PSYC 415 -- Study Points for Substance (Ab)Use Disorders (revised 10/7/2013) I. Definitions A. substance abuse - use of a drug in such a way that the drug is taken in amounts or in circumstances not approved or supervised by a medical professional (not necessarily a psychoactive drug) B. substance use disorder - includes substance abuse and substance dependence C. addiction - an old term (which might also become the new term in DSM V) D. dependence - "when an individual persists in use of alcohol or other drugs despite problems related to use of the substance" (DSM IV-TR) 1. physical - defined by the appearance of characteristic withdrawal symptoms when the substance is suddenly discontinued 2. psychological - craving leading to habitual use II. spectrum of psychoactive substance use A. beneficial use B. casual/non-problematic use C. problematic use D. chronic dependence III. which drugs are the most harmful? A. it depends on who you ask and what criteria are used B. there is no doubt that alcohol and tobacco are the biggest public health problems and harm more people than any other drugs IV. Reinforcement A. drug-taking behavior, like all voluntary behavior, is maintained by reinforcement 1. positive reinforcement - behavior is motivated by acquisition of an appetitive stimulus (the reinforcer) 2. negative reinforcement - behavior is motivated by escape from an aversive stimulus 3. Note: Anyone who tells you that negative reinforcement and punishment are the same thing simply doesn't know what he's talking about! B. Thorndike's law of effect - talked about "stamping in" and "stamping out" behaviors C. immediate reinforcement is especially powerful 1. drugs that have rapid effects are the most addictive 2. heroin vs. morphine a. heroin is converted to morphine in the brain - they are essentially the same drug b. but heroin crosses the blood-brain barrier more easily - so gets into the brain faster c. users prefer heroin because its effect is more rapid - "rush" produced by a fast-acting drug V. Neural Mechanisms A. Olds & Milner (1954) - found that rats would press a lever in a Skinner box to obtain electrical stimulation to certain areas of the brain 1. long story short... 2. it was subsequently found that the highest rates of lever pressing were maintained by electrodes in the medial forebrain bundle 3. which is, in fact, a bundle of a lot of different pathways (including dopamine, norepinephrine, and others) 4. but it turned out to be dopamine that was important for electrical self-stimulation B. dopamine pathways 1. nigrostriatal tract - from the substantia nigra to the neostriatum (caudate nuc. and putamen) 2. mesolimbic pathway - from the ventral tegmental area to the nuc. accumbens (meso-ventral striatal) and limbic structures 3. mesocortical pathway - ventral tegmental area to prefrontal cortex C. DA fibers from the VTA to the nuc. accumbens are necessary (although not sufficient) for positive reinforcement 1. these fibers pass partially through the MFB 2. When a rat presses a lever to deliver electrical stimulation to the VTA (or MFB), dopamine is released in the nuc. accumbens. 3. Blocking the action of DA in the nuc. accumbens decreases the rewarding effect of MFB stimulation. 4. all known natural reinforcers (that have been studied so far) cause the release of DA in the nuc. accumbens 5. all known drugs of abuse (that have been studied so far) also cause the release of DA in the nuc. accumbens D. how reinforcement works (roughly) 1. voluntary behaviors are executed from the motor areas of the frontal lobe via the motor pathways (pyramidal tract) 2. there are two pathways into the frontal motor areas a. transcortical b. cortex to basal ganglia to thalamus to frontal motor areas - BG receive input from all areas of cortex 3. when behaviors are new and just being learned, they are executed via transcortical pathways - a very heavy processing load on the cortex 4. as behaviors are reinforced, learned, and repeated (automated,"stamped in"), they are transferred to the basal ganglia loop to take the processing load off the cortex 5. the reward pathway from VTA to nuc. accumbens determines which behaviors are "stamped in" - but how does it know what behaviors to choose? 6. input to VTA from prefrontal cortex (in front of the motor areas) - this area of cx appears to be the "evaluator" D. drugs of abuse bypass the "evaluator" and directly activate the reward pathway - "hijack" VI. Abstinence and Relapse A. tolerance - with repeated use, many drugs have decreased effectiveness, thus requiring that the user take bigger doses to get the same effect B. probably due to several feedback pathways in the body and brain that tend to counteract the effect of the drug C. abstinence then causes withdrawal -opposite effects from those the drug produces D. After chronic use of high doses of morphine or heroin, a characteristic abstinence syndrome occurs when the drug is withheld - notice that the effects are generally the opposite of the effects of the drugs themselves 1. 6 hrs: craving, anxiety 2. 12 hrs: yawning, sweating, runny nose, teary eyes 3. 18 hrs: goose bumps, tremors, hot and cold .ashes, aching bones and muscles, loss of appetite 4. 24 hrs: increased BP, increased body temperature, increased respiratory rate and depth, nausea 5. 