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DRUG_ABUSE-2011-C-lecture-publishkey - Drug Addiction and...

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Unformatted text preview: Drug Addiction and Drug Abuse PMY 406 / 512 / 516 Spring 2011 Reading Golan, Chapter 17 Goodman and Gilman, Chapter 23* Recommended reading Volkow and Li (2004) “Drug addiction: The neurobiology of behaviour gone awry,” Nat. Revs Neurosci, 5, 963-970. Hyman, Malenka, and Nestler (2006) “Neural mechanisms of addiciton: The role of reward-related learning and memory,” Ann. Rev. Neurosci, 29, 565-598. Specific Drugs of Abuse • Opioids • CNS depressants – Barbiturates – Alcohol • CNS stimulants – Amphetamines – Methamphetamine – Cocaine • • • • • Nicotine and tobacco Cannabinoids Hallucinogens PCP Inhalant anesthetic gases, and volatile solvents ANRV278-NE29-20 ARI 9 May 2006 14:29 Cingulate gyrus Striatum Prefrontal cortex Figure 2 Substantia nigra Nucleus accumbens Ventral tegmental area Neurosci. 2006.29:565-598. Downloaded from arjournals.annualreviews.org te University of New York - Buffalo on 12/28/09. For personal use only. Dopamine projections to the forebrain. Illustrated are projections from the ventral tegmental area to the nucleus accumbens, and prefrontal cerebral cortex, and projections from the substantia nigra to the dorsal striatum (caudate and putamen and related structures). responses (pleasure), desire or “wanting,” and increase synaptic dopamine in the nucleus acrapid learning of both predictive cues and effi- cumbens (NAc), the major component of the cient behavioral sequences aimed at obtaining ventral striatum (Wise & Bozarth 1987, Koob the reward. Two major differences between & Bloom 1988, Di Chiara 1998, Wise 1998) natural rewards and addictive drugs conspire (Figure 2). Whether acting directly or indito make addiction remarkably harmful. First, rectly (Johnson & North 1992, Jones et al. drug rewards tend to become overvalued at 1998, Tapper et al. 2004, Waldhoer et al. 2004, Hyman, Malenka, and Nestler (2006) Ann. Rev. Neurosci, 29, 565-598. the expense of other rewards, contributing Justinova et al. 2005), all addictive drugs into compulsion and to a marked narrowing of crease levels of synaptic dopamine within the life goals to obtaining and using drugs. Sec- NAc. The source of dopamine to the NAc ondly, unlike natural rewards, addictive drugs (as well as to the amygdala, hippocampus, and do not serve any beneficial homeostatic or re- PFC) is the ventral tegmental area (VTA) of productive purpose but instead often prove the midbrain (Figures 2 and 4). The NAc Substance dependence (addiction) is a “maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following symptoms ....” Golan, p. 285 “ ..... substance dependence (addiction) as a cluster of symptoms indicating that the individual continues use of the substance despite significant substance-related problems.” APA as cited in Goodman-Gilman, p. 607 Definitions Tolerance Pharmacokinetic tolerance Pharmacodynamic tolerance Learned tolerance Cross-tolerance Dependence Physical dependence Psychological dependence Cross-dependence Effects of tolerance and sensitization in the dose-response curve Golan, Figure 17.1 Induction of tolerance by increased metabolism of the drug Barbiturates Alcohol Tobacco smoke St. John’s wort Carbamazepine Golan, Figure 17.2 Pharmacodynamic mechanisms of tolerance Golan, Figure 17.3 Induction of tolerance to morphine ↓ ↓ activation cAMP response element-binding protein ↑ ↑ regulation Golan, Figure 17.4 Importance of the route of administration on PK and PD drug PK PD Golan, Figure 17.5 Role of opioid in the brain reward pathway Golan, Figure 17.6 Opioids - Heroin • Development of tolerance depends on pattern of use: – Intermittent use ⇒ can obtain analgesic and sedative actions for an indefinite period. – Continuous use ⇒ significant tolerance – Thus, user in search of high ⇒ requires constant increase in dose . • Lethal dose may be increased. • But there is a dose at which respiratory depression ⇒ death. Opioids • In clinical practice, care is taken to avoid establishment of tolerance: – Give