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The Biopsychology of Drugs and Drug Addiction Biopsychology Lecture 9 Blair Saunders Drugs & health Psychoactive Drugs Many (but not all) drugs alter our experience and consciousness: • • • • Perception Attention Cognition Behaviours Psychoactive properties of drugs vary in severity (coffee vs...

The Biopsychology of Drugs and Drug Addiction Biopsychology Lecture 9 Blair Saunders Drugs & health Psychoactive Drugs Many (but not all) drugs alter our experience and consciousness: • • • • Perception Attention Cognition Behaviours Psychoactive properties of drugs vary in severity (coffee vs. cocaine) Use of drugs for their psychoactive effects differs in cultural acceptance and legality (also coffee vs. cocaine) Psychoactive drug use is often instrumental, and culturally reinforced Types of psychoactive drugs Analgesics Stimulants Depressants Hallucinogens Negative consequences of drugs Many (but not all) people who start using psychoactive substances consume these substances compulsively, despite harm Physical harm • • • Certain cancers (e.g., lung cancer and smoking) Liver damage (e.g., alcohol metabolism) Infection (e.g., HIV and drug injection) Societal harm • • • • • Healthcare costs associated with drug misuse Arrest and Incarceration Loss of employment Antisocial behaviours (e.g., alcohol & violence) Breakdown of social and romantic relationships Notice that not all negative impact is a direct consequence of the drugs action on the body Society Societal costs associated with substance abuse are high Themes Overall aim: Understand the basic principles of drug action and drug addiction from a biopsychological perspective Theme 1: Drug action and Drug addiction • • • • Describe the ways in which drugs enter the nervous system Explain drug tolerance, withdrawal, and physical dependence Describe the disease model of addiction Situate drug addiction within the framework of chronic diseases Theme 2: The behavioural neuroscience of addiction • • • • Describe various methods in animal studies of drug reinforcement Identify pathways within the mesotelencephalic dopamine system Evaluate the strengths/weaknesses of animal studies of addiction Discuss instrumental drug use using evidence from animal and human studies The Biopsychology of Drugs and Drug Addiction Part 1: Introduction to drug use and addiction Blair Saunders How do drugs enter and pass through body? Most addictive substances have to enter the body’s nervous system through one of these other routes Goal Drug Administration and Drug Absorption Oral Administration • • • • Drug absorbed by digestive tract, either the stomach (fast) or intestines (slow) Alcohol, Pills, Edible Marijuana Pros: Relatively Easy and Safe compared to other drugs Cons: unpredictable doseresponse properties, damage to liver and other internal organs Inhalation • • • • Drugs enter bloodstream through capillaries in the lungs Tobacco, Marijuana Pros: Socially acceptable, lower risk of immediate infection Cons: Unpredictable doseresponse properties (depends on inhalation), often damages lungs, second-hand smoke Injection • • • • Drug injected into fatty tissue, large muscles, or veins Morphine, Heroin, anaesthetics Pros: Fast and efficient, drug has direct access to brain through bloodstream Cons: Infection risk (HIV, Hep C), overdose, arterial damage, social stigma Mucous membranes • • • • Drugs enter bloodstream through mucous membranes in nose, mouth, rectum Cocaine, Tobacco Pros: Self-administration is easy, fast effects Cons: Long-term usage causes damage to the mucous membranes How do drugs enter the brain? Mechanisms of drug action Some drugs have relatively general, system-wide mechanisms of action:  Alcohol molecules are fat/water soluble, and can enter and have a depressant effect on almost all parts of the body Many drugs have highly specific effects on particular neurotransmitter systems:  Many stimulants (e.g., cocaine) act to increase dopamine levels at neural synapses Neurotransmission of drugs Drug metabolism and elimination Drug Metabolism • • • • Metabolism refers to the conversion of one chemical to another Drug metabolism terminates the action of the substance Most drug metabolism is mediated by enzymes produced in the liver Many drugs (e.g., alcohol, paracetamol) cause liver damage Drug tolerance and withdrawal Drug tolerance Decreased effects of a drug dosage level after repeated exposure Conditioned Drug Tolerance Crowel, Hinson, & Siegel (1981) 2 groups of rats who received 20 alcohol and 20 saline injections Group 1: 20 alcohol injections in distinct test room, 20 saline injections in colony room Group 2: Exact opposite alcoholsaline schedule to group 1 Conclusion? Suggests situational specificity of drug tolerance Conditioned Drug Tolerance and Overdose These findings suggest that drug administration in novel contexts might be particularly deadly Situational drug use Conditione d Drug tolerance Drug use in novel situation No Conditione d Drug tolerance Elevated drug dose Elevated dose Predicted Effect Unpredicte d effect Siegel et