Ch. 15 Drug Use, Addiction, Brain\'s Reward Circuits PDF

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Chapter 15 Drug Use, Drug Addiction, and the Reward Circuits (p 415) LO 15 Drug Administration, Absorption, and Penetration of the CNS Psychoactive drugs drugs that influence subjective experience and behavior acting on the Nervous System. There are 4 ways drugs can be administered: oral ingestion, ...

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Chapter 15 – Drug Use, Drug Addiction, and the Brain’s Reward Circuits (p.389 – 415) LO 15.1 Drug Administration, Absorption, and Penetration of the CNS  Psychoactive drugs – drugs that influence subjective experience and behavior by acting on the Nervous System.  There are 4 ways drugs can be administered: oral ingestion, injection, inhalation, and absorption through mucous membranes. 1. Oral Ingestion: Preferred route; drugs dissolve in fluids in stomach >> intestines >> absorbed into bloodstream; some drugs readily pass through the stomach wall, others need to be broken down into inactive metabolites before they can be absorbed (takes another route).  Metabolites = breakdown products of the body’s chemical reactions  Advantages: ease and relative safety  Disadvantages: unpredictable 2. Injection: Common in medical practice  Subcutaneously (SC) – into the fatty tissue just beneath the skin (most common)  Intramuscularly (IM) – into the large muscles  Intravenously (IV) – directly into veins; Most drug-addicted persons prefer this route; delivers drugs directly to the brain  Advantages: strong, fast, and predictable  Disadvantages: little or no opportunity to counteract the effects of an overdose, an impurity, or an allergic reaction. 3. Inhalation: through the network of capillaries in the lungs; e.g. anesthetics (tobacco)  Disadvantages: (1) difficult to precisely regulate the dose of inhaled drugs, and (2) many substances damage the lungs if they are inhaled chronically. 4. Absorption through Mucous Membranes : aka with nose, mouth, and rectum  Commonly self-administered (e.g. cocaine is “snorted”)– causes damage LO 15.2 Drug Action, Metabolism, and Elimination  Mechanisms of Drug Action (how drugs can influence NS) o Diffuse on neural membranes throughout the CNS (e.g. alcohol) o Bind to particular synaptic receptors o Influence the synthesis, transport, release, or deactivation of certain neurotransmitters o Influence the chain of chemical reactions elicited in postsynaptic neurons by activation of their receptors.  Drug Metabolism and Elimination o The actions of most drugs are terminated by enzymes synthesized by the liver. o Drug metabolism – The conversion of a drug from its active form to a non-active form.  Eliminates drugs ability to pass through lipid membranes of cells o Small amounts of some psychoactive drugs are also passed in urine, sweat, feces, breadth, and mother’s milk. LO 15.3 Drug Tolerance, Drug Withdrawal Effects, and Physical Dependence DRUG TOLERANCE  Drug tolerance – a state of decreased sensitivity to a drug that develops as a result of exposure to it 1) A given dose of the drug has LESS EFFECT than it had before 2) It takes MORE OF THE DRUG to produce the same effect  This means that there is a shift to the RIGHT on the dose-response curve.  3 Important Points to Remember

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Chapter 15 – Drug Use, Drug Addiction, and the Brain’s Reward Circuits (p.389 – 415)

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1) Cross tolerance – one drug can produce tolerance to other drugs that act by the same mechanism. 2) Drug tolerance often develops to some effects of a drug but to others  Drug sensitization – increasing sensitivity to a drug 3) There is no single mechanism that underlies it Metabolic tolerance – Tolerance that results from a reduction in the amount of a drug getting to its sites of action. Functional tolerance – Drug tolerance that results from changes that reduce the reactivity of the sites of action to the drug. - Tolerance is largely functional – can result in several different types of adaptive neural changes: EX >> reduce number of receptors

DRUG WITHDRAWAL EFFECTS AND PHYSICAL DEPENDENCE  Withdrawal syndrome – the illness brought on by the elimination from the body of a drug on which the person is physically dependent.  The effects of drug withdrawal are virtually ALWAYS OPPOSITE to the INITIAL effects of the drug o Example: withdrawal of anticonvulsant drugs triggers convulsions  Theory: Withdrawal effects may be produced by the same neural changes that produce drug tolerance >>> hence, exposure to a drug produces compensatory changes in the NS that offset the drug’s effects and produces tolerance.  Severity Depends On… o Drug in question o Duration and degree of drug exposure o Speed the drug is eliminated  Greatest Withdrawal Effects – longer exposure to greater doses + rapid elimination LO 15.4 Drug Addiction: What is it?  Drug-addicted individuals – habitual drug users who continue to use a drug despite its adverse effects on their health, social life, and despite their repeated efforts to stop using it. o BUT not all habitual drug users are drug-addicted individuals.  The major motivating factor in addiction is not physical dependence – most addicted individuals RENEW their drug taking even after MONTHS of enforced abstinence.  You can also be addicted to food, gambling, the internet, etc. ROLE OF LEARNING IN DRUG TOLERANCE LO 15.5 Contingent Drug Tolerance  Contingent drug tolerance refers to demonstrations that tolerance develops only drug effects that are actually experienced. o Most studies of contingent drug tolerance employ the before-and-after design. LO 15.6 Conditioned Drug Tolerance  Conditioned drug tolerance – tolerance effects that are maximally expressed only when a drug is administered in the same situation in which it has previously been administered. o Lethal effects of a drug overdose when the drug is administered in a NEW CONTEXT.