minimum dose sufficient to achieve analgesia. – Keep interval between doses as long as possible. • Since most opioids not completely selective for a single sub-type, extent of cross-tolerance is variable among opioids. CNS Depressants: Extent and pattern of use • Barbiturates – Use exceeds opioids. – Use includes • Short-acting barbiturates are preferred to long-acting agents (phenobarbital). – Pentobarbital = "yellow jackets” – Secobarbital = "red devils" • Benzodiazepines are uncommon for deliberate abuse. – Except the short-acting agents (e.g., triazolam) which have high street value. • Dependence not readily recognized. CNS Depressants - Withdrawal syndrome Alcohol - Sedative-Hypnotics - Gaseous Anesthetics • Marked similarities seen with all sedative-hypnotic agents • Not identical, but reasonable to describe a general depressant withdrawal syndrome • Mildest form – Paroxysmal EEG abnormalities – Rebound increases in REM sleep, insomnia, anxiety – Tremulousness and weakness General depressant withdrawal syndrome has all the components of ethanol-induced delirium tremens. • In severe dependence, withdrawal can lead to – Tonic-clonic grand mal seizures – Status epilepticus • In contrast to opioid withdrawal, the withdrawal syndrome with these agents can be a lifethreatening emergency CNS Depressants • While there may be considerable tolerance to the sedative and intoxicating effects, the lethal dose is not much greater in addicts than in normal individuals. • Cross-tolerance between various agents in this group is common. • Babies born to mothers physically dependent on general CNS depressants will manifest withdrawal syndromes of varying severity. – Signs similar to opioid withdrawal in newborn – Treatment: Administer CNS depressant or benzodiazepine. Two types of tolerance develop with respect to barbiturates • Pharmacokinetic (or metabolic) tolerance – This is due to induction of the hepatic drug metabolizing enzymes. Pharmacodynamic (adaptive) tolerance: Illustration • Naive individual takes phenobarbital to achieve 5 µg/cc plasma concentration ⇒ drowsiness • After 12 days use there are no subjective impressions of drowsiness or sedation even though the plasma concentration approaches 25 µg/cc. • YET – tolerance does not develop to the life-threatening medullary respiratory depression. • There is no difference in concentration required to depress respiration ! Pharmacodynamic tolerance • An important characteristic of the pharmacodynamic tolerance in this class of agent: – Tolerance develops to sedative effects. – Yet the lethal dose is not increased. – Acute barbiturate poisoning with marked respiratory depression may be accidentally superimposed on chronic intoxication at any time (same as for alcohol; see below). Psychological dependence • Minor abstinence syndrome • Feelings of anxiety, apprehension, insomnia. • That is, there is a re-emergence of the state for which the drug was originally prescribed. Alcohol 1. 2. 3. 4. Pharmacokinetic ⇐ increased metabolism. • • Only seen in severely alcoholic subjects Higher blood concentrations are needed to produce intoxication in tolerant than in normal individuals Pharmacodynamic tolerance due to adaptation. BUT - there is no marked elevation in lethal dose Thus - acute intoxication with marked respiratory depression may be super-imposed on chronic alcoholic intoxication at any time (similar to case for barbiturates). Cross-tolerance to other agents • Alcohol with sedatives-hypnotics – Barbiturates and benzodiazepines – Due to pharmacodynamic tolerance and metabolic tolerance Cross-tolerance • Cross-tolerance is seen only in sober alcoholic. • When blood ethanol concentrations are high, the synergistic actions of the “cross-tolerant” drugs remain. – Combined effect ⇒ profound depression • No cross-tolerance between ethanol and opioids. • Chronic high-dose use of ethanol ⇒ physical dependence • Withdrawal syndrome similar—but not identical—to barbiturates. • Three distinct withdrawal stages. Signs of ethanol withdrawal: 3 phases (Detail) A. W ithdrawal with mild-to-moderate dependence Onset of withdrawal occurs 8-24 hours after