al. (1982) More heroin-tolerant rats died from a large dose of heroin in a novel environment compared to the environment in which drugs were characteristically administered Drug Withdrawal Withdrawal syndrome can occur after large amounts of a drug have been in the system for longer periods of time Effects often oppose drug effects Example: Withdrawal of sleeping pills  insomnia Drug withdrawal likely produced by the same neural adaptations that produce drug tolerance • • Drug tolerance = compensatory response to dosage Drug withdrawal = lingering “overcompensation” effect after dosage ends Physical/Substance Dependence Withdrawal-relapse as a model for addiction Drug Taking Drug Tolerance Can withdrawal-relapse model account for addiction? Physical Dependenc e/ withdrawal Drug addiction/substance dependence Common term: we all have some idea of drug addiction looks like. But, as you will see, it is harder to define in practice Some features of drug addiction: • • • • • • • • • • Compulsive and frequent use of a rewarding or reinforcing substance Engaging with substances from a sense of need and wanting, rather than enjoyment Sensed loss of self-control, failed attempts to stop using Tolerance: needing more drug to get same response Withdrawal effect Physical changes (weight, skin condition, bloodshot eyes, vein damage) Changes in personality and/or social groups Irritability Change in priorities, financial and work problems Criminal behaviour (often a consequence of the drug itself being illegal) Defining addiction Common theme: Compulsively needing (wanting) something that feels rewarding but nevertheless has negative consequences Why do people become addicts? Why do people become overweight? Three common theories: 1. Willpower/conventional wisdom. • • Overweight people should resist eating unhealthy snacks and get more exercise Idea associated with stigma 2. Lifestyle/environmental factors • We live in an obesogenic environment. High access to unhealthy foods makes people more likely to become overweight 3. Biological/Genetic factors • Metabolism and genetic factors drives our body weight, and also how much we eat Why do people become overweight addicts? Three common theories: 1. Willpower/conventional wisdom. • • • Addicts are some how weak, immoral, or unable to resist immediate gratification Idea associated with stigma Validates criminal/legal approach to drug policy–immoral people should be punished, people will make better decisions if there is a strong deterrent 2. Lifestyle/environmental factors • Drug use is driven by environmental influences (e.g., peers, neighbourhood, advertisements). 3. Biological/Genetic factors • Genetic heritability predisposes individuals to drug use. • Drug tolerance and sensitivity is driven by certain innate biological factors Disease model of addiction Medical Model of Disease: abnormal condition that causes discomfort, dysfunction, or distress in the individual BIOLOGY (e.g., Brain, Genetics, Prior Exposure). ADDICTIO N ENVIRONMENT (e.g., social groups, family, stress, drug cues). Key premise: drug addiction should share many of the features (e.g., heritability, treatment-response, lifestyle factors, relapse rates) Drug addiction is not an inevitable outcome from drug exposure HEROIN MORPHIN E Addiction has a genetic component: Heritability Many diseases show high-levels of genetic heritability in siblings and twins • • • Hypertension (heritability: 0.25-0.50) Diabetes (heritability: type-I = 0.30-0.55; type-II = 0.80) Asthma (heritability: 0.36-0.70) Drug addiction also shows considerable heritability • • • • Heroin dependency in males (heritability: 0.34) Alcohol dependency in males (heritability: 0.55) Marijuana dependency in females (heritability: 0.52) Cigarette dependent twins of both sexes (heritability: 0.61) Personal Responsibility “Even if genetics predict becoming addicted, the individual still has to make a personal decision to take a drug” “People don’t choose to get hypertension, diabetes, heart disease, but people do choose to start smoking, drinking alcohol…” Well, many illnesses have seemingly voluntary components • • • Salt intake is highly related to the development of hypertension Sensitivity to salt is also determined in part by genetics Personal taste preferences are not entirely under volitional control McLellan et al. (2000), JAMA Genetics x Environment Involuntary genetic predispositions can interact with seemingly volitional decision making in the context of drug use Alcohol tolerance • Sons of alcohol-dependent fathers tend to inherit increased alcohol tolerance and reduced hangovers Aldehyde Dehydrogenase • • • • Enzyme involved in the metabolism of alcohol Individuals can have aldehyde dehydrogenase genotype meaning that they are deficient in the enzyme 50% East Asian origin, 20% Jewish men Leads to flushing of the skin when alcohol is less effectively metabolised McLellan et al. (2000), JAMA Drug Pathophysiology Pathophysiology - the disordered physiological processes associated with disease or injury (e.g., muscle deterioration in heart disease). Most drugs of abuse