Transcript Cocaine
2009 - Lecture 8 Artificial & Natural Ligands: Drugs Chinese Tea Stimulant Vikings Amanita Muscaria GABA agonist Drugs have been used for centuries American Indian Peyote 5HT & DA agonist Egyptians Beer DA & GABA Agonist 5HT & Glutamate Antagonist Not just humans… Animals self administer ETOH coca leaf Everybody takes drugs!..in one form or another DRUG USE = Ubiquitous 7 out of the 10 of leading causes of disabilities in US Drug Use Major depression Manic Depressive Illness Schizophrenia Dementia Degenerative CNS OCD Drug Abuse 2/3 of Americans older than 12 drink alcohol 1/4 of Adult Americans are smokers (~458 pks/year) 100gm of Caffeine/year 1/2 of Americans older than 12 have used illicit drugs at least once Marijuana Socially acceptable National Surveys Reported drug and alcohol use by high school seniors, 2004 Used within the last: Drugs 12 months* 30 days Alcohol 70.6 % 48.0 % Marijuana 34.3 19.9 Stimulants 10.0 4.6 Other opiates 9.5 4.3 Tranquilizers 7.3 3.1 Sedatives 6.5 2.9 Hallucinogens 6.2 1.9 Cocaine 5.3 2.3 Inhalants 4.2 1.5 Steroids 2.5 1.6 Heroin 0.9 0.5 *Including the last month. Source: Press release: Overall teen drug use continues gradual decline; but use of inhalants rises, University of Michigan News and Information Services, December 21, 2004. College Students YEAR Marijuana Cocaine 93 94 27.9 29.3 2.7 2.0 95 96 31.2 33.1 3.6 2.9 97 31.6 3.4 98 99 00 01 35.9 35.9 35.2 34.0 4.6 4.6 4.8 4.7 Source: University of Michigan, Monitoring the Future National Survey Results on Drug Use, 1975-2003, Volume II: College Students, 2004. 02 03 35.6 33.7 % 4.8 5.4 % Percent of College Students/Young Adults Using Marijuana, 2003–2004 College Students 2003 2004 Young Adults 2003 2004 19.3% 18.9% 17.3% 16.5% Past year 33.7 33.3 29.0 29.2 Lifetime 50.7 49.1 57.2 57.4 Past month National Institute on Drug Abuse and University of Michigan, Monitoring the Future National Survey Results on Drug Use, 1975–2004, Volume II: College Students & Adults Ages 19–45, 2005 New phenomena: Baby boomer overdosing 197022 yrs 198532 yrs Now 43 yrs Cocaine Heroin Marijuana 1999 168,751 82,192 87,068 2000 174,881 94,804 96,426 2001 193,034 93,064 110,512 2002 199,198 93,519 119,472 Total number of drug mentions in drug abuse-related emergency department visits, by type of drug, 1999-2002 What is a drug? Chemical that alters one or more normal biological processes Psychoactive, Psychotropic Alter behavior, cognitive function or emotions DRUGS… Good/Bad???? How much? For what reason? In what context? EX: Heroin SET: Psychological Makeup of person & expectations SETTING: Social physical environment + biochemical unique body chemistry Tolerance: state of decreased sensitivity to a drug as a result of continued exposure to it effect Takes more drug to get the same affect Dose response curve: shift to the right dose Tolerance??? compensatory mechanisms that oppose the effects of the drug Biological Tolerance: Two Types metabolic tolerance : the body increases its ability to get rid of the drug e.g. an increase in the level of enzymes in the body that break down the drug physiological tolerance: may involve compensatory changes at a synaptic level VERY IMPORTANT!!! Setting: Social, physical environmental Seigel et al. (1982) Tested the hypothesis that setting is important in drug tolerance Heroin can be conditioned to the environment 30 days of heroin in varying environments Group 1 Group 2 Heroin (colony) Placebo (noisy room) Placebo (colony) Heroin (noisy room) Group 3 Placebo (colony) Placebo (noisy room) All animal injected with lethal dose (15mg/kg) Colony noisy room colony 64% died Only 32% died noisy room colony noisy room 96% died Lethal effects when drug was taken in new environment (no compensatory) Conditioned Drug Response: tolerance effects (compensatory: work against drug) are maximally shown when drug taken in same situation/ environment Classical Conditioning Model: Heroin Overdosing Tolerance??? compensatory mechanisms that oppose the effects of the drug Withdrawal symptoms are compensatory reactions in the body that oppose the Effects of heroin Heroin withdrawal symptoms euphoria dysphoria constipation diarrhea & cramps relaxation agitation Psychopharmacology: Study of drugs on NS behavior What Determines Drug Efficacy? PHARMACOKINETICS Absorbed Distributed Metabolized Eliminated bloodstream bloodstream broken down Urine, sweat feces, mother’s milk Pharmacokinetics Absorbed Distributed Metabolized Eliminated Site of Action routes of