cessation of ethanol intake. (previous ethanol load already cleared by this time) 1. feeling of nervousness; 2. apprehension; 3. muscle weakness; 4. tremor and nausea; 5. retching and anorexia 6. abdominal quivering ("butterflies in the stomach") is a common feeling 7. experienced on awakening; controlled by ingestion of ethanol B. W ithdrawal with moderate-to-severe dependence If abstinence continues for 12-24 hours in the 1st phase, leads to this second phase characterized by: 1. marked tremor and muscle cramps 2. rise in body temperature; sweating; diarrhea 3. nausea and vomiting 4. tachycardia and rise in blood pressure 5. hyperpnea; accompanied by a swing from the previous metabolic acidosis to respiratory alkalosis; 6. insomnia; any sleep is of only REM-type sleep; full of nightmares; 7. agitation becomes more pronounced as this phase progresses. C. W ithdrawal with third phase reactions: Delirium tremens 1. Begins 2-4 days after start of abstinence ! 2. "Muttering delirium"; confusion, disorientation; marked agitation and panic reactions; paranoid reactions; hallucinations ("pink elephants"). 3. Clonic muscle jerks may progress to grand mal seizures and then to status epilepticus. 4. Mortality rate in the fully developed untreated state of delirium tremens is high (range: 15-to-greater-than-50 % of cases). a. Treatment with benzodiazepines CNS Sympathomimetics Amphetamine, Cocaine 1. 2. 3. 4. 5. Euphoric effects of amphetamine (i.v.) and cocaine very similar Reduced sense of fatigue ⇓ Decrement in performance caused by lack of sleep Subjective effects are indistinguishable. Duration of effects a. b. c. Cocaine ...............50 minutes Amphetamine ......10 hours Methamphetamine 5 hours • Cocaine: Inhibits dopamine re-uptake in – Ventral tegmental area – Nucleus accumbens – Frontal cortex • Amphetamine: Promotes release of newly synthesized dopamine from intraneuronal stores – Ventral tegmental area – Nucleus accumbens – Frontal cortex Golan, Figure 17.9 Mechanisms of action of amphetamine and cocaine Golan, Figure 17.8 Annu. R by Figure 3 Psychostimulant action. The psychostimulant drugs cocaine and amphetamine increase synaptic dopamine. (Upper panel) Cocaine blocks the dopamine reuptake transporter located on the presynaptic membrane, thus acutely increasing synaptic dopamine. (Right panel) Amphetamines enter dopamine neurons via their reuptake transporters and interact intracellularly with the vesicular monoamine transporter (VMAT) to release dopamine into the presynaptic terminal. Dopamine (DA) is then “reverse transported” out of the neuron into the synapse. 572 Hyman · Malenka · Nestler Annu. Rev. Neurosci. 2006.29:565-598. Downloaded from arjournals.annualreviews.org by State University of New York - Buffalo on 12/28/09. For personal use only. neurons, for example, do not abolish intravenous heroin self-administration. Moreover, animals will self-administer opiates directly into the NAc, where µ opioid receptors exa pressed on NAc neurons appear to bypass dopamine inputs from the VTA (Pettit et al. Cocaine inhibits monoamine reuptake 1984, Bardo 1998). Cannabinoids, ethanol, and nicotine are also thought to produce Cocaine DAT reward partly via nondopaminergic mechaDA Dopamine nisms. Further, mice in which TH has been VMAT genetically inactivated not only continue to show hedonic responses to food rewards (liking), but can also still learn relevant cues. Animals without dopamine cannot, however, use b Amphetamines cause monoamine release Amphetamines DA Dopamine Hyman, Malenka, and Nestler (2006) Ann. Rev. Neurosci, 29, 565-598. Figure 3 Psychostimulant action. The psychostimulant drugs cocaine and amphetamine increase synaptic dopamine. (Upper panel) Cocaine blocks the dopamine reuptake transporter located on the presynaptic membrane, thus acutely increasing synaptic dopamine. (Right panel) Amphetamines enter dopamine neurons via their reuptake transporters and interact intracellularly with the vesicular monoamine transporter (VMAT) to 2005), whic stantia nigr within the m Despite dopamine, what inform release in t thought to tation of a has been sh imals can s sponses in