1.  General Issues  More Specific Drugs and how they work

2.  Psychopharmacology – study of drugs and behavior  Drugs and behavior – PSY 459  Clinical Psychopharmacology – PSY 565  Psychoactive drugs – drugs that change the way you feel  All these must reach the brain!

3. 1. To feel good (positive reinforcement – likely cause DA release!)  psychological dependence ** greatest amount of psychological dependence occurs if the rewarding effects of drugs happen very quickly after behaviors associated with them.

4. drug rewards that happen very soon after a behavior – strong positive reinforcement for that behavior ex. prep for heroin injection, crack smoking, etc.

5. 2. To avoid feeling bad (reduce withdrawal) (negative reinforcement) ◦ chemical dependence-

6.  Often a combination of positive and negative reinforcing effects or transition from positive to negative……

7.  pharmacokinetics:  includes how the drug is taken in (absorption)  how it gets to the brain (distribution)  what it does in the brain (nt?; pharmacodynamics)  how it is broken down (metabolism)  how it leaves the body (excretion)

8. - how a drug is taken into the body…… -for drugs of abuse - the more rapidly the drug gets to the brain – the greater the abuse liability!

9.  oral  injection ◦ subcutaneous ◦ intramuscular ◦ intravenous - reaches brain in ~ 10 secs  quick response but also most dangerous  inhalation - reaches brain in ~8 secs  dermal – absorbed through the skin  buccal or nasal membranes

10. 1. cocaine – blocks reuptake of monoamine neurotransmitters (most important DA) 2. nicotine ◦ acts as an agonist at nicotinic cholinergic receptors 3. alcohol ◦ works on virtually every neurotransmitter

11. 4. metabolism (detoxification or breakdown) how a drug is broken down or made into inactive forms mostly done by the liver – via enzymes!

12. 5. excretion (elimination) how a drug once broken down (or not) is eliminated from body most psychoactive drugs metabolites excreted in urine

13.  tolerance – either decreased effectiveness or potency of a drug

14.  metabolic tolerance – ◦ enzyme induction-  enzymes – speed up a chemical reaction ◦ with repeated exposure, enzymes get better at breaking down drug or liver makes more enzymes

15.  metabolic tolerance – ◦ enzyme induction- enzymes are either better at breaking down drug or liver makes more of them ◦ implications?

16.  metabolic tolerance – ◦ enzyme induction  cross tolerance – tolerance to one drug results in tolerance to other drugs (usually that need similar enzymes for breakdown) ◦ Implications:

17.  cross tolerance – tolerance to one drug results in tolerance to other drugs (usually that need similar enzymes for breakdown) ◦ Implications: ◦ Person shows up unconscious at ER and is an alcoholic – given a barbiturate for surgery;

18.  tolerance can still occur when the amount of drug reaching the brain/body is unchanged  pharmacodynamic or physiological tolerance –

19. “for every action, there is an equal and opposite reaction (in your brain)”

20.  Use alcohol as an example –  Acutely – alcohol decreases glutamate activity and increases GABA activity  Chronic alcohol -------- brain’s compensatory response?

21.  upregulation of GLU receptors – ◦ increase the number or sensitivity of glutamate receptors to compensate for decreased activity and try to get activity back to normal levels….  what happens during alcohol withdrawal? ◦ now have too many (or too sensitive) glutamate receptors – overexcitation, seizures, etc.

22.  Use alcohol as an example –  Acutely – alcohol decreases glutamate activity and increases GABA activity  Chronic alcohol -------- brain’s compensatory response?

23.  down regulation of GABA receptors – ◦ to compensate for increased activity and try to get activity back to normal levels…. – reduce n or sensitivity of GABA receptors  what happens during alcohol withdrawal? ◦ now have too few (or too insensitive) GABA receptors – overexcitation, seizures, etc.

24.  the exposure of compensatory changes in brain (and body perhaps) likely explain a number of withdrawal symptoms (that are often opposite of the effects that the drug causes)

25. chemical see-saw drugChange from norm

26. heroinconstipation chemical see-saw

27. The brain wants to rebalance the activity

28. heroin WD diarrhea

29.  Drugs taken in the same environment can also display tolerance associated with the conditioned cues  ex. heroin  explanation – compensatory changes in brain in EXPECTATION of drug

30.  most treatments do best with both pharmacotherapy and behavioral therapy (of some sort) but the data is still LOUSY!!!

31.  In terms of health –  Which drugs have the most significant health effects (for the largest number of people)?  KY issues?

32.  most treatments do best with both pharmacotherapy and behavioral therapy (of some sort) but the data is still LOUSY!!!