administration IV IP IM PO Sublingual inhalation PO: Most common, easiest, safe, cheapest Swallowed Stomach (enzymes) Intestine Liver bloodstream (alcohol) Bloodstream Unpredictable & time consuming PO (Cons) absorbed more slowly..not good for emergencies need to be awake..choke need bigger doses irritate stomach …eat food Inhalation: quick, lungs Lung damage Not precise IM: Muscle more rapid/PO hurts!! IV: Strong effect, fast (15 sec) Overdose Scar tissue/ collapse of veins Infections …What else impacts Efficacy of a drug? Weight Circadian cycle Genetic Makeup Drug Efficacy Age Food Intake loratadine (Claritin) Aspirin Polypharmacy Sunlight Immune system ~12 meds Very Important Site of Action BBB: lipid-solubility Quick distribution Ex: Morphine vs Heroin = efficacy but…. Varying site of action for the same effect Ex: Morphine vs Aspirin Analgesic suppresses neurons increases chemical Depressants, Sedatives, Anxiolytics Alcohol Barbiturates Benzodiazapines Alcohol (ethanol) small & lipophillic Depressant Mod-Hi Low Decrease Neuronal Firing Stimulate neuronal firing Mod: Cog, perceptual, verbal motor impairment High: unconscious > 0.5 % death from respiratory depression Alcohol’s Immediate Effects on NT GABA Agonist Sedation, incoordination Glutamate Antagonist Memory loss & Cog dysfunction 5HT Antagonist Impulsiveness,violent behaviors, sleepiness Agonist Reinforces alcohol habitat DA Dilation of blood vessels red face Urination diuretic urine by kidneys A) Alcohol stimulate the release of endogenous opioids B) Endogenous opioids (e.g., beta-endorphin) are released into the synapse C) stimulate activity at opiate receptors, which produces a signal in the target neuron D) Exogenous opiates (morphine) stimulate opiate receptors http://www.youtube.com/watch?v=wDcyBXJAZNM Alcohol (ethanol) Korsakoff’s Syndrome: memory loss sensory motor dysfunction, dementia Binges: no Vitamins…carbohydrates Brain damage due to thiamine (vitamin B1) Brain needs thiamine to metabolize glucose Shrinkage of neurons Mamillary bodies, Hippocampus Depressants, Sedatives, Anxiolytics Barbiturates Benzodiazapines Barbiturates: Sedation Sleep inducing Anesthesia Muscle relaxant (0ld drug: 1903) Phenobarbital anticonvulsant Pentobarbital Indirect agonist GABA the duration of CL- channels (hyperpolarize) “Drugged” next day…reduce respiration Replaced by BENZODIAZEPINES Benzodiazepines: First BZ patented in 1959 Chlordiazepoxide (Librium) greater muscle relaxant properties vs respiratory effect anxiolytic Indirect agonist GABA BARBITS: the duration of CL- channels (hyperpolarize) BZ: the frequency of CL- channels (hyperpolarize) Diazapam (Valium) - No “Drugged” next day Alprazolam (Xanax) Indirect Agonist Psychostimulants Cocaine Amphetamine Caffeine Cocaine local anesthetic and CNS stimulant coca bush lipid soluable Behavioral Effects: •euphoria •excitement •reduced hunger •a feeling of strength • friendly, outgoing Neurological and Behavioral problems: •dizziness •headache •movement problems •anxiety •insomnia •depression •hallucinations Caudate Nucleus VTA Nucleus Accumbens Cocaine concentrates especially in the reward areas. Cocaine accumulation in caudate nucleus can explain other effects such as increased stereotypic behaviors (pacing, nail-biting, scratching, etc). Cocaine Agonist of Catecholamines Blocks reuptake of DA, Norepi, Epi to presynaptic terminal PNS: constricts of blood vessels dilation of pupils irregular HB Reuptake pumps DA Cocaine DA receptors PET Scan red = high use of glucose yellow = medium use blue = least use of glucose cocaine user do not use (metabolize) glucose as effectively as the brain of the normal person = Risk of Stroke & Epilepsy D2 Receptors in Monkeys Cocaine – Environment alters receptors Subordinate Subordinate Dominant Dominant Patient died of an overdose of cocaine – DA constricts brain vessels • small lesions - cell death, or strokes •acute hemorrhages - can happen in heart = •hypoxia (lack of oxygen) infarction or attack (sudden death). Psychostimulants Amphetamine Caffeine Amphetamines (stimulant): http://www.psych.ualberta.ca/~ITL/flash/stimulants_draft.swf CNS & Sympathetic NS (asthma, sleep disorders) 1. cause the release of dopamine from axon terminals 2. block dopamine reuptake 3. inhibit the storage of dopamine in vesicles . dextroamphetamine, benzedrine, and Ritalin Short-term effects: •Increased heart rate •Increased blood pressure •Reduced appetite •Dilation of the pupils •Feelings of happiness and power •Reduced fatigue CAFFEINE - most