have (different) effects on midbrain dopaminergic pathways associated with motivation and learning • • • Cocaine increases synaptic DA by blocking dopamine reuptake in pre-synaptic neurones Amphetamine increases presynaptic release of DA Opiates and alcohol increase firing rates of dopamine neurons. Sustained drug use results in impairments in these midbrain pathways. • Abstinent cocaine users show impairments in DA system > 3 months after withdrawal McLellan et al. (2000), JAMA Lifestyle and Treatment Heart Disease Addiction • Engage in healthy eating and exercise • Know your family history • Reduce stress and develop positive coping strategies • Get treatment when needed and adhere to your regimen • Stay active in healthy activities: sports, arts, education • Know your family history • Reduce stress and develop positive coping strategies • Get treatment when needed and adhere to your regimen McLellan et al. (2000), JAMA Treatment adherence and relapse The effectiveness of drug treatment programs (e.g., methadone, nicotine patches, counselling etc.) depend on longterm adherence. This is also true for the treatment of most chronic diseases • • Patients must comply with drug replacement Drug treatments must be affordable/funded over the long term Common reasons for relapse across all conditions? • Socioeconomic status • Lack of social or familial support • Comorbid psychiatric illness or mental health problems Disease model of addiction Suggests that drug addiction is a public health issue that could be treated with a range of preventative and curative interventions. BIOLOGY (e.g., Brain, Genetics, Prior Exposure). ADDICTIO N ENVIRONMENT (e.g., social groups, family, stress, drug cues). Key premise: drug addiction should share many of the features (e.g., heritability, treatment-response, lifestyle factors, relapse rates) of other BREAK The Biopsychology of Drugs and Drug Addiction Part 2: The Biopsychological Basis of addiction Blair Saunders Early Behavioural Neuroscience Intracranial self-stimulation Mesotelencephalic Dopamine System Mesocortical and Nigrostriatal Pathways Mesocortical Pathway (red) • • • Dopamine neurons with cell body in Ventral Tegmental area Projects to numerous cortical and limbic sites Mesocortical Pathway seems particularly important for reward processing and drug self-administration Nigrostriatal Pathway (green) • • • • Dopamine neurons with cell body in the substantia nigra Major projections to the dorsal striatum Associated with motor control Degeneration associated with Parkinson’s disease Mesocortical pathway and self-administration Mesocortical Pathway seems particularly important for reward processing and drug self-administration • • • Reinforcing intracranial-stimulation sites tend to be occur in mesocortical pathway Self-stimulation  increased DA in mesocortical pathway (Hernandez et al., 2006) Lesions to mesocortical path tend to disrupt self-stimulation Is the mesocortical pathway the neural basis of addiction? Dopamine and drug addiction Intracranial-stimulation studies implicated dopamine systems in compulsive behaviours Experiments then started to explore the reinforcing effects of dopamine manipulation using two paradigms DA antagonists: drug that interferes with or inhibits the physiological action of DA • • DA antagonists largely abolish self-administration and conditioned place preference effects Is dopamine the neurochemical basis of pleasure? Nucleus Accumbens and drug addiction Nucleus Accumbens • • Part of the mesocortical DA pathway Receives inputs from ventral tegmental area Evidence from laboratory animal studies • • Lesions to Nucleus Accumbens, Ventral Tegmental area, and mediating pathway abolish self-administration and conditioned place preference in rats Lab animals selectively self-administer drugs into the nucleus accumbens Conclusion? Nucleus accumbens itself appears to be particularly related to reward and pleasure Societal impact of laboratory studies of addiction Led to a wide-spread notion that exposure to drugs (and the resulting physiological effects) lead to uncontrollable addiction Societal impact of laboratory studies of addiction Led to a wide-spread notion that exposure to drugs (and the resulting physiological effects) lead to uncontrollable addiction Societal impact of laboratory studies of addiction Led to a wide-spread notion that exposure to drugs (and the resulting physiological effects) lead to uncontrollable addiction “The Myth of Drug-Induced Addiction” Alexander suggested that behavioural neuroscience studies of addiction have two central claims: A) “All or most people who use heroin or cocaine beyond a certain point become addicted” B) “No matter what proportion of the users of heroin and cocaine become addicted, their addiction is caused by exposure to the drug” Early work on environmental moderators of addiction Classic self-administration studies • • • Rats are socially isolated, and kept in relatively stimulus impoverished environments Well controlled studies are very informative about brain function But do they resemble “real-world” addiction? Rat