W7 Substance Use Disorders PDF

9/5/24 Substance Use Disorders PSYU2236 BIOLOGICAL PSYCHOLOGY & LEARNING Prof Jen Cornish, School of Psychological Sciences [email protected]...

9/5/24 Substance Use Disorders PSYU2236 BIOLOGICAL PSYCHOLOGY & LEARNING Prof Jen Cornish, School of Psychological Sciences [email protected] PSYU2236 Substance Use Disorders. Cornish. 1 1 Substance Use Disorders Revisit Reward What is Substance Use Disorder (Addiction)? How do we model this disorder? Brain regions involved PSYU2236 Substance Use Disorders. Cornish. 2 2 1  9/5/24 Substance Use Disorders ► What is a substance use disorder (addiction)? ► How does brain function change in the addict? Outcome: main brain areas affected & research to support this PSYU2236 Substance Use Disorders. Cornish. 3 3 Why do ‘we’ take them? They make us feel good! Reward Pathway: Dopamine (DA) All drugs of abuse Increase Dopamine (DA) here Nucleus accumbens: NA Ventral Tegmental Area: VTA The mesolimbic dopamine system PSYU2236 Substance Use Disorders. Cornish. 4 4 2  9/5/24 Reward Reward: positive reinforcement Initial exposure to certain drugs will produce feelings of reward: – Elation – Excitement – Relaxation Usage reinforced (repeated) - becomes a drug of abuse Repetitive behaviour (drug usage) - when does this become Substance Use Disorder? PSYU2236 Substance Use Disorders. Cornish. 5 5 What is Substance Use Disorder? PSYU2236 Substance Use Disorders. Cornish. 6 6 3  9/5/24 What is Substance Use Disorder? A state characterized by: A compulsion to take drugs continuously or periodically Experience rewarding effects (A) Avoid the discomfort of its absence (B) World Health Organisation Solomon’s opponent-process theory.. Drug Drug How does this work for craving years after drug-taking? PSYU2236 Substance Use Disorders. Cornish. 7 They have to take more of the drug to overcome the state of B in the dependent example. 7 Physical vs Psychological Dependence Diagnostic and Statistical Manual of Mental Disorders DSMIV: kept substance abuse and dependence separate DSM5: substance use disorder one category - continuum Physical dependence Stop taking the drug produces withdrawal symptoms Heroin - abrupt cessation causes sweating, goosepimples, diarrhoea, muscular spasms, aches and pains Alcohol and benzodiazepines (valium) - hypersensitivity to sound and light, anxiety, convulsions, coma and even occasionally death (if withdrawal is too abrupt) Psychological dependence Craving of the drug during abstinence PSYU2236 Substance Use Disorders. Cornish. 8 benzodiapines is an anti-anxiety drug 8 4  9/5/24 You become tolerant to it because of repetition but you sensitise to it once you come back on the drug so 500 mg would kill you. Components of Substance Abuse Disorders Tolerance - loss of effect of a drug (reward) with repeated administration Withdrawal - appearance of symptoms associated with termination of chronic drug use Neuroadaptive processes to counter the acute effects of the drug A key element in drug dependence is also sensitisation: the increased ‘response’ to a drug following repeated administration LONG TERM (chronic) neuroadaptations which are manifest after repeated drug administration The brain is re-wiring to accomodate drug PSYU2236 Substance Use Disorders. Cornish. 9 taking e.g. more anxious 9 Liking vs Wanting Incentive-sensitization theory of addiction Terry Robinson & Kent Berridge – 1993 Compulsive drug use & inability to stop (relapse) ‘Excessive amplification’ of wanting the drug Less reliance on ‘liking’ the drug 4 Main components Addictive drugs share the ability to cause enduring neural adaptations Neural adaptations occur in regions involved in incentive motivation and reward (mesolimbic/mesocortical) These regions become hypersensitive (sensitized) But instead of sensitizing the reward (liking) component, drug ‘wanting’ is now dominant. The brain has changed to accommodate maladaptive behaviour. PSYU2236 Substance Use Disorders. Cornish. 