t ies in which pharmacolo Robinson 1 tyrosine hy enzyme in d Palmiter 20 mals contin Because an defect in th and thus ca be placed in test prefere blocked or (liking) for or nonnutri alternatives substances. Dopami be required or for learn ministration antagonists neurons, fo venous hero animals wil into the NA pressed on dopamine i 1984, Bard and nicotin reward part nisms. Furt genetically show hedon • Cocaine – Tolerance develops toward euphorigenic, anorectic effects. – Psychological dependence – No physical dependence. • That is, there is no characteristic withdrawal syndrome. • Amphetamine – Tolerance develops toward some of the central effects (euphorigenic; anorectic effects; hyperthermic; lethal actions). – Psychological dependence – No physical dependence (??) – Cross-tolerance among amphetamine-like agents. • Tolerance does not develop to psycho-toxic effects of cocaine and amphetamine; I.e., schizophrenic-like symptoms (toxic psychosis). • • • • Suspiciousness; paranoia; paranoid ideations; visual hallucinations; Tactile hallucinations ("cocaine bugs" in the skin) and visual hallucinations ("snow lights"). Bruxism; touching-picking the face-andextremities; feeling of being watched. Stereotypical repetitious behaviour. • Withdrawal signs? 1. There are no grossly observable disturbances or disruptions that necessitate gradual withdrawal of cocaine or amphetamine-like agents. 2. Withdrawal syndrome for both includes drug craving, prolonged sleep, general fatigue, depression. Ephedrine, Ψ-Ephedrine and Methamphetamine 1 2 Methamphetamine Meth and the Brain • • • • Meth releases a surge of dopamine, causing an intense rush of pleasure or prolonged sense of euphoria. Over time, meth destroys dopamine receptors, making it impossible to feel pleasure. Although these pleasure centers can heal over time, research suggests that damage to users' cognitive abilities may be permanent. Chronic abuse can lead to psychotic behavior, including paranoia, insomnia, anxiety, extreme aggression, delusions and hallucinations, and even death. Visible Signs • • • Meth abuse causes the destruction of tissues and blood vessels, inhibiting the body's ability to repair itself. Acne appears, sores take longer to heal, and the skin loses its luster and elasticity, making the user appear years, even decades older. Poor diet, tooth grinding and oral hygiene results in tooth decay and loss. Meth Mouth • • • "Meth mouth" is characterized by broken, discolored and rotting teeth. The drug causes the salivary glands to dry out, which allows the mouth's acids to eat away at the tooth enamel, causing cavities. Teeth are further damaged when users obsessively grind their teeth, binge on sugary food and drinks, and neglect to brush or floss for long periods of time. Sex and Meth • • Meth heightens the libido and impairs judgment, which can lead to risky sexual behavior. Many users take the drug intravenously, increasing their chances of contracting diseases such as Hepatitis B or C and HIV/AIDS. http://www.pbs.org/wgbh/pages/frontline/meth/body/methbrainflash.html 2.5 years later Cigarettes and Tobacco 5000 CIGARETTE CONSUMPTION 4000 3000 2000 1000 0 1900 1920 1940 1960 1980 2000 YEAR Cigarette consumption (Billions) Cigarette consumption per capita BRITISH MEDICAL LONDON SATURDAY SEPTEMBER 30 JOURNAL 1950 SMOKINGAND CARCINOMAOF THE LUNG PRELIMINARY BY RICHARD Member of the Statistical REPORT 3VLR.C.P. the Medical Research Council DOLL, Unit AND M.D., of Research A. Professor of Medical Statistics, BRADFORD HILL, Ph.D., D.Sc. Director of the Statistical School London Research and Tropical Medicine ; Honorary of Hygiene Unit Research Council of the Medical In England number of and Wales deaths the phenomenal to cancer of increase the For lung in the pro whole may attributed explanation, well have and proper although been to no one would As causes. Increase to of and time a deny corollary, that it it is vides one of mortality annual of the most by striking changes the Registrar-General. in the pattern example, of right contributory. seek for other Causes have the from surface of the time dust recorded number out of