33.  Psychostimulants – increase arousal; sympathetic nervous system ◦ cocaine ◦ amphetamines  methamphetamine  drugs used to treat ADD  Ritalin (methylphenidate)  Adderall (mixed salts amphetamine)

34.  naturally derived (often from plants) ◦ cocaine – comes from the coca plant  synthetically derived (in the lab) ◦ amphetamine – synthesized in laboratories

35.  Cocaine – block reuptake (DA, NE) ◦ block the transporter  amphetamines – block reuptake (actually reverse the transporter) and stimulate release!  methylphenidate – blocks reuptake

36.  stereotypic behavior ◦ repetitive behaviors  Appetite suppression ◦ weight loss  Possible aggression ◦ several descriptions of murder and other violent offenses attributed to amphetamine intoxication

37.  Psychological dependence – ◦ very strong for drugs that are either smoked, or injected IV

42.  Psychological dependence – ◦ very strong for drugs that are either smoked, or injected IV  Physical dependence- ◦ do we see a withdrawal syndrome? ◦ “cocaine crash” – cause less certain

43.  cardiovascular ◦ increased risk for CVA ◦ cardiac arrhythmia ◦ increased blood pressure  respiratory ◦ chest painrespiratory complications ◦ difficulty breathing  CNS

44. CNS ◦ seizures ◦ intracranial hemorrhages (strokes) ◦ cocaine or amphetamine induced psychosis ◦ formication

45.  produce relaxation, sleep and ultimately (for some sedative hypnotics), unconsciousness and death from respiratory depression if dose is too high  alcohol, barbiturates, benzodiazepenes

46.  virtually all sedative hypnotic drugs work on the GABA receptor to make GABA bind better to its receptor!

47.  First written “recipe” for making beer – about 3000 BC (Egyptians)  fermenting fruit – sugar dissolved in H20 and exposed to air – microorganisms (yeasts) LOVE it

48.  http://videosift.com/video/Drunk-Animals- of-Africa-the-longer-version

49. Biphasic Alcohol Effects Scale Stimulant scale Elated Talkative Energized Up ExcitedVigorous Stimulated Sedative scale Inactive Sedated DownSlow thoughts Heavy head Sluggish Difficulty concentrating

50.  Alcoholism costs the nation $150 Billion / annum  many organ systems are affected including ◦ liver- fatty liver and cirrhosis ◦ pancreas - pancreatitis ◦ heart - cardiomyopathy ◦ immune function - compromised ◦ endocrine function - altered

51.  ethanol affects many NT  chronic ethanol is not good for CNS ◦ Wernicke’s – thiamine deficiency? ◦ Korsakoff’s – more permanent memory deficits

52.  affects many neurotransmitter systems  inhibits glutamate activity  enhances GABA activity ◦ R0-15-4513

53. Copyright © Allyn & Bacon 2007

54.  Psychological – perhaps some but certainly not as strong as psychostimulants  Physical dependence – absolutely ◦ alcohol withdrawal – only withdrawal syndrome that is potentially LETHAL if not done under medical supervision!!!!

55.  First need to treat acute withdrawal  Then follow up with more long-term strategies ◦ pharmacotherapies ◦ groups like Alcoholics Anonymous

56.  GABA ◦ a down regulation of GABA receptors  Glutamate ◦ an upregulation of GLU receptors  Treat with benzodiazepenes during WD ◦ reduces the risk of seizures

57.  probably 2 nd most commonly used drug in US

59.  rewarding, pleasurable effects ◦ how?  paradoxical effects on arousal ◦ biphasic effect with increased attention at lower doses but decreased anxiety/arousal at higher doses  decreased hunger and resulting weight reduction ◦ nt release and increased metabolism because of sympathetic NS activation

60.  nACh receptors – nicotinic subtype of ACh receptors

61.  Where are these receptors found? ◦ PNS  autonomic ns – so can affect heart rate; blood pressure, etc  muscles – all postsynaptic receptors on muscles are nicotinic!

62.  Where are these receptors found? ◦ PNS  autonomic ns  muscles  biphasic effect ◦ low dose – stimulation; high dose – brief stimulation followed by blockade of transmission ◦ (WHICH IS WHY NICOTINE IS SUCH A POTENT POISON)

63.  OH YES!!!!!  Psychological Dependence ◦ nicotine produces strong psychological dependence  Physical Dependence ◦ for regular smokers – nicotine produces strong physical dependence ◦ TTFC – time to first cigarette –  sometimes used as an indicator of dependence

64.  Pharmacotherapy- ◦ substitution therapy – provide nicotine via a safer (and less rewarding route) ◦ intent is to reduce the positive reinforcing effects AND provide negative reinforcement (ie reducing withdrawal symptoms)

65.  Opioid based drugs ◦ heroin, morphine, oxycodone, methadone, etc ◦ activate endogenous opiate receptors  treatment often uses substitution therapy ◦ methadone ◦ buprenorphine ( )

66.  hallucinogens – a mix of types of drugs  some examples - ◦ LSD like hallucinogens – work on 5HT neurons ◦ Amphetamine like hallucinogens – MDMA (Ecstasy) – seems to have effects on serotonin (in some cases it is neurotoxic to 5HT neurons) ◦ psychedelic anesthetics – PCP; ketamine  work on the glutamate receptor