10 10 5  9/5/24 Dopamine & Addiction What makes a substance addictive? Speed and magnitude of increased dopamine in the nucleus accumbens “RUSH” Determined by: Potency Route of administration – Oral – Subcutaneous – Intramuscular – Intranasal (snorting) – Inhalation – Intravenous PSYU2236 Substance Use Disorders. Cornish. 11 Least to most lethal route of administration 11 Dopamine = Reward ► Lead to the hypothesis that if dopamine is causative of the sensation of reward then it is responsible for addiction to abused substances “Dopamine Theory of Addiction” Dopamine may make you LIKE to take drugs but is it responsible for obsessive CRAVING (NEED)? PSYU2236 Substance Use Disorders. Cornish. 12 12 6  9/5/24 Limitations of the Dopamine Theory of Addiction 1. Aversive stimuli such as the stress of handling, electric footshock, tailpinch or aggressive attacks increase dopamine transmission PSYU2236 Substance Use Disorders. Cornish. 13 13 Limitations of the Dopamine Theory of Addiction 2. Mice lacking the dopamine transporter (DAT) will still self-administer cocaine (remember cocaine blocks the DAT) DAT knockout (-/-) is determined by analysing the DNA sequence of a small piece of the mouse tail Hair colour gene can also be altered to help recognise gene depleted mouse !!Beware of data: developmental neural compensation may occur!! PSYU2236 Substance Use Disorders. Cornish. 14 14 7  9/5/24 Limitations of the Dopamine Theory of Addiction 3. Individual differences - all abused drugs increase dopamine transmission but only a small percentage of people become addicted A similar percentage of rats become ‘addicted’: individual differences between them exist (high responders vs low responders) It's only 15% of them that show a truly addictive phenotype PSYU2236 Substance Use Disorders. Cornish. 15 15 Limitations of the Dopamine Theory of Addiction 4. A major component of addiction is craving. Animal models of drug addiction (behavioural sensitisation and drug self- administration) show that the major neurotransmitter involved in craving is glutamate (learned associations with environmental cues - prefrontal & orbitofrontal cortex). PSYU2236 Substance Use Disorders. Cornish. 16 We believe that's from the learned associations from learned cues in the environment 16 8  9/5/24 Addiction Symptoms arising from drug addiction Anxiety Depression Psychosis ► may be treated with available pharmacotherapies ► How can we stop people from taking and craving drugs of abuse?? PSYU2236 Substance Use Disorders. Cornish. 17 We don't really have a lot of stopping cravings at the moment. 17 Animal model of Addiction ► Common animal model of drug addiction is the drug ‘self-administration’ technique ► Animals (mice, rats, monkeys) will lever press to receive intravenous infusions of most drugs abused by humans (esp. cocaine, amphetamine, heroin, nicotine, but not LSD, THC?) Serotonin is involved in hallucinations ► Rats will self-administer alcohol orally ► Rats will also ‘self-stimulate’ brain areas associated with reward PSYU2236 Substance Use Disorders. Cornish. 18 18 9  9/5/24 Drug Self-Administration Rats will self-administer cocaine until death (90%) Heroin less toxic at 36% deaths (Bozarth & Wise, 1985) Rewarding effect of cocaine is blocked by: Dopamine receptor antagonists What brain regions are involved? - animal studies - human imaging studies Rat lever pressing for cocaine PSYU2236 Substance Use Disorders. Cornish. 19 Why was Heroin less toxic? Because they fall asleep because it's a narcoleptic. 19 What Drives Addiction Processes? There are very few effective pharmacotherapies for drug addiction -particularly psychostimulants (cocaine, methamphetamine (“ice”)) How does repeated psychostimulant usage affect the brain - what regions are involved …and why? PSYU2236 Substance Use Disorders. Cornish. 