of in the quarter of a century deaths all between This to 1922 and from of age 1947 the 612 to Two main of Possible causes from recorded increased been put for 9,287, or roughly fifteenfold. course, tion?both proportion in total and, changes, males remarkable the increase in its older increase is, popula groups. ward fumes from former : (1) a general atmospheric cars, gas-works, have has industrial pollution Some more Such than from the exhaust tarred coal and roads, fires ; and particularly, shows the females plants, Stocks these (1947), using population in 1936-9, standardized death rates to allow trend The rise for : rate (2) the smoking of tobacco. become increased. be no more been characteristics prevalent associated in of the the last following 2.5. per 100,000 in 1901-20, males 10.6, 1.1, females 0.7 ; rate per seems 50 years, and there is also no doubt cigarettes in time recently dence. records, male greatly can, however, has there That relates evidence, mainly certainly that the smoking suggestive, little more of 100,000 to have been particularly rapid since the end of the first world war ; between 1921?30 and \94b-4 the death rate of men the at ages 45 and over same ages approximately It has Canada, and Japan. increased sixfold and This of women increase of is still threefold. changes and until direct evi singularly based upon to the use of the of clinical tobacco. and experience For instance, continuing. the U.S.A., from Many whether Turkey too, occurred, and Australia, in Switzerland, Denmark, and has been reported in Germany, M?ller with (1939) found cancer that only 3 out of 86 have studied these considering changes, a real increase in the incidence of the they denote or are due merely to improved disease standards of diag can be regarded nosis. Some believe that the latter factor as wholly, or at least mainly, responsible?for example, writers patients while 56 were smokers, heavy " men of the same age healthy 31 heavy smokers. and only smokers non-smokers, lung were 86 in contrast, among and, " 14 non there were groups Similarly, lung were in America, Schrek 82 male and his co-workers 23.9% of 522 male other In this than the country, patients with cancer (1950) reported of the that 14.6% of non-smokers, against of sites tracts. patients admitted with and cancer Willis (1944). (1948), Clemmesen On the other and Busk (1947), and Steiner and upper Thelwall respiratory Jones digestive (1949?personal “Light” cigarettes Nicotine and tobacco • • Nicotine (1-3 mg/cigarette) absorbed rapidly. Nicotine is selfadministered; a less powerful reinforcer than amphetamine or cocaine. But, nicotine dependence is durable ! • Role of cholinergic neurotransmission in the brain reward pathway β2 α4 β2 α4 β2 Cholinergic (α4)2(β2)3 β2 α4 β2 α4 α4 α7 α7 α7 α7 α7 (α4)3(β2)2 α2βγδ α2βγε Golan, Figure 17.7 α4β2 (α7) Nicotine and tobacco Involve stereospecific receptors for nicotine and DA pathways. Blocked by mecamylamine: not by muscarinic antagonists. Varenicline (Chantix) Antidepressants NRT (patches / gums) • • • • • • Absorption: – Respiratory tract • Reaches brain within 7 seconds !! – Buccal membrane – Skin • Severe acute poisoning through percutaneous absorption • Acute nicotine poisoning: – Nausea, Salivation, Abdominal pain, Vomiting, Diarrhea, Cold sweat, Headache, Dizziness, Disturbed hearing / vision, Mental confusion, Weakness. • This can lead to • Fainting • ⇓ BP • • • • • See Goodman/Gilman “Manual” pp. 143-146 Difficult breathing Pulse is weak, rapid, irregular Collapse convulsion Death due to respiratory failure Therapy of acute nicotine poisoning: – – – Induce vomiting Or gastric lavage with a slurry of activated charcoal left in stomach Avoid alkaline solutions • Nicotine is a strong base – – – – pKa ≈ 8.5 Absorption from stomach is limited Absorption from intestines is better Chewing tobacco has a more long-lasting effect because it is absorbed more slowly than is an inhaled dose. • Metabolism – – – – 80-90 % of the absorbed dose is altered Liver >> kidney and lungs Major metabolite: cotinine Metabolites and the rates of metabolism are equal in smokers and nonsmokers. • Nicotine