6 8 10 Lesion studies 6-hydroxydopamine lesions Control Lesion Neurochemical studies Relationship between behavior and extracellular DA 900 800 700 Striatum Control Amphet. N. accumbens Control Amphet. 300 Behavioral score 250 200 DA (% control) 600 500 400 300 200 Activity 150 100 50 100 0 60 120 180 Time post-injection (min) 13.9 Correlational studies Cocaine & analogs Molecular biological studies The DA transporter knockout mouse Normal Cytoplasmic DA Knockout Cytoplasmic DA Dopamine transporter DA sub-systems Mesolimbic projections q from VTA > nucleus accumbens q ventral striatum Nigrostriatal projections q substantia substantia nigra > caudate-putamen q dorsal striatum Nigrostriatal DA system Psychostimulant-induced stereotyped behavior q lesions q local injections Mesolimbic DA system Locomotor hyperactivity and reward q lesions q local Cocaine into N. Accumbens ** Locomotor activity injections * * 13.19 Saline 10 30 Dose (mg) 100 DA sub-systems Mesolimbic projections q from VTA > nucleus accumbens q locomotor activity and reward Nigrostriatal projections q substantia substantia nigra > caudate-putamen q stereotyped motor patterns Amphetamine neurotoxicity Amphetamine and methamphetamine Are potentially neurotoxic q requires high doses q 10 to 50 times normal street dose (in rats; primates may be more sensitive) q high extracellular DA necessary d-Amphetamine q Depletes DA q Degeneration of DA terminals q Primarily caudate (accumbens Primarily relatively spared) relatively q Cell bodies intact Methamphetamine q Depletes Depletes DA and serotonin and q Degeneration of terminals q Caudate Caudate DA and cortical and hippocampal 5-HT hippocampal q Cell bodies intact from Villemagne et al., J. Neurosci. (1998) Baboons (humans?) PET PET Binding 1 inj/2hr X 4 - 2-3 wks off Amphetamine neurotoxicity Does methamphetamine cause Does degeneration of striatal dopamine terminals in amphetamine addicts? terminals from McCann et al., J. Neurosci. (1998) Humans PET images from control subjects, Parkinson’s patients, and abstinent methamphetamine and methcathinone users (average period of abstinence, 3 years) WIN-35,429 binding to DA transporter DAT vs. VMAT Does methamphetamine cause Does degeneration of striatal dopamine terminals in amphetamine addicts? terminals The controversy: The DAT vs. VMAT as markers of The dopamine terminal density dopamine DAT vs. VMAT (a) H+ DA DA Vesicular monoamine transporter DA (b) VMAT DA Dopamine transporter DA DAT DA 13.4 A DAT vs. VMAT The controversy: The DAT vs. VMAT as markers of The dopamine terminal density dopamine The DAT is highly regulated, the VMAT is The not. Therefore, the VMAT and not the DAT provides a reliable indicator of DA terminal density terminal Wilson et al. (1996) Brain tissue from addicts show no Brain change in VMAT binding, although is decrease in DAT decrease Suggest is no neurotoxicity in Suggest amphetamine addicts amphetamine Wilson et al., Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nature Medicine (1996) O CH 3 O CH 2 CH NH CH 3 Methylenedioxymethamphetamine MDMA Methylenedioxymethamphetamine MDMA (extacy, E, X, XTC,Adam) and MDA Synthesized in 1912, 1913 patent (Merck) q anorectic in 1961 q not used clinically q Dr. Shulgin O CH 3 O CH 2 CH NH CH 3 Street use q early MDMA 1980’s; popular at “raves” q also adjunct to psychotherapy (clin trials 1993) q illegal since 1985 (1st Schedule I by DEA) Several analogues DOM - dimethoxyamphetamine - SF designer drug (late '60s) - "STP" (Serenity Transquility Peace) DOB - 4-bromo-2,5-dimethoxyamphetamine MDA - 3,4-methylenedioxyamphetamine MDMA - 3,4-methylenedioxymethamphetamine 2-CB - 4-bromo-2,5,-dimethoxyhenethylamine (NEXUS) (hallucinogen similar to LSD) Synthesis Safrole is distilled from sassafras or nutmeg oil (>1000 doses 1 kg of safrole) MDMA Effects on behavior and affect Low doses q relaxation, serenity, emotional closeness Moderate doses q mild hallucinogenic effects q intensification of feelings q notorious memory impairment High doses q amphetamine-like effects q hyperthermia (heat stroke) q “hangover” Distribution Typical use is in pill form • "love" "hug" "club" drug "love" • permasmile permasmile • mostly recreational mostly • 60-120 mg per pill 60-120 LD50 = 50 mg/kg (3000 mg) • take 1-2 pills take • $20-30 per pill (whl=$5) $20-30 Different class than traditional drug users Effects on behavior and affect Can't recognize content from pill What is PMA? q q q q q q q paramethoxyamphetamine "Death" "Mitsubishi Double Stack" "Killer" "Red Mitsubishi" substitute for MDMA cheaper to make slower longer effects more hallucinogenic incidence of toxic side effects much higher incidence than MDMA (narrow safety margin) than Effects on behavior and affect MDMA on the rise 1997 • 400,000 tablets seized 1999 • 3.3 million tablets seized 2000 • 9 million tablets seized • During a period of time when enforcement is very low. 2001 • dealers can unload >100,000 tablets per week in major cities • 1 in 4 teens in NYC say have tried. MDMA on the decline? Arrests Seizures Primary markets remain LA, Miami, and NYC Neurochemical effects Monoamine neurotransmission q increase synaptic DA and 5-HT q blocks 5-HT transporter q enters neuron and causes Calciumindependent release of 5-HT Neurotoxic effects q potent neurotoxin q 1-2 times street dose q depletes forebrain 5-HT (not DA) MDMA & MDA neurotoxicity Degeneration of 5-HT terminals q fine axons from dorsal raphe q beaded axons from median raphe spared q can get 30% loss with single injection q up to 80% with repeated injections Species differences q primates more sensitive q some evidence in humans (CSF 5-HIAA down) (CSF some MDMA Neurotoxicity Fischer, C.; Hatzidimitriou, G.; Wlos, J.; Katz, J.; and Ricaurte, G. Reorganization of ascending 5-HT axon projections in animals previously exposed to recreational drug 3,4-methelenedioxymetham-phetamine (MDMA, "Ecstasy"). Journal of Neuroscience 15:5476-5485, 1995. MDMA & MDA neurotoxicity 5-HT immunoreactive fibers in rat parietal cortex PCA Normal MDA 9.9 Squirrel monkeys 18 mo post- trtmt Control 5-HT immunoreactivity Neocortex Hippocampus Caudate MDMA McCann et al. (1997) PET image from 1 control and one MDMA user McN-5652, to label the 5-HT transporter Normal McCann et al., Lancet, 352(1998)1433. Cereberal Blood Flow L. Chang et al. Psychiatry Research: Neuroimaging, Section 98, pp. 15-28, 2000. Amphetamine neurotoxicity d-Amphetamine q DA only Methamphetamine q DA and 5-HT Methylenedioxymethamphetamine (and MDA) q 5-HT only ...
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