20 20 10  9/5/24 Cocaine & Amphetamine - Once Off Effect Amphetamine affects similar regions to cocaine Both increase dopamine transmission by activity at DAT Striatum - stereotypy (repetitive movement) DAT = Dopamine Transporter (A type of Biogenic Amine/Monamine Transporter) PSYU2236 Su bstance Use Disorders. Cornish. 21 21 Cocaine & Amphetamine - Repeated Use Prefrontal Cortex Dorsal Striatum Orbitofrontal Cortex Nucleus Accumbens Hippocampus & Amygdala Nucleus Accumbens: Motivation, Reward & Reinforcement Hippocampus & Amygdala: Memory & Emotion Dorsal Striatum: Decisions & Habit formation Prefrontal Cortex: Decisions & Control (appropriate behaviour) Orbitofrontal Cortex: Drive (value of reward) PSYU2236 Substance Use Disorders. Cornish. 22 22 11  9/5/24 The Ventral Striatum is the same as the NaC (Nucleus Accumbens) and the Dorsal Striatum is the same thing as the Caudate & Putamen. Drug use increases activity in Striatum: activity correlates with perceived “rush” Ventral Striatum is Nucleus Accumbens Dorsal Striatum is Caudate & Putamen “Rush” is Euphoria DA = Saliency of drug Inflates reward prediction error (Drevets et al, 2001) PSYU2236 Substance Use Disorders. Cornish. 23 23 Dopamine & Predicted Reward The anticipation of reward produces a large increase in dopamine The reward itself produces some dopamine release, yet an error in the value of the reward has more of an effect on dopamine The effect of drugs to increase dopamine inflates the predicted value of the rewarding effect of drug use Increased dopamine levels enhances drug taking due to the over inflated signal that taking the drug is so much better than it actually is PSYU2236 Substance Use Disorders. Cornish. 24 24 12  9/5/24 Drug use increases activity in Striatum: activity correlates with perceived “rush” Ventral Striatum is Nucleus Accumbens: “Rush” Dorsal Striatum is Caudate & Putamen: Habit Formation “Rush” is Euphoria DA = Saliency of drug Addicts: DA response to natural rewards is reduced or absent! Volkow et al 1997 (Drevets et al, 2001) PSYU2236 Substance Use Disorders. Cornish. 25 25 Shift in Saliency by Increased Activation of Orbitofrontal Cortex Look at the OFC in healthy controls OFC activity increased while drug-taking only in addicts The OFC enhances the reinforcing properties of the drug - compulsive drug seeking & usage (Volkow 2003) PSYU2236 Substance Use Disorders. Cornish. 26 26 Darker areas of the brain indicate that there's a lower supply, whereas brighter areas of the OFC indicate that there's more brain glucose. Here they're in withdrawal (not on drugs atm) 13  9/5/24 Hippocampus & Amygdala remind Addict of how good drug use feels Abstinent cocaine addicts shown two videos Nature Crack paraphenalia/taking of the drug Craving (Grant et al, 1996 Childress et al, 1999) PSYU2236 Substance Use Disorders. Cornish. 27 27 Hippocampus & Amydgala remind Addict of how good drug use feels DL= dorsolateral PFC AM= amygdala Neutral Cocaine PH= parahippocampul gyrus (Grant et al, 1996) PSYU2236 Substance Use Disorders. Cornish. 28 28 14  9/5/24 Associations With Drug-taking Stimulates Glutamate Transmission to Nucleus Accumbens Anterior cingulate cortex, DL PFC, OFC and Amygdala neurons contain & OFC glutamate which signals to neurons in the nucleus accumbens Glutamate is involved with learned associations (cues) with the drug-taking environment Amygdala & hippocampus Glutamate in Nucleus Accumbens Craving PSYU2236 Substance Use Disorders. Cornish. 29 (Cornish & Kalivas, 2000 McFarland et al., 2003) 29 Which Neurotransmitters are Involved? ► Use of animal models with direct injections into brain regions/use of viral technologies ► Intravenous self-administration - reinstatement/craving model PSYU2236 Substance Use Disorders. Cornish. 