is both a stimulant and a depressant – Smokers feel alert. – Yet there is muscle relaxation • Nicotine activates the NAc reward system – Increased extracellular DA in NAc post-nicotine (rats) – Also increases release of endogenous opioids and glucocorticoids • There is tolerance to the subjective effects of nicotine ‣ e.g., First cigarette in morning is the “best’ feeling. Next cigarette, not so “best”. ‣ After abstinence, returning to the previous dose nausea ‣ Naïve smokers, at low dose nausea • That is, smokers get nausea at higher doses than their usual dose. • In dependent smokers, the urge to smoke correlates with a low blood nicotine level. • Thus, smokers smoke in order to: ‣ Achieve the reward of nicotine effects ‣ Avoid the pain of nicotine withdrawal ‣ Or both • Nicotine withdrawal symptoms vary greatly and include a. Intense craving b. Irritability, impatience, hostility c. Anxiety d. Dysphoric or depressed mood e. Difficulty concentrating f. Restlessness g. Decreased heart rate h. Increased appetite or weight gain i. BUT - this does not represent a well-defined syndrome. Psychedelic and Hallucinogenic Agents General Considerations • Psychedelic agents reliably induce states of altered perception, thought, and feeling. • There exist several classes of drugs that can induce illusions, hallucinations, delusions, alterations of mood and thought. Major effects • Heightened awareness of sensory input; diminished control over what is experienced. • "Spectator ego": view self as passive spectator. • Attention is turned inward, toward "self". • Low capacity to distinguish self from environment. LSD-like Psychedelic Agents Indoleamines C2H5 O H NC C2H5 β-Phenethylamines H3CO N CH3 H3CO H3CO NH2 Mescaline N LSD N N CH3 CH3 H3C H3CO OCH3 NH2 CH3 DM T OH N N CH3 CH3 H3CO DOM O CH3 NH2 CH3 Psilocin DM A Mixed H3C O O H3CO O O NH2 Amphetamine-like CH3 NH2 MDA H3C NH2 Amphetamine H3C H3CO NH2 M M DA p-Methoxyamphetamine • LSD-like agents ‣ ‣ ‣ ‣ ‣ ‣ ‣ LSD (Lysergic acid diethylamide) Lysergic acid amide DMT (Dimethyltryptamine) Mescaline DOM (dimethoxymethyl amphetamine) DMA (dimethoxy amphetamine) Psilocin • Mixed agents ‣ MDA (Methylene dioxyamphetamine) ‣ MDMA (Methylene dioxymethamphetamine) LSD-like agents • LSD; Mescaline; Psilocin • Will discuss – Subjective or Psychic effects – Cross-tolerance – Response to selective antagonists Psychic effects • Distortion of sensory perceptions – Involves all senses – Colors may be very bright – Distortions of near-far perception; body image (size; body parts); time-taste • Visions and hallucinations • Thought-flow–&–dreams – Film-strip-like stream of thoughts – Vivid dreams – Depersonalization – Euphoria or depression or anxiety – Synesthesias common • Overflow of one sensory modality into another (colors "heard"; sounds "seen") Sources of Drugs • LSD - synthesized in 1938; "discovered" by Hoffman in 1943. • Mescaline - derived from peyote cactus. • Psilocin - extract of mushrooms ("magic mushrooms” – The genus Psilocybe (among other genera) – Used in Southwest. – Use of these mushrooms goes back 3500 years ! Chemistry of LSD-like Agents • Indole nucleus • LSD-like • Phenylethylamine moiety • Mescaline Golan, Figure 17.4 Mechanism of Action • Act as agonists on 5HT receptors in cortical and sub-cortical area. • Multiple subtypes of 5HT receptors. • LSD-like agents act as agonist or (more likely) partial agonists at 5HT2 receptor. • Down regulation of 5HT receptors may account for tolerance to LSD-like agents. Administration and Dose • Usual dose of LSD: 1-2 µg/kg – One of the most potent pharmacological agents known • Usually taken by mouth – It is equi-efficacious orally and parenterally – Compare doses: • LSD: • Psilocybin: • Mescaline: 1-2 µg/kg 250 µg/kg 5-6 mg/kg – Large differences in potency – Yet, the effects are virtually indistinguishable Somatic Effects of LSD 1. Sympathomimetic actions – – – – Pupils dilate ⇑ Blood pressure ⇑ Heart rate ⇑ Body temperature – Hyper-reflexia – Tremor – Pilo-erection – Muscle weakness – Laughing-crying 2. Occur within 2-3 minutes; more than a single feeling seems to co-exist at same time; after 2-3 hours, visual illusions - wave-like recurrence of perceptual changes (micropsia; macropsia); after images are prolonged; 3. 