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Siegel  conditioned compensatory responses = hypothetical conditional physiological responses that are opposite to the effects of a drug that are thought to be elicited by stimuli that are regularly associated with experiencing the drug effects. o Same thing occurs with meals and hunger. o Have employed exteroceptive or interoceptive stimuli as the conditional stimuli. Exteroceptive stimuli = external, public stimuli, such as the drug-administration environment. Interoceptive stimuli = internal, private stimuli; e.g. thoughts and feelings produced by the drugtaking ritual and the drug effects experienced. o IMPLICATION: just thinking about a drug can evoke conditioned compensatory response. Drug sensitization can also be situationally specific Drug withdrawal effects & conditioned compensatory responses o Similarity – both responses are opposite to the unconditioned effect of the drug o Difference – drug withdrawal effects are produced by the ELIMINATION of the drug from the body; whereas conditioned compensatory responses are ELICITED by drug-predictive cues in the absence of the drug.

THINKING ABOUT DRUG CONDITIONING  Conditioned stimuli may elicit responses similar (not opposite) to the drug.  The Pavlovian misunderstanding >> o Unconditional stimulus: the drug o Unconditional response: whatever changes in physiology or behavior recorded.  Ramsay and Woods (1997) = o Unconditional stimulus (US): disruption of neural functioning that has been directly produced by the drug. o Unconditional responses (UR): various neutrally mediated compensatory reactions to the US, which the experimenter may or may not be recording.  Findings = once one determines the US and UR, it is easy to predict the direction of the conditional response in any drug-conditioning experiment. o The conditional response is always similar to the unconditional response. FIVE COMMONLY USED DRUGS Tobacco, alcohol, marijuana, cocaine, and the opioids LO 15.7 Tobacco  When a cigarette is smoked, nicotine + 4,000 other chemicals are absorbed in the lungs o Nicotine = major psychoactive ingredient of tobacco  Leading cause of preventable death  Effect of Smoking: o Nonsmokers – nausea, vomiting, coughing, sweating, abdominal cramps, dizziness, flushing, and diarrhea o Smokers – relaxed, more alert, less hungry  Withdrawal effects: depression, anxiety, restlessness, irritability, constipation, and difficulties in sleeping and concentrating.  Smoker’s syndrome – The chest pain, labored breathing, wheezing, coughing, and heightened susceptibility to infections of the respiratory tract commonly observed in tobacco smokers.  Smokers as susceptible to… o Bronchitis – chronic inflammation of the bronchioles of the lungs

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Chapter 15 – Drug Use, Drug Addiction, and the Brain’s Reward Circuits (p.389 – 415)

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o Emphysema of loss of elasticity of the lung from chronic irritation o Cancer in lungs, larynx, mouth, esophagus, kidneys, stomach Buerger’s disease – blood vessels, especially those supplying the legs, become constricted o Occurs in 15 of 100,000 individuals, mostly in male smokers Nicotine is teratogen – an agent that can disturb the normal development of the fetus >> increases likelihood of miscarriage, stillbirth, and early death of a child.

