Addiction. Copyright © 2006 by Allyn and Bacon Chapter 15 Drug Addiction and the Brain’s Reward Circuits Chemicals That Harm with Pleasure This multimedia

Addiction

Copyright © 2006 by Allyn and Bacon

Chapter 15Drug Addiction and the

Brain’s Reward Circuits Chemicals That Harm with Pleasure

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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


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 – into veins – drug delivered directly to

brain


Drug Administration

• Ingestion• Injection – SC, IM, IV• Inhalation – tobacco and marijuana

– Absorbed through capillaries in lungs

• Absorption through mucous membranes– Nose, mouth, rectum


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


Drug Tolerance

• Decreased sensitivity to a drug as a consequence of exposure to it– Shift in the dose-response curve

• Cross tolerance – exposure to one drug can produce tolerance to similar drugs

• Tolerance often develops to some effects and not others

• More than one form of tolerance


Drug Tolerance

• 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


Physical Dependence

• Indicated by occurrence of withdrawal– 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


Addiction: What Is It?

• “Addicts” are those who continue to use a drug despite its adverse consequences

• Addiction and physical dependence are not the same thing

• While they may co-occur, each can exist independently


Learning in Tolerance and Withdrawal

• Contingent drug tolerance– Tolerance only develops to drug effects that are

experienced

• Conditioned drug tolerance– Maximal tolerance effects are seen in the environment

in which a drug is usually taken

• Conditioned withdrawal effects– Withdrawal elicited by drug-related cues



Conditioned Tolerance and Withdrawal

• Situational specificity of drug tolerance is well-documented

• Environmental cues associated with drug-taking become conditioned stimuli that elicit conditioned compensatory responses, producing tolerance prior to drug use or withdrawal in the absence of the drug


5 Commonly Abused Drugs

• Tobacco• Alcohol• Marijuana• Cocaine • Opiates


Tobacco

• Nicotine – major psychoactive ingredient• About 70% of those who experiment with

smoking become addicted• Only about 20% of attempts to stop are

successful


Alcohol

• A depressant• High heritability estimate for alcohol addiction

- ~55%• Metabolic and functional tolerance develops• Attacks almost every tissue in the body


Effects of Chronic Alcohol Consumption

• Severe withdrawal – 3 phases– 5-6 hrs post-drinking: tremors, nausea, sweating,

vomiting, etc.– 15-30 hrs: convulsive activity– 24-48 hrs: delirium tremens – may last 3-4 days

• Korsakoff’s syndrome• Cirrhosis


Alcohol and the Brain

• Reduces flow of Ca++ into neurons

• Interferes with 2nd messenger systems

• Disrupts GABAergic and glutaminergic transmission

• Triggers apoptosis


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 are far less severe than those

associated with alcohol and tobacco


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


Medicinal Uses of Marijuana

• Treat nausea

• Block seizures

• Dilate bronchioles of asthmatics

• Decrease severity of glaucoma

• Reduce some forms of pain


THC

• Fat-soluble

• Binds to receptors in basal ganglia, hippocampus, cerebellum, and neocortex

• Endogenous ligand is anandamide

• Function of anandamide is not known


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


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 minor


Amphetamine

• AKA “speed” – another abused stimulant• Effects are comparable to those of cocaine –

also can produce psychosis• MDMA (ecstasy) – a relative of amphetamine• Evidence suggests that stimulants are

neurotoxins


Ecstasy

• Studies of lab animals find that MDMA has toxic effects on serotonergic and dopaminergic neurons

• But are the doses used in studies comparable to what humans use?

• Human studies do find abnormalities of serotonergic function and deficits in memory, mood, and psychomotor tasks


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


Factors Increasing Opiate Popularity

• China’s ban of tobacco smoking led to opium smoking– More addicting than eating opium

• Isolation of morphine – Opium’s most potent constituent

• The hypodermic needle– During the Civil War morphine addiction came to be

known as “soldiers’ disease”


U.S. Opiate History

• 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


Opiate Addiction

• Drawn to use by the rush following IV injection• Tolerance and physical dependence develop• Desire to avoid withdrawal adds to motivation to use• Although highly addictive, direct health hazards are

relatively minor• Many health hazards related to use of needles• Severity of withdrawal has been exaggerated


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



Reducing Drug Abuse

• Current approaches are not effective.• What recommendations would you

make to decrease the incidence of drug abuse?

• Which abused drugs should we be most concerned about?


Biopsychological Theories of Addiction

• Physical-Dependence Theory – – Use continues to avoid withdrawal

• Why relapse after detoxification? • Why begin use? • Why does addiction develop to drugs that do not produce

severe withdrawal?

• Positive-Incentive Theories– Use continues due to craving for drug effects– Supported by research


Causes of Relapse

• Stress – Drug use as a coping mechanism

• Priming – A single exposure leads to a relapse

• Environmental cues


Pleasure Centers of the Brain

• Brain circuitry exists that makes certain behaviors pleasurable

• 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



Mesotelencephalic Dopamine (DA) System and Self-Stimulation

• DA neurons projecting from the midbrain to areas in telencephalon

• Nigrostriatal pathway– Substantia nigra > Dorsal striatum

• Mesocorticolimbic pathway– Ventral tegmental area > cortical and limbic sites– Involved in reward



Mesocorticolimbic Pathway and Reward

• Self-stimulation sites that do not contain DA neurons project here

• Increase in DA release seen here in self-stimulation studies

• DA agonists tend to increase self-stimulation and antagonists to decrease

• Lesions here disrupt self-stimulation


Neural Mechanisms of Motivation and Addiction

• How do drugs act on existing reward circuitry to motivate addicts to continue to use?

• Asking animals what they like – necessary to explore positive-incentive theories– Drug self-administration– Conditioned place-preference


Behavioral preference tests


Dopamine and Drug Addiction

• DA’s role suggested by self-stimulation studies

• DA antagonists interfere with self-stimulation and reduce the reinforcing effects of food

• Nucleus accumbens appears to play a primary role


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


DA and Addiction

• Role is well-established• Cocaine acts as a DA agonist by binding to DA

transporters and blocking reuptake• Addicts only report a high when cocaine is effectively

blocking DA reuptake, increasing extracellular dopamine• IV amphetamine study – euphoria reported correlated

with DA levels in nucleus accumbens


Addiction

• While pieces of the puzzle are understood, many questions remain

• Some studies suggest that DA is involved in expecting reward, as opposed to reward itself

• Considering what we do know, how can addiction best be explained?

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Addiction. Copyright © 2006 by Allyn and Bacon Chapter 15 Drug Addiction and the Brain’s Reward Circuits Chemicals That Harm with Pleasure This multimedia