303 Lecture 8 Ch. 5

1. 303 Lecture 8 Ch. 5 Artificial & Natural Ligands: Drugs

2. 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

3. Not just humans… Animals self administer ETOH coca leaf

4. 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 OCD Dementia Drug Abuse Degenerative CNS

5. National Surveys • 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

6. Reported drug and alcohol use by high school seniors, 2004

7. College Students YEAR 93 94 95 96 97 98 99 00 01 02 03 Marijuana 27.9 29.3 31.2 33.1 31.6 35.9 35.9 35.2 34.0 35.6 33.7 % Cocaine 2.7 2.0 3.6 2.9 3.4 4.6 4.6 4.8 4.7 4.8 5.4 % Source: University of Michigan, Monitoring the Future National Survey Results on Drug Use, 1975-2003, Volume II: College Students, 2004.

8. Percent of College Students/Young Adults Using Marijuana,2003–2004 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

9. New phenomena: Baby boomer overdosing 197022 yrs 198532 yrs Now 43 yrs Total number of drug mentions in drug abuse-related emergency department visits, by type of drug, 1999-2002

10. What is a drug? Chemical that alters one or more normal biological processes Psychoactive, Psychotropic Alter behavior, cognitive function or emotions

11. 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

12. Tolerance: state of decreased sensitivity to a drug as a result of continued exposure to it Takes more drug to get the same affect effect Dose response curve: shift to the right dose

13. Tolerance??? compensatorymechanisms that opposethe 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

14. 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 Group 3 Heroin (colony) Placebo (colony) Placebo (colony) Placebo (noisy room) Heroin (noisy room) Placebo (noisy room) All animal injected with lethal dose (15mg/kg) Colony noisy room colony noisy room colony noisy room 64% died 96% died Only 32% died

15. 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

16. Classical Conditioning Model: Heroin Overdosing

17. Tolerance??? compensatorymechanisms that opposethe effects of the drug Withdrawal symptoms are compensatory reactions in the body that oppose the

18. Psychopharmacology: Study of drugs on NS  behavior What Determines Drug Efficacy? • PHARMACOKINETICS • Absorbed bloodstream • Distributed bloodstream • Metabolized broken down • Eliminated Urine, sweat feces, mother’s milk

19. Pharmacokinetics • routes of administration • Absorbed IV • Distributed IP • Metabolized IM • Eliminated PO Sublingual Site of Action inhalation

20. PO: Most common, easiest, safe, cheapest • Swallowed • Stomach (enzymes) bloodstream • Intestine (alcohol) • Liver Bloodstream Unpredictable & time consuming

21. 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 IV: Strong effect, fast (15 sec) • Overdose • Scar tissue/ collapse of veins • Infections IM: Muscle • more rapid/PO • hurts!! …What else impacts Efficacy of a drug?

22. Weight Circadian cycle Genetic Makeup Drug Efficacy Food Intake Age loradadine(Claritin) Aspirin Polypharmacy Sunlight ~12 meds Immune system

23. Poison

24. After IV injection • Hi [ ] in blood but quickly leaves to other tissue • After leaving blood…to muscle…greatest [ ] because • lots of muscle • Although Fat highly vascularized…drug stays longer

26. Site of Action Very Important 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

27. Depressants, Sedatives, Anxiolytics Alcohol Barbiturates Benzodiazapines

28. Alcohol (ethanol) • small & lipophillic • Depressant • Mod: Cog, perceptual, verbal motor impairment • High: unconscious > 0.5 % death from respiratory depression Decrease Neuronal Firing Mod-Hi Low Stimulate neuronal firing

29. Alcohol’s Immediate Effects on NT GABA Agonist Sedation, incoordination Glutamate Antagonist Memory loss & Cog dysfunction 5HT Antagonist Impulsiveness,violent behaviors, sleepiness DA Agonist Reinforces alcohol habitat Dilation of blood vessels  red face Urination  diuretic urine by kidneys

30. Alcohol stimulate the release of endogenous opioids • Endogenous opioids (e.g., beta-endorphin) are released into the synapse • stimulate activity at opiate receptors, which produces a signal in the target neuron • Exogenous opiates (morphine) stimulate opiate receptors

31. 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

32. Depressants, Sedatives, Anxiolytics Barbiturates Benzodiazapines

33. Barbiturates: (0ld drug: 1903) • Sedation Phenobarbital  anticonvulsant • Sleep inducing Pentobarbital • Anesthesia • Muscle relaxant Indirect agonist  GABA the duration of CL- channels (hyperpolarize) “Drugged” next day…reduce respiration Replaced by BENZODIAZEPINES

34. 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)

35. Indirect Agonist

36. Psychostimulants Cocaine Amphetamine Caffeine

38. Cocaine • local anesthetic and CNS stimulant • coca bush • lipid soluable • Neurological and Behavioral problems: • dizziness • headache • movement problems • anxiety • insomnia • depression • hallucinations • Behavioral Effects: • euphoria • excitement • reduced hunger • a feeling of strength • friendly, outgoing

39. 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).

40. Cocaine • Agonist of Catecholamines • Blocks reuptake of DA, Norepi, Epi to presynaptic terminal PNS: constricts of blood vessels dilation of pupils irregular HB

41. Reuptake pumps DA Cocaine DA receptors

42. 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

43. D2 Receptors in Monkeys Cocaine – Environment alters receptors Subordinate Subordinate Dominant Dominant

44. Patient died of an overdose of cocaine – DA constricts brain vessels • small lesions • acute hemorrhages • hypoxia (lack of oxygen) - cell death, or strokes - can happen in heart = infarction or attack (sudden death).

45. Psychostimulants Amphetamine Caffeine

46. Amphetamines (stimulant): • http://www.psych.ualberta.ca/~ITL/flash/stimulants_draft.swf • CNS & Sympathetic NS (asthma, sleep disorders) • cause the release of dopamine from axon terminals • block dopamine reuptake • 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

47. 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

48. 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

49. 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

50. Marijuana