Lecture 14 Flashcards
Definition of substance abuse
Harmful/hazardous use of psychoactive substances e.g. alcohol and illicit drugs
Definition of drug dependence
Body’s physical need/addiction to a specific agent
Why are certain drugs addictive?
- act in reward pathways to produce euphoria - adaptation of CNS circuits and withdrawal symptoms occur when activation stops - tolerance occurs so increased doses are required
What are the brain areas associated with the reward pathway?
- frontal cortex - nucleus accumbens - VTA - striatum - substantia nigra - hippocampus - raphe nