Drugs and Addiction

1. Drugs and Addiction

2. Drugs and Addiction • What is a drug? • An exogenous substance that, when absorbed into the body of a living organism, alters normal bodily function • What are psychoactive drugs? • Drugs that influence subjective experience and behavior by acting on the nervous system • How are drugs administered? • Drugs are typically administered in one of four ways: • Oral Ingestion (e.g. alcohol) • Injection (e.g. heroin) • Inhalation (e.g. tobacco) • Absorption through Mucous Membranes (e.g. cocaine)

3. Mechanisms of Drug Action • Psychoactive Drugs influence the CNS is many ways, including: • Binding to pre- and postsynaptic receptors • Influencing synthesis, transport, release, or deactivation of neurotransmitters • Influencing the chain of chemical reactions elicited by the activation of postsynaptic receptors

4. Drug Metabolism • Most drugs are deactivated by enzymes synthesized by the liver. • Drug Metabolism • Process by which liver enzymes covert active drugs to non-active forms. • Typically enzymes covert drugs into a more hydrophilic form, preventing the drug from being able to pass through the lipid membranes of cells. • Drug Elimination • Small amounts of some psychoactive drugs are passed out of the body in urine, sweat, feces, breath, and mother’s milk

5. Drug Tolerance • Drug Tolerance • State of decreased sensitivity to a drug that develops as a result of exposure to it. • Drug tolerance can be shown in two ways: • A given dose of a drug has LESS of an effect than that before exposure to it. • A HIGHER dose of a drug is required to produce the same effect.

6. Drug Tolerance • Drug Tolerance • A shift of the dose-response curve (fig. 15.1) to the right.

7. Drug Tolerance • Cross Tolerance • One drug can produce tolerance to other drugs that act by the same mechanisms • Drug Sensitization • Increasing sensitivity to a drug • A given dose of a drug has MORE of an effect than it had before exposure to it. • A LOWER dose of a drug is required to produce the same effect.

8. Drug Tolerance • Drug Sensitization • A shift of the dose-response curve (fig. 15.1) to the left.

9. Drug Tolerance • Metabolic Tolerance • Drug tolerance that results from changes that reduce the amount of the drug getting to its sites of action. • E.g. liver increases the production of enzymes that metabolize a drug • Functional Tolerance • Drug tolerance that results from changes that reduce the reactivity of the sites of action to the drug. • E.g. reduction in the number of receptors for a drug • Tolerance to psychoactive drugs is largely functional

10. Drug Withdrawal • Withdrawal Syndrome • Occurs when significant amounts of a drug that have been in the body for a period of time suddenly decrease. • E.g. long-time smokers attempt to quit by going “cold turkey.” • Withdrawal effects are opposite the initial effects of the drug (fig. 15.2). • Individuals that suffer withdrawal reactions when they stop taking a drug arePhysically Dependent.

11. Role of Learning in Drug Tolerance • Contingent Drug Tolerance • Tolerance develops only to drug effects that are actually experienced.

12. Role of Learning in Drug Tolerance • Conditioned Drug Tolerance • Tolerance effects are maximally expressed only when a drug is administered in the same situation in which it has previously been administered. Group A – tested in different context as drug administration Group B – tested in same context as drug administration

13. Role of Learning in Drug Tolerance • Conditioned Drug Tolerance • Tolerance effects are maximally expressed only when a drug is administered in the same situation in which it has previously been administered. • Conditioned Compensatory Responses • Stimuli that predict drug administration elicit conditional responses opposite the effects of the drug. • Exteroceptive stimuli • Interoceptive stimuli • Views every drug administration as a Pavlovian conditioning trial.

14. Five Commonly Abused Drugs • Tobacco • Alcohol • Marijuana • Cocaine • Opiates

15. Five Commonly Abused Drugs • Tobacco • Nicotine • The major psychoactive ingredient of tobacco. • Stimulates nicotinic ACh receptors • Highly addictive • About 70% of those who experiment with smoking become addicted. • Compare to 10% with alcohol and 30% for heroin • Only about 20% of attempts to stop smoking are successful.