36-48 hrs: vomiting, diarrhea, seizures in those prone to them E. withdrawal and negative reinforcement 1. if the withdrawing user relapses and begins taking the drug again, the unpleasant effects of withdrawal are eliminated 2. in general, it's thought that craving plays more of a role in relapse than withdrawal avoidance F. craving and relapse 1. the reinstatement model a. Renewed drug-taking can be produced by a small dose of the drug, or even by the presence of stimuli associated with drug use. b. a small sip or stimuli associated with use caused craving in alcoholics, but not in normal control subjects c. fMRI studies found that different areas of the brain were activated i. normal controls - anterior cingulate cx ii. alcoholics - nuc. accumbens, ventral tegmental area, anterior cingulate cx, and the insula (see .gure next slide) 2. craving and insula a. the case of Mr. N (see text) b. a stroke damaged his insula c. he "forgot that I was a smoker" d. actually, he forgot that his body had the urge to smoke (the craving was gone) e. for an interesting discussion of the insula, see the Wikipedia article on the "insular cortex" 3. craving and medial prefrontal cortex a. mPFC - judgment, reward valence, decision-making, risk-taking, inhibition of inappropriate behavior b. the mPFC has not yet fully matured in adolescents, which (the book suggests) may be responsible for that fact that most drug use disorders occur (or begin) in adolescence c. activation in these regions allowed UCLA researchers to predict a person's behavior better than the person himself could (in this study, use of sunscreen). d. activation of the mPFC predicted daily cocaine use VII. Commonly Abused Drugs A. opiates - morphine and heroin B. stimulants - cocaine and amphetamine C. nicotine (tobacco) D. alcohol E. cannabis VIII. Morphine and Heroin A. morphine is derived from opium B. heroin is a synthetic form of morphine 1. diacetylmorphine 2. called diamorphine when used medically for the treatment of severe pain (the name heroin is used only when illegal drug use is being referred to) 3. heroin is converted to morphine in the brain but is taken up more rapidly C. agonists at endogenous opioid receptors in the brain - endogenous ligands are enkephalins, endorphins, and dynorphins D. rats bar pressing for IV heroin injections show 150-300% increase in DA release in the nuc. accumbens IX. Cocaine and Amphetamine A. cocaine inactivates the DA transporter protein, thus inhibiting DA reuptake and inactivation B. amphetamines stimulate the release of DA C. if drugs that block DA receptors are injected directly into the nuc. accumbens, cocaine losses much of its reinforcing properties D. cocaine (and probably also methamphetamine) is such a potent reinforcer that rats will bar press for IV injections until they die (from starvation or exhaustion) X. Nicotine A. was once used as an insecticide B. is extremely fast acting and poisonous - can be absorbed through the skin C. there is enough nicotine in a cigar to kill two human beings D. children have been known to die from eating cigarette butts left in ashtrays E. the "crack baby" scare of the 1980s and 1990s appears to have been mostly media hype 1. prenatal cocaine exposure does have effects, but they are usually not severe or disabling 2. certainly not as serious as prenatal alcohol exposure F. the jury is still out on prenatal nicotine exposure 1. but if you want to read a genuinely scary article, read Slotkin (1998) - ref in the text 2. the public health consequences could be large, since 25% of babies in the U.S. are exposed prenatally to nicotine through maternal smoking G. nicotine is one of the most addictive drugs known 1. only 4% of people who attempt to quit smoking on their own remain abstinent for 6 months 2. people continue to smoke after laryngectomy for throat cancer, lung removal for lung cancer, leg amputation due to nicotine-induced reduction in blood .ow, and heart attacks H. nicotine use is associated with psychiatric disorders - 34% of cigarettes smoked in this country are smoked by people with psychiatric disorders I. nicotine administration increases activity of DA neurons in the mesolimbic pathway and DA release in the nuc. accumbens XI. Alcohol A. alcohol has two major actions in the brain 1. indirect GABA-A agonist (producing effects similar to those of barbiturates and benzodiazepines) 2. indirect NMDA receptor antagonist B. the most obvious effects of alcohol are apparently due to its action at GABA-A receptors (see next page) 1. Ro15-4513 blocks the alcohol binding site at the GABA-A receptor 2. don't count on being able to get this drug any time soon a. there are legal issues (see textbook) b. the drug causes anxiety and convulsions as side effects c. the drug wears off very quickly, so it wears off before the alcohol is out of the system - its effect is temporary C. prenatal exposure to alcohol can be devastating to brain and other aspects of development - fetal alcohol syndrome D. there is tolerance to the effects of alcohol 1. withdrawal can be very severe and even fatal (a medical emergency, more dangerous than heroin withdrawal) a. anxiety and irritability b. nausea and vomiting c. tremor - particularly severe in DTs ("the shakes") d. depression e. insomnia f. delirium tremens (DTs) - nightmares, agitation, global confusion, disorientation, visual and auditory hallucinations g. fever h. convulsions E. injection of a dopamine antagonist directly into the nuc. accumbens decreases alcohol intake F. injection of a drug into the VTA that decreases DA release in the nuc. accumbens also decreases alcohol intake G. drugs that block opiate receptors also block the reinforcing effects of alcohol XII. Cannabis A. low doses of THC cause release of DA in the nuc. accumbens B. THC acts at the CB-1 receptor in the CNS C. a targeted genetic mutation that blocks production of this receptor in mice abolishes the reinforcing effect of THC D. it also abolishes the reinforcing effects of morphine and heroin E. and reduces the reinforcing effects of alcohol XIII. Heritability A. drug abuse is a heritable trait (what isn't?) B. this knowledge by itself is not very useful C. we need to know the mechanisms which mediate this heritability 1. alcohol - there are heritable differences in the action of enzymes that break down alcohol a. alcohol dehydrogenase - to acetaldehyde b. acetaldehyde dehydrogenase - to acetic acid and carbon dioxide 2. people with high alcohol dehydrogenase activity and low acetaldehyde dehydrogenase activity tend to find drinking unpleasant XIV. Treatment - nothing new or exciting here