Copyright © 2009 Allyn & Bacon Chemicals That Harm with Pleasure This multimedia product and its contents are protected under copyright law. The following are prohibited by law: any public performance or display, including transmission of any image over a network; preparation of any derivative work, including the extraction, in whole or in part, of any images; any rental, lease, or lending of the program. Chapter 15 Drug Addiction and the Brain’s Reward Circuits

Copyright © 2009 Allyn & Bacon Basic Principles of Drug Action Psychoactive drugs – drugs that influence subjective experience and behavior by acting on the nervous system Drug administration – route of administration influences the rate at which and the degree to which the drug reaches its site of action

Copyright © 2009 Allyn & Bacon Drug Administration Ingestion – oral route Easy and relatively safe Absorption via digestive tract is unpredictable Injection – bypasses digestive tract Subcutaneously (SC) – under the skin Intramuscularly (IM) – into large muscles Intravenously (IV) – into veins, drug delivered directly to brain

Copyright © 2009 Allyn & Bacon Drug Administration (continued) Inhalation – tobacco and marijuana Absorbed through capillaries in lungs Absorption through mucous membranes Nose, mouth, rectum

Copyright © 2009 Allyn & Bacon Mechanisms of Drug Action In order for a psychoactive drug to have an effect, it must get to the brain – it must pass through the blood-brain barrier Action of most drugs terminated by enzymes in the liver – drug metabolism Small amounts may also be excreted in urine, sweat, feces, breath, and mother’s milk

Copyright © 2009 Allyn & Bacon Drug Tolerance Decreased sensitivity to a drug as a consequence of exposure to it Shift in the dose-response curve to right Cross tolerance – exposure to one drug can produce tolerance to similar drugs Example: alcohol and benzodiazepines Tolerance often develops to some effects and not others More than one form of tolerance

Copyright © 2009 Allyn & Bacon Drug Tolerance (continued)

Copyright © 2009 Allyn & Bacon Drug Tolerance (continued) Metabolic Less drug is getting to the site of action Functional Decreased responsiveness at the site of action, fewer receptors, decreased efficiency of binding at receptors, receptors less responsive

Copyright © 2009 Allyn & Bacon Drug Withdrawal Effects and Physical Dependence Seen when drug use is terminated Symptoms are the opposite of the drug’s effects Body has made changes to compensate for drug’s presence – functions normally with the drug present Severity varies with drug and pattern of use

Copyright © 2009 Allyn & Bacon Addiction: What Is It? “Addicts” are those who continue to use a drug despite its adverse effects on health and social life Addiction and physical dependence may occur together or separately After withdrawal symptoms due to physical dependence have subsided, addicts may still crave the drug

Copyright © 2009 Allyn & Bacon Five Commonly Abused Drugs Tobacco Alcohol Marijuana Cocaine Opiates

Copyright © 2009 Allyn & Bacon Tobacco Nicotine – major psychoactive ingredient About 70% of those who experiment with smoking become addicted Only about 20% of attempts to stop are successful

Copyright © 2009 Allyn & Bacon 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 Quitting smoking by age 40 adds an average of 9 years to life span

Copyright © 2009 Allyn & Bacon Alcohol A depressant Heritability estimate for alcohol addiction is about 55% Metabolic and functional tolerance develops Attacks almost every tissue in the body

Copyright © 2009 Allyn & Bacon Effects of Chronic Alcohol Consumption Severe withdrawal in three phases: 5-6 hrs post-drinking: tremors, nausea, sweating, vomiting, etc hrs: convulsive activity hrs: delirium tremens – may last 3-4 days Korsakoff’s syndrome Cirrhosis Fetal alcohol syndrome (affects children of mothers who are heavy alcohol users during pregnancy)

Copyright © 2009 Allyn & Bacon Alcohol and the Brain Reduces flow of Ca 2+ into neurons Interferes with 2 nd messenger systems Disrupts GABAergic and glutaminergic transmission Triggers apoptosis

Copyright © 2009 Allyn & Bacon 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

Copyright © 2009 Allyn & Bacon 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