16. Tobacco • Effects of Long-Term Tobacco Use • Smoker’s syndrome – chest pain, labored breathing, wheezing, coughing, increased susceptibility to respiratory infections • Susceptible to various lethal lung disorders – pneumonia, bronchitis, emphysema, lung cancer • Buerger’s disease • Some good news: quitting smoking by age 40 adds an average of 9 years to life span

17. Five Commonly Abused Drugs • Alcohol • A depressant • Heritability estimate for alcohol addiction is about 55% • Metabolic and functional tolerance develops • Attacks almost every tissue in the body

18. Alcohol • Effects of Chronic Alcohol Consumption • Severe withdrawal in three phases: • 5-6 hrs post-drinking: tremors, nausea, sweating, vomiting, etc. • 15-30 hrs: convulsive activity • 24-48 hrs: delirium tremens (DTs) – may last 3-4 days • The convulsions and DTs can be fatal • Korsakoff’s syndrome • Cirrhosis • Fetal alcohol syndrome

19. Alcohol • Alcohol and the Brain • Reduces flow of Ca2+ into neurons • Interferes with 2nd messenger systems • Disrupts GABAergic and glutaminergic transmission • Triggers apoptosis

20. Five Commonly Abused Drugs • Marijuana • Cannabis sativa – common hemp plant • THC – primary psychoactive constituent – although over 80 others are present • High doses impair short-term memory and interfere with tasks involving multiple steps • Addiction potential is low • Negative effects of long-term use are far less severe than those associated with alcohol and tobacco

21. Five Commonly Abused Drugs • Marijuana • THC binds to endogenous cannabinoid receptors (CB receptors.) • CB1 receptor is the most common G-protein linked receptor in the brain. • CB2 receptor is found in the brain stem and in cells in the immune system. • Cannabinoid receptors are found on pre-synaptic neurons! • endocannabinoids are released from the post-synaptic neuron, and bind to CB receptors on the pre-synaptic neuron, acting as a retrograde neurotransmitter.

22. Five Commonly Abused Drugs • Marijuana

23. Marijuana • Adverse Effects of Heavy Marijuana Use • Respiratory problems – cough, bronchitis, asthma • Single large doses can trigger heart attacks in susceptible individuals • No evidence that marijuana causes permanent brain damage • Possible correlation between marijuana use and schizophrenia, but no causal link has been shown

24. Marijuana • Medicinal Uses of Marijuana • Treats nausea • Blocks seizures • Dilates bronchioles of asthmatics • Decreases severity of glaucoma • Reduces some forms of pain

25. Five Commonly Abused Drugs • Stimulants • Increase neural and behavioral activity • Cocaine, Amphetamine, MDMA – commonly abused • Crack – a potent, cheap, and smokable form of cocaine • Cocaine is an effective local anesthetic • Synthetic analogues procaine and lidocaine used today

26. Stimulants • Cocaine • Cocaine binges or sprees may lead to cocaine psychosis • Looks like paranoid schizophrenia • While tolerance may develop to some effects of cocaine, sensitization is seen to motor and convulsive effects • Although highly addictive, withdrawal is relatively mild

27. Stimulants • Cocaine • Blocks the re-uptake of dopamine by the dopamine re-uptake transporter

28. Stimulants • Other Stimulants • Stimulants are neurotoxins • Amphetamine (“speed”) • Effects like cocaine – can produce psychosis • MDMA (“ecstasy”) • Impairs dopaminergic and serotonergic function in animal studies; human relevance unclear • Impairs executive function, inhibitory control, and decision making (as shown by cortex and limbic functional brain scan abnormalities)

29. Five Commonly Abused Drugs • Opiates: Heroin and Morphine • The endogeneous chemicals that bind to opiate receptors are called endorphins, and there are at least 20 different kinds of endorphins. • Morphine and codeine, which also bind to these receptors, are drugs obtained from the opium poppy • Medicinal uses • Analgesics (painkillers) • Treatment of cough and diarrhea • High risk of addiction

30. Opiates: Heroin and Morphine • U.S. Opiate History • Opium was readily available in a variety of “potions” until 1914 • Harrison Narcotic Act (1914) • Illegal to sell or use opium • Heroin, a synthetic opiate, was still legal • Structure similar to morphine, but better able to cross the blood-brain barrier • More addictive • Heroin illegal as of 1924

31. Opiates: Heroin and Morphine • Treatment for Heroin Addiction • Opiates bind to endorphin receptors • Methadone binds to these receptors • Produces less pleasure • Administered orally • Prevents withdrawal • Buprenorphine – similar to methadone but longer lasting • Substituting a less dangerous drug for the abused drug

32. Opiates: Heroin and Morphine • Prevalence of drug use in the United States

33. Reducing Drug Abuse • Current approaches (e.g. War on Drugs) are not effective • What recommendations would you make to decrease the incidence of drug abuse? • Which abused drugs should we be most concerned about?

34. Addiction • What is addiction? • Habitual drug use despite its adverse effects on health, social life, and despite repeated efforts to stop. • Drug addicts are habitual drug users. • Not all habitual drug users are addicts. • Is addiction the same thing as physical dependence? • NO! • Drug addicts will renew drug taking even after withdrawal effects have subsided.