LO 15.8 Alcohol  Alcohol invades all parts of the body o because alcohol molecules are small and soluble in both fat and water  Classified as a depressant, because at moderate-to-high doses it depresses neural firing; however, at low doses, it can stimulate neural firing and facilitate social interaction. o Moderate doses >> cognitive, perceptual, verbal, and motor impairment o High doses (blood levels at 0.5) >> risk of death from respiratory depression  Tolerance & physical dependence o Functional tolerance o Withdrawal symptoms: headache, nausea, vomiting, and tremulousness (hangover)  4 Phases of Withdrawal Phase 1: 6 to 8 hours Anxiety, tremor, nausea, and tachycardia (rapid heartbeat). Hyperactivity, insomnia, and hallucinations Phase 2: 10 to 30 hours Phase 3: 12 – 48 hours Convulsive activity Delirium tremens (DTs) = characterized by disturbing hallucinations, Phase 4: 3 to 5 days; bizarre delusions, disorientations, agitation, confusion, hyperthermia can last to a week (high body temperature), and tachycardia.  Chronic alcohol consumption can cause… o Korsakoff’s syndrome = neuropsychological disorder characterized by memory loss, sensory and motor dysfunction, and, in its advanced stages, severe dementia  (indirectly cause); by inducing thiamine deficiency o Affects the brain function o Extensive scarring (cirrhosis) of the liver – major cause of death for alcohol users  Even low to moderate regular drinking (a drink or two per day) is associated with elevated levels of many cancers, including breast, oral cavity, and colorectal cancer.  Alcohol Consumption and Effects on Children o Offspring of mothers who consume substantial quantities of alcohol during pregnancy can develop fetal alcohol syndrome (FAS) >>>  causing: brain damage, intellectual disability, poor coordination, poor muscle tone, low birth weight, retarded growth, and/or physical deformity. o Transgenerational epigenetic effects = even if mother doesn’t drink but father is an alcoholic, children are born with the effects of FAS  Moderate alcohol consumption has NO BENEFIT in terms of reducing mortality LO 15.9 Marijuana  Commonly given to the dried flower buds of Cannabis – the common hemp plant of which there are 3 species >> cannabis sativa, cannabis indica, and cannabis ruderalis  Mode of consumption: (1) smoke in a joint (cigarette) or (2) orally ingested (aka brownies)

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Psychoactive effects largely attributable to THC (delta-9-tetrahydrocannabinol); also 80 cannabinoids o Hashish – dark corklike material extracted from the resin on the leaves and flowers of Cannabis. Legally classified as a narcotic (referring to opioids), but actually a hallucinogen and depressant Difficult to measure depending on high or low doses o LOW DOSES: increased state of well-being, carefree state of relaxation, alteration of sensory perceptions, feeling of hunger, subtle changes in thought and expression.  Difficult to measure; Influenced by the social situation o HIGH DOSES: short-term memory is impaired, ability to carry out tasks w/multiple tasks declines, meaningful conversations are difficult, sensory distortion, paranoia, motor impairment, emotional intensification. Addiction potential is LOW! Tolerance develops during periods of sustained use Withdrawal symptoms (e.g. nausea, diarrhea, sweating, chills, tremor, sleep disturbances) are rare! No convincing evidence that marijuana causes brain damage. 3 lines of indirect correlation w/Marijuana o Hippocampal volumes tend to be slightly reduced o Heavy marijuana users tend to have memory problems o Slightly more likely to be diagnosed w/schizophrenia Marijuana may have neuroprotective effects o 80% less likely to die from brain injury 2 Receptors for THC = CB1 and CB2 o Turned out to be one of the most prevalent G-protein linked receptors in the brain; WHY?  o Discovery of Endogenous cannabinoid neurotransmitters – the endocannabinoids. o Anandamide = the first endocannabinoid neurotransmitter to be isolated and characterized. Therapeutic effects of THC o Suppress nausea and vomiting in cancer patients o Stimulate the appetite of patients with AIDS o Block seizures, reduce anxiety o Sativex (mouth spray w/THC) – treatment of multiple sclerosis

LO 15.10 Cocaine and Other Stimulants  Stimulants – drugs whose primary effect is to produce general increases in neural and behavioral activity; stimulants differ greatly in their potency.  Prepared from the leaves of the coca shrub (western S. America); coca paste made directly from the leaves and eaten.  Today, extracted cocaine hydrochloride (white powder)  Consumed by snorting or injection.  Crack – potent, cheap, smokeable form of cocaine; impure residue  Cocaine hydrochloride is an effective local anesthetic Cocaine  Psychological effects: well-being, self-confident, alert, energetic, friendly, outgoing, fidgety, and talkative  Cocaine sprees – binges of cocaine use o Effects: sleeplessness, tremors, nausea, hyperthermia o Cocaine psychosis – sometimes mistaken for schizophrenia  Tolerance develops to most effects of cocaine (e.g. euphoria)  Repeated cocaine exposure sensitizes subjects (e.g. makes them even

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Chapter 15 – Drug Use, Drug Addiction, and the Brain’s Reward Circuits (p.389 – 415)

   Amphetamine  Methampheta mine (“meth”) 3,4methylenediox ymethampheta mine (MDMA) aka Ecstasy

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more responsive) to its motor effects Withdrawal effects triggered by abrupt termination of a cocaine spree are mild = mood swing and insomnia Most widely misused stimulants Consumed orally in the potent form – d-amphetamine (dextroamphetamine) Some effects are similar to cocaine >> ex: can produce a syndrome of psychosis called amphetamine psychosis Relative of amphetamine drugs Smokeable, crystalline form (crystal meth) Taken orally Another potent relative of amphetamine Is an empathogen – psychoactive drugs that produce feelings of empathy