4. 5. 6. 7. 8. 9. Somatic Effects of LSD In contrast to naturally occurring psychoses, auditory hallucinations are rare. Synesthesias Subjective time is altered. Loss of boundaries; fear of fragmentation create a need for supporting environment. Mood may be labile. Dose dependence over range 1-16 µg/kg. Effects dissipate after 12 hours. Note: t1/2 ≈ 3 hours !! 10. Little evidence for long-term changes in personality Blocking of Effects • Most pharmacologic effects of LSD are blocked by 5-HT antagonists – Ketanserin (Sufrexal) – Cyproheptadine (Periactin) – Chlorpromazine (Thorazine) – Haloperidol (Haldol) Tolerance • High degree of tolerance to behavioural effects (after 3-4 daily doses) • Little tolerance to CV effects. • Cross-tolerance: LSD-Mescaline-Psilocin. • No cross-tolerance: – LSD-vs-amphetamine – LSD-vs-scopolamine – LSD-vs-Δ9-THC Toxicity 1. Does not give rise to patterns of repetitive use. 2. Withdrawal symptoms not seen after abrupt discontinuation of LSD-like agents. 3. The "bad trip"; treat with supportive care. 4. "Flashback" - experienced; apparently persists for years. 5. Reports of • Precipitated depression • Paranoid behaviour • Prolonged psychotic episodes • 6. • Tend to resemble naturally occurring schizophrenic psychotic states. Not clear whether such episodes would have occurred without the drug. Teratogenicity (??) Therapeutic use • None • Controversy? Cannabinoids http://video.google.com/videoplay? docid=-6696582420128930236# Not LSD-like Agents Cannabinoids Cannabinoids • Active ingredient – Δ9-tetrahydrocannabinol (Δ9-THC) CH 3 OH H3C H3C O Cannabinoid receptor • Identified in brain (1988) and cloned (1990) • Receptor localization: highest densities in – – – – Cerebral cortex Hippocampus Striatum Cerebellum CB2 Cannabinoid receptors 1 and 2 CB1 GPCR Endogenous cannabinoids Plant cannabinoids Cannabinoid receptor • Proposed endogenous ligand: – Anandamide • A derivative of arachidonic acid • Physiological function: as yet unknown • What is needed to learn more? Rimonabant: CB1 antagonist Blocks CB1 receptor selectively ↓ Food intake Helps regulates body-weight gain Cannabinoid - Metabolism • THC is hydroxylated prior to excretion in urine and feces. • After peak in plasma concentrations is achieved, the concentrations of Δ9-THC and 11-Hydroxy-Δ9-THC fall with half-life of minutes. Metabolism of Δ9-THC Δ9-THC 11-Hydroxy- 9-THC Δ Polar metabolites Excreted in urine/feces Active metabolite; produces effects identical with Δ9 -THC. Very little Δ9-THC is found in urine. CNS actions of Δ9-THC • “high” or “mellowing out” • Impaired cognitive function, perception, reaction times, learning and memory • Impaired coordination and tracking behaviour • Reported to persist for several hours beyond the perceived high • Obvious implications with regard to operation of a motor vehicle, in the workplace and in school Cannabinoid use produces complex behavioral changes • Giddiness • ⇑ Hunger • Increased insight during marijuana use ? • No data to support this notion Therapeutic use ?? • As analgesics and anticonvulsants • Used to lower the increased intraocular pressure associated with glaucoma. • To reduce nausea and emesis associated with cancer chemotherapy – Δ9-THC (Dronabinol) – Nabilone (Cesamet), a synthetic cannabinoid • But, these benefits come at the cost of psychoactive effects. • Institute of Medicine (1999) indicates no clear advantage of cannabinoids over conventional therapy. Nutmeg Nutmeg • Source – Derived from the seed of Myristica fragrans – Nutmeg tree is indigenous to Indonesia • History – 17th century – nutmeg used primarily as a medicine – Esteemed as an aphrodisiac and as an abortifacient Nutmeg: Chemistry • Components • Non-volatile ether-extractable lipids (25-40 %) • Volatile oils (10-15 %) • Contains the psychoactive components • Myristicin (3 %) • Elemicin (1 %) Nutmeg: Chemistry • Ring structure resembles mescaline and its methylenedioxy derivative. • Addition of ammonia across double bond in myristicin and elemicin produce