popular drug in the world -coffee, tea, cocoa, chocolate, some soft drinks, & drugs - coffee bean, tea leaf, kola nut and cocoa pod - Pure caffeine is odorless and has a bitter taste •increase alertness •reduce fine motor coordination •cause insomnia •cause headaches, nervousness and dizziness www.youtube.com/watch?v=JP7EQ6e5d1c What NT does caffeine affect: Adenosine • inhibitory of synaptic transmission Caffeine antagonist of Adenosine Increase firing of cortical neurons & locus coeruleus (regulator of arousal & vigilance) (RAS) http://www.psych.ualberta.ca/~ITL/flash/stimulants_draft.swf Caffeine also: increase heart rate, constrict blood vessels, relax air passages to improve breathing and allow some muscles to contract more easily Massive Doses: Fatal! 10 grams 80-100 cups of coffee in rapid succession (U.S. = avg. 100g/yr) 160mg Coffee: 60-150 mg Coca-Cola: 46 Pepsi: 38 Chocolate: 1-35 (U.S. = 200-300mg/day) Vivarin, Excedrin, Dextrim, Dristan, No Doz Marijuana "We now know that marihuana – •Destroys will power, making a jellyfish of the user. He cannot say no. •Eliminates the line between right and wrong, and substitutes one's own warped desires or the base suggestions of others as the standard of right. •Above all, causes crime; fills the victim with an irrepressible urge to violence. •Incites to revolting immoralities, including rape and murder. •Causes many accidents, but industrial and automobile. •Ruins careers forever. •Causes insanity as its specialty. •Either in self-defense or as a means of revenue, users make smokers of others, thus perpetuating the evil." 1930’s Reefer Madness!!!!! H. Anslinger (1930’s) FBN •Brain damage •Criminal behavior •Insanity •Sexual perversion Marijuana (cannabis sativa) • Dried leaves and flowers cannabis plant • Contains over 400 different chemicals • 60 are cannabis Delta 9-Tetrahydrocannabinol (THC) • 1 joint = 10 to 20 mg of THC • Inhalation Lungs Brain (BBB) • Lipid soluable: weeks in system 2 Receptors (1988) CB1 GPCR’s CB2 Brain regions in which cannabinoid receptors are abundant Cerebellum Body movement coordination Hippocampus Learning and memory Cerebral cortex, especially cingulate, frontal, and parietal regions Higher cognitive functions Nucleus accumbens Reward Basal ganglia Movement control moderately concentrated Hypothalamus temp reg, salt, water balance, reproductive function Amygdala Emotional response, fear Spinal cord Peripheral sensation, pain Brain stem Sleep, arousal, temp reg, motor control Central gray Analgesia Nucleus of the solitary tract Visceral sensation, nausea vomiting Localization of THC Binding Sites VTA, nucleus accumbens, caudate nucleus, hippocampus, and cerebellum THC affects two neurotransmitters: Dopamine & GABA levels may also be altered Dopamine GABA Dopamine Dopamine Receptor Why do we have these receptors? Anandamide (1992): endogenous THC! (just like "endorphin" is the brain's own morphine) • binds to THC receptors • is synthesized from lipid, a fat-like material in the cell membranes – not made in terminal!!! • Synthesized in the hippocampus, thalamus, cortex, striatum, lowest in the cerebellum, pons and medulla • Important signal early in development: embyro to uterus wall Why would we have a chemical in the brain that disrupts short-term memory?? Anandamide may be involved in eliminating unneeded information from memory • Anandamide discovered in chocolate • slows the destruction of chemicals that activate marijuana's receptor in the brain Use of Marijuana for Chemo Patients Vomiting: 5 HT3 receptors in raphe nucleus Medicinal Purposes Serotoninergic THC binds 5 HT3 anti-emetic (anti vomiting) MARINOL® (dronabinol): synthetic version of a naturally occurring delta-9THC: Anandamide Agonist Heroin Heroin (Opiate) •Analgesia (reduced pain) •Brief euphoria (the "rush" or feeling of well-being) •Nausea •Sedation, drowsiness •Reduced anxiety •Hypothermia •Reduced respiration; breathing difficulties •Reduced coughing Heroin (Opiate) •Derived from sticky resin of opium poppy •Raw opium is morphine heroin •Opiate receptors •Endogenous ligand endorphins Periaqueductal Gray analgesia Reticular formation sedation Preotic area hypothermia VTA & Nucleus Accumbens reinforcement Heroin crosses through the BBB 100 X faster than morphine because it is highly soluble in lipids = addictive Opiate Receptors Endorphins (endogenous ligand) feel-good chemicals naturally-manufactured in the brain when the body experiences pain or stress They are called the natural opiates of the body