Copyright © 2009 Allyn & Bacon Medicinal Uses of Marijuana Treats nausea Blocks seizures Dilates bronchioles of asthmatics Decreases severity of glaucoma Reduces some forms of pain

Copyright © 2009 Allyn & Bacon Stimulants Increase neural and behavioral activity Cocaine and its derivatives – commonly abused Crack – a potent, cheap, and smokable form of cocaine Cocaine is an effective local anesthetic Synthetic analogues procaine and lidocaine used today

Copyright © 2009 Allyn & Bacon 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

Copyright © 2009 Allyn & Bacon 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)

Copyright © 2009 Allyn & Bacon Opiates: Heroin and Morphine Morphine and codeine obtained from the opium poppy Opiates – these drugs and others with similar structures or effects Medicinal uses Analgesics (painkillers) Treatment of cough and diarrhea High risk of addiction

Copyright © 2009 Allyn & Bacon Prevalence of drug use in the United States

Copyright © 2009 Allyn & Bacon Biopsychological Theories of Addiction Physical-dependence theory (dependence due to pain of withdrawal) does not explain why… addicts relapse long after detoxification individuals begin using drugs addictions develop to drugs that do not produce severe withdrawal symptoms Positive-incentive theories must explain… the difference between the hedonic value and the positive incentive value of the drug how a drug user becomes an addict

Copyright © 2009 Allyn & Bacon Biopsychological Theories of Addiction (continued) Incentive-sensitization theory Positive-incentive value (wanting) – the anticipated pleasure associated with the action (taking the 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

Copyright © 2009 Allyn & Bacon 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 compen- satory responses (tolerance/withdrawal), craving, and relapse

Copyright © 2009 Allyn & Bacon Intracranial Self-Stimulation and Brain “Pleasure Centers” Brain circuitry exists that reinforces behaviors Many species will work for stimulation of brain “pleasure centers” Discovered by Olds and Milner Drug use may be reinforced by acting on this circuitry

Copyright © 2009 Allyn & Bacon Intracranial Self-Stimulation (ICSS) A rat pressing a lever to obtain rewarding brain stimulation

Copyright © 2009 Allyn & Bacon Mesotelencephalic Dopamine System and Self-Stimulation Neurons projecting from two midbrain areas to telencephalon Nigrostriatal pathway Substantia nigra neurons projecting to dorsal striatum (degenerates in Parkinson’s disease) Mesocorticolimbic pathway Ventral tegmental area neurons projecting to cortical and limbic sites, including the nucleus accumbens (the major “reward” pathway for ICSS, natural rewards, and addictive drugs)

Copyright © 2009 Allyn & Bacon Mesotelencephalic dopamine system of the human brain

Copyright © 2009 Allyn & Bacon Mesocorticolimbic Pathway and Reward Increase in dopamine release seen here in self-stimulation studies Dopamine agonists tend to increase self- stimulation and antagonists to decrease Lesions here disrupt self-stimulation

Copyright © 2009 Allyn & Bacon Two Ways to Measure Drug Positive Incentive in Animals Drug self-administration through cannulas to brain Conditioned place-preference: lab animals choose to spend more time in cage com- partment where drugs were administered than elsewhere

Copyright © 2009 Allyn & Bacon Behavioral Preference Tests

Copyright © 2009 Allyn & Bacon Dopamine and 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

Copyright © 2009 Allyn & Bacon Nucleus Accumbens (NA) and 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

Copyright © 2009 Allyn & Bacon Dopamine Release in the NA: Reward or Expectation of Reward? Role is well-established Cocaine acts as a dopamine agonist by binding to dopamine transporters and blocking reuptake Addicts only report a high when cocaine is effectively blocking dopamine reuptake, increasing extracellular dopamine IV amphetamine study – euphoria reported correlated with dopamine levels in nucleus accumbens

Copyright © 2009 Allyn & Bacon Brain Mechanisms of Addic- tion: Recent Developments Addicts show poor decision making and lack of self control, suggestive of prefrontal cortex role Other neurotransmitters: glutamate, endo-genous opioids, norepinephrine, GABA, and endocannabinoids Drug addiction may be related to other non-adaptive behaviors, such as compulsive eating, gambling, sexual behavior, klepto-mania, shopping, etc.