30 You can either stop or inhibit a behaviour using CNO 30 15  9/5/24 GABA is usually inhibitory, it showed that if you injected GABA it reduced craving The dorsal PFC is active during craving as inhibiting dPFC neurons reduces craving Inhibit PFC neurons & OFC X Amygdala & hippocampus Reduces Glutamate in GABA agonist Nucleus Accumbens (McFarland & Kalivas, 2001. J Nsci 21:8655) No Craving Inhibition of dPFC neurons is important for the control of behaviour PSYU2236 Substance Use Disorders. Cornish. 31 31 Incorporating the brain circuits PFC Inhibitory control by PFC is ignored or overridden STR NA OFC/PFC Hippocampus 2016 Review & Amygdala 2021 Review Increased drug/cue saliency (NA, OFC, Hipp ‘feels good’) Decreased interest in other rewards (NA & OFC) Loss of control (PFC) - compulsive use (OFC) – Habit (Striatum STR) Main neurotransmitters: Dopamine & Glutamate PSYU2236 Substance Use Disorders. Cornish. 32 32 16  9/5/24 Cocaine & Amphetamine - Addiction Prefrontal Cortex Dorsal Striatum Orbitofrontal Cortex Nucleus Accumbens Hippocampus & Amygdala Nucleus Accumbens: Sooo good (so unexpected)! Hippocampus & Amygdala: I remember how good that feels Dorsal Striatum: It’s a habit! Prefrontal Cortex: I can’t help it! Orbitofrontal Cortex: So good and I don’t care about anything else!!Use Disorders. Cornish. 33 PSYU2236 Substance 33 What does that really mean? “Normal” brain function is replaced by maladaptive brain function The drive for natural rewards is replaced by the NEED for drug: experience the reward to avoid the discomfort of drug absence Even when abstinent, cues of drug use produce craving & relapse Addiction is a complex neural disorder (Hyman, 2005 & reviews on slide 32) PSYU2236 Substance Use Disorders. Cornish. 34 34 17  9/5/24 Summary There are several components to drug addiction (psychological and physical) Substances which enhance the level of dopamine are addictive – greatly enhanced by fast routes of administration to the brain The dopamine theory of addiction exists, however there are limitations to this theory We can study addiction behaviours in animal models Together with these models and brain imaging in humans it has been shown that there are several key brain regions involved in addiction: nucleus accumbens/striatum, hippocampus, amygdala, orbitofrontal cortex and prefrontal cortex PSYU2236 Substance Use Disorders. Cornish. 35 35 Classic References Bozarth MA & Wise RA (1985). Toxicity associated with long-term intravenous heroin and cocaine self- administration in the rat. JAMA 254:81 Childress AR et al (1999). Limbic activation during cue induced cocaine craving. American Journal of Psychiatry 156:11 Cornish JL & Kalivas PW (2000). Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. Journal of Neuroscience 20:RC89 Drevets WC et al (2001). Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biological Psychiatry 49:81 Grant S et al (1996). Activation of memory circuits during cue-elicited cocaine craving. Proceedings of National Academy Sciences USA 93:12040 Hyman SE (2005). Addiction: a disease of learning and memory. American Journal of Psychiatry 162: 1414- 22. McFarland K et al (2003). Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behaviour. Journal of Neuroscience 23:3531. Robinson TE, Berridge KC (1993). The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Research Reviews 18:247-291 Volkow ND et al (2003). The addicted human brain: insights from imaging studies. Journal of Clinical Investigation 111:1444 https://www.aihw.gov.au/reports/illicit-use-of-drugs/national-drug-strategy-household-survey- 2019/contents/table-of-contents https://www.aihw.gov.au/reports/illicit-use-of-drugs/national-drug-strategy-household-survey/contents/about PSYU2236 Substance Use Disorders. Cornish. 36 36 18