35. Biopsychological Theories of Addiction • Physical-dependence theory • dependence due to pain of withdrawal • Addicts caught in a cycle of drug taking, withdrawal, drug taking to relieve withdrawal. • Detoxified addicts • No longer have drugs in their system and do not experience withdrawal symptoms does not explain why… • addicts relapse long after detoxification • individuals begin using drugs • addictions develop to drugs that do not produce severe withdrawal symptoms

36. Biopsychological Theories of Addiction • Positive-incentive theories • The primary factor in most cases of addiction is the craving for a drug’s pleasurable effects. must explain… • the difference between the hedonic value and the positive incentive value of the drug • the transition from being a drug user to becoming a drug addict

37. Biopsychological Theories of Addiction • Incentive-sensitization theory • Positive-incentive value (wanting) • the anticipated pleasure of taking a drug • Hedonic value (liking) • the actual pleasure experienced • With drug use, the positive-incentive value increases due to memory of the pleasure of early drug experience • The hedonic value decreases due to drug tolerance • Result: addicts crave drugs more and enjoy them less

38. Causes of Relapse • Stress • drug use as a coping mechanism • Priming • a single exposure leads to a relapse • Environmental cues • Conditioned drug tolerance • Returning to place where drugs once taken (or even thinking about drug) causes conditioned compensatory responses, craving, and relapse

39. Intracranial Self-Stimulation and Brain “Pleasure Centers” • Reward Circuits • Brain circuitry exists that reinforces behaviors • Many species will work for stimulation of brain “pleasure centers” • Discovered by Olds and Milner (1954) • Proposed that the same brain regions are activated by natural rewards, such as food, water, and sex. • Drug use may be reinforced by acting on this circuitry

40. Intracranial Self-Stimulation (ICSS) Fig. 15.6 A rat pressing a lever to obtain rewarding brain stimulation

41. Mesotelencephalic Dopamine System and Self-Stimulation • Dopaminergic neurons projecting from two midbrain areas to telencephalon • Nigrostriatal pathway • Substantianigra neurons projecting to dorsal striatum • Mesocorticolimbic pathway • Ventral tegmental area neurons projecting to cortical and limbic sites, including the nucleus accumbens • This is the major “reward” pathway for ICSS, natural rewards, and addictive drugs

42. Fig. 15.7 Mesotelencephalic dopamine system of the human brain

43. Mesocorticolimbic Pathway and Reward • Evidence that the mesotelencephalic pathway plays an important role in ICSS. • Self-stimulation sites that do not contain dopaminergic neurons project to the mesotelencephalic dopamine system • Increase in dopamine release seen in the mesocorticolimbic pathway following self-stimulation (fig. 15.8). • Dopamine agonists tend to increase self-stimulation and antagonists to decrease self-stimulation • Lesions of the mesocorticolimbic pathway disrupt self-stimulation

44. Two Ways to Measure Drug Positive Incentive in Animals • Drug self-administration paradigm • Lab animals press a lever to inject drugs into themselves through cannulas (thin tubes) implanted in the brain • Conditioned place-preferenceparadigm • Lab animals choose to spend more time in the cage compartment where drugs were administered, compared to a compartment not associated with drug administration.

45. Behavioral Preference Tests Fig. 15.9

46. Dopamine and Drug Addiction • Evidence of the Involvement of Dopamine in Drug Addiction • Dopamine’s role suggested by self-stimulation studies • Dopamine antagonists interfere with self-stimulation and reduce the reinforcing effects of food • Nucleus accumbens appears to play a primary role

47. Nucleus Accumbens (NA) and Drug Addiction • Evidence of the Involvement of the Nucleus Accumbens in Drug Addiction • Animals self-administer microinjections of addictive drugs into NA • Microinjection of drugs into NA produce conditioned placed preferences • Lesion NA or ventral tegmental area – no drug self-administration or drug-related place preference • Both self-administration of addictive drugs and natural reinforcers result in increased dopamine in the NA

48. Dopamine release: Reward or Expectation of Reward? • Reward: • Ventral tegmental neurons fire in response to a stimulus at a rate proportional to its reward value • Expectation of Reward: • Neutral stimuli that predict a reward can trigger dopamine release in the NA • Current view: • An increase in the activity of dopaminergic neurons in the ventral tegmental area occurs: • when a conditional stimulus predicts a reward • when a reward is presented in an unpredictable fashion

49. Structures That Mediate Addiction: The Current View • Initial drug taking • involves activation of the mesocorticolimbic pathway (nucleus accumbens), prefrontal lobes, and amygdala • Craving and compulsive drug use • Involves activation of the dorsal striatum and hypothalamic stress circuits • Relapse • stress (hypothalamic stress circuits) • priming doses (prefrontal cortex) • drug associated cues (amygdala)