mescaline and its methyldioxy derivative (MMDA). Suggests that if this occurs metabolically, it might be responsible for CNS actions of nutmeg. O O O CH3 Myristicin CH3 O H3C O CH3 O Elemicin [NH3] Myristicin Mescaline [NH3] Elemicin MMDA Pharmacologic actions • Causes large subjective changes. ‣ Commonly used for this purpose among prison inmates ‣ See: Autobiography of Malcolm X • Oral ingestion of two grated nutmegs produces (after a latency of several hours) ‣ Leaden feelings in the extremities ‣ CNS feelings of depersonalization; unreality ‣ Agitation; apprehension are common ‣ Dry mouth; thirst; rapid heart rate; red, flushed face; (mimics atropine poisoning). Nicotine, alcohol Opiates – + Opioid peptides Glutamate inputs (e.g. from cortex) Alcohol ? – NMDAR NMDAR D1R or VTA interneuron Alcohol ? GABA Stimulants DA NAChR NAChR + DA Cannabinoids Opiates – PCP Nicotine + D2R – ownloaded from arjournals.annualreviews.org ffalo on 12/28/09. For personal use only. Glutamate inputs (e.g. from amygdala) + VTA NAc Figure 4 Actions of opiates, nicotine, alcohol, and phencycline (PCP) in reward circuits. Ventral tegmental area (VTA) dopamine neurons (bottom left) project to the nucleus accumbens (NAc) (bottom right). Different interneurons, schematically diagrammed above, interact with VTA neurons and NAc neurons. The rewarding properties of opiates are mediated by µ opiate receptors found in two locations in brain reward Hyman, Malenka, and Nestler (2006) Ann. Rev. Neurosci, 29, 565-598. circuits. VTA dopamine neurons are tonically inhibited by GABAergic interneurons that express µ opiate receptors. Opiates acutely inhibit these interneurons thus disinhibiting the dopamine projection neurons, which then release dopamine in the NAc and other terminal fields. In addition, there are µ opiate receptors expressed by NAc and dorsal striatal neurons. Opiates can stimulate these receptors directly D2R Glutamate inputs (e.g. from amygdala) + Cannabinoids – by State University of New York - Buffalo on 12/28/09. For personal use only. VTA NAc Figure 4 Actions of opiates, nicotine, alcohol, and phencycline (PCP) in reward circuits. Ventral tegmental area (VTA) dopamine neurons (bottom left) project to the nucleus accumbens (NAc) (bottom right). Different interneurons, schematically diagrammed above, interact with VTA neurons and NAc neurons. The rewarding properties of opiates are mediated by µ opiate receptors found in two locations in brain reward circuits. VTA dopamine neurons are tonically inhibited by GABAergic interneurons that express µ opiate receptors. Opiates acutely inhibit these interneurons thus disinhibiting the dopamine projection neurons, which then release dopamine in the NAc and other terminal fields. In addition, there are µ opiate receptors expressed by NAc and dorsal striatal neurons. Opiates can stimulate these receptors directly and produce reward in a dopamine-independent manner. Nicotine, acting on nicotinic acetylcholine receptors (NAChRs) in the VTA, cause dopamine release. Ethyl alcohol, acting on GABAA receptors in the VTA, can also cause dopamine release. Phencyclidine (PCP), which blocks the NMDA glutamate receptor channel and cannabinoids acting via CB1 cannabinoid receptors in the VTA (not shown), also produce dopamine release. Cannabinoids, alcohol, and PCP can also act directly on the NAc. PCP, phencyclidine (“angel dust”). information about rewards to motivate goal- there is strong evidence (e.g., in intact nondirected behaviors (RobinsonHyman, Malenka, and Nestler primates) to Rev. Neurosci, 29, 565-598. et al. 2005); i.e., human (2006) Ann. suggest that, under northey cannot act on their preferences. Overall, mal circumstances (e.g., in the absence of however, the conclusions to be drawn from le- lesions), dopamine plays a central role in sions or from dopamine-deficient TH knock- reward-related learning (Schultz et al. 1997, out mice are not entirely clear. The knockout Schultz 2006). Finally, dopamine appears to mice, for example, likely have developmental be required for motivated behaviors aimed The End ...
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