Long-Term Effects of Stimulants  Cognitive impairments in meth and MDMA users  Meth and amphetamine users have a greater risk of developing Parkinson’s disease o But not cocaine users  Electrocardiographic abnormalities  Less gray matter in their prefrontal cortex LO 15.11 The Opioids: Heroin and Morphine  Opium – dried form of sap exuded by the seedpods of the opium poppy; have several psychoactive ingredients; most notable are morphine and codeine (weaker) >> these are opioids  Opioids exert their effects by binding to receptors whose normal function is to bind to endogenous opioids; 2 classes: (1) endorphins and (2) enkephalins  Jekyll-and Hyde character o Effective as analgesics (painkillers); effective in treatment of cough and diarrhea o Huge risk of addiction. 3 Historic Events of Opioid Addiction 1. 1644: ban of tobacco smoking in China  increase of opium a. Smoking opium had greater effect than eating it; many ppl became addicted 2. 1803: Morphine (most potent constituent of opium) isolated a. Became available commercially in the 1830s. 3. 1856: Hypodermic needle invented – the injured introduced to morphine through a needle The Harrison Narcotics Act  1914: made it illegal to sell or use opium, morphine, or cocaine; but did not include the semisynthetic opioid heroin.  Heroin – synthesized w/2 acetyl groups added to the morphine molecule  greatly increased its ability to penetrate the blood-brain barrier. o More potent analgesic than morphine o Less likely to induce nausea and vomiting o Marketed as not addictive, but is very much so  fanned addiction

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Chapter 15 – Drug Use, Drug Addiction, and the Brain’s Reward Circuits (p.389 – 415) Effects of Opioids  Heroin rush – wave of intense abdominal, orgasmic pleasure that evolves into a state of serene, drowsy euphoria.  Opioid tolerance encourages users to progress to higher doses, to more potent drugs, and to more direct routes of administration + physical dependence  highly addictive Withdrawal Syndrome  Begins 6-12 hours after last dose = increase in restlessness o User begins to pace and fidget o Watering eyes, running nose, yawning, and sweating  Then... person falls into fitful sleep (lasts several hours) o When they wake up = original symptoms + extreme case of chills, shivering, profuse sweating, gooseflesh, nausea, vomiting, diarrhea, cramps, dilated pupils, tremor, muscle pains and spasms o “going cold turkey”  2nd or 3rd day = most severe  7th day = all symptoms disappear Health Risks  Main direct risks = constipation, pupil constriction, menstrual irregularity, and reduced sex drive  There are no serious ill effects  Opioid addiction is prevalent among doctors, nurses, and dentists Treatment  Methadone and buprenorphine – have high and long-lasting affinity for opioid receptors  Both are opioids with many the same adverse effects as heroin – but produce less pleasure  Strategy – block heroin withdrawal effects with either methadone or buprenorphine  until the individual can be weaned from heroin.  Buprenorphine has fewer adverse side effects, but less effective than methadone. LO 15.12 Interpreting Studies of the Health Hazards of Drugs  Interpretation of the adverse effects observed in drug users is almost always complicated by the fact that relevant research is correlational. LO 15.13 Comparison of the Hazards of Tobacco, Alcohol, Marijuana, Cocaine, and Heroin  Society as a whole: Tobacco and alcohol have a greater negative impact than marijuana, cocaine, and heroin. Globally as well – Tobacco: 5 million deaths/year and Alcohol = 2 million deaths/per LO 15.14 Physical-Dependence and Positive Incentive Perspectives of Addiction  Physical-Dependence Theories of Addiction = physical dependence traps addicted individuals in a vicious circle of drug taking and withdrawal symptoms. o In this case: users are driven by their withdrawal symptoms to self-administer the drug o Detoxification was used as a treatment under this theory, but flopped =  (1) some highly addictive drugs (like cocaine and amphetamines) do not produce severe withdrawal distress, and  (2) Habitual drug users involves an alternating cycle of binges and detoxification.  Positive-Incentive Theories of Addiction = the primary factor in most cases of addiction is the craving for the positive-incentive (expected pleasure-producing) properties of the drug. o Physical dependence does still play a role

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Chapter 15 – Drug Use, Drug Addiction, and the Brain’s Reward Circuits (p.389 – 415) o

But most important factor is the drugs’ hedonic effects

LO 15.15 Intracranial Self-Stimulation and the Mesotelencephalic Dopamine System  Intracranial self-stimulation (ICSS) – The repeated performance of a response that delivers electrical stimulation to certain sites of the animal’s brain (discovered by Olds and Milner). o Pleasure centers = brain sites capable of mediating the phenomenon o Normally mediate the pleasurable effects of natural rewards (i.e., food, water, sex)  Mesotelencephalic dopamine system – a system of dopaminergic neurons that projects from the me...