Park Studies • • • • • Alexander and colleagues compare animals in a rich, social environment to isolated rats In an initial acquisition phase the rats were given morphine to develop substance dependence Choice days: Rats given access to both fresh drinking water and water containing morphine Isolated rats increased self-administration on choice days, while the animals in rat park decreased drug use Do environmental stressors create drug addiction? Rat park is provocative and important, but perhaps also overly simplistic Too good to be true? Maybe… Just as it is unlikely that drug exposure is not the sole determinant of addiction, environment is also unlikely to be the only cause. Addiction is complex and multi-faceted: • Learning and drug exposure are still a factor in drug addiction • Environments can also be sources of both stress (e.g., workplace) or social facilitation of drug use (e.g., peer pressure) • Genetics and predispositions towards drug addiction Contemporary approaches to understanding drug addiction Positive incentive view. People do not take drugs to avoid withdrawal effects, but, instead to experience the drugs anticipated positive effects. What factors might moderate peoples’ anticipated pleasure associated with drugs? Why do some people start taking drugs? Drug self-administration can be brought about by stress People might take drugs (e.g., marijuana, alcohol) to relieve experiences of stress Think back to rat park study Rat studies of drug self-administration is moderated by factors that increase or decreases stress • • • Social Isolation (Ahmed, 2005) Environmental Stress (Ambroggi et al ., 2009) Food restriction (Carroll & Meisch, 1984) Why do some people start taking drugs? Individual differences associated with novelty seeking • • Novelty seeking: rats that are highly active in novel environments tend to also show increased drug self-administration Sensation-seeking in humans. Associated with seeking thrill and adventure, disinhibition, seeking new experiences, and susceptibility to boredom. This trait has been linked to a number of risky behaviours, including unprotected sex and drug use Example items from the Sensation Seeking Scale (Zuckerman, 1979) 1. A) “I get bored seeing the same old faces” B) “I like the comfortable familiarity of everyday friends” 2. A) “I would not like to be hypnotized” B) “I would like to have the experience of being hypnotized” Why do some people start taking drugs? Instrumental drugs Drugs will be reinforced particularly if they bring desired effects. These effects can vary between people and contexts Think of examples of other instrumental drug use? Coffee? Stimulants? Marijuana? Why do people use drugs habitually? Positive incentive theory suggests that drug-seeking behaviour is motivated by anticipated pleasure of the drug (e.g., craving or wanting) Paradox: Frequent drug users often report decreased liking (hedonic value) of drug during actual consumption • • Drug users can often come to crave drugs despite the substance having very negative influences on their daily happiness and wellbeing How can this be? Do separable neural and psychological processes underlie positive-incentive value (wanting) and hedonic value (liking). Mesotelencephalic DA system • • Rather than signalling pleasure or hedonic value of drug taking, recent evidence suggests that DA system reflects drug anticipation Neutral stimuli that reliably predict drug administration reliably predict increased firing of DA activity in rats (Weiss et al., 2000). DA as wanting vs. liking Positive incentive theory suggests that drug-seeking behaviour is motivated by anticipated pleasure of the drug (e.g., craving or wanting) Pecina et al. (2003) Hyperdopaminergic mutant mice: knock-down of dopamine transporter (DAT) that results in elevated dopamine extracellular levels in the striatum Wild-type mice: non-mutant mice that have naturally occurring dopamine processes. Incentive Runway task DA as wanting vs. liking Pecina et al. (2003) Wanting results Pleasure from food Sweet tastes produce liking responses across species, while bitter tastes produce aversive responses (Berridge, 2004) Summary Define drug tolerance and drug withdrawal, and how these processes are created by neural adaptations to drug exposure Define and differentiate the withdrawal-relapse /physical dependence model of addiction from the disease model of addition. Describe a range of behavioural neuroscience methods used to explore the neural correlates of addiction, and explain how these procedures implicated the mesocortical DA system in addition Provide a critique of classic laboratory studies of addiction, and explain how a range of environmental and individual difference factors might account for variation in addiction. Readings Core Text Pinel & Barnes (2014). Introduction to Biopsychology (Chapter 15) Additional Readings McLellan, A. T., Lewis, D. C., O'brien, C. P., & Kleber, H. D. (2000). Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA, 284, 1689-1695. Leshner, A. I. (1997). Addiction is a brain disease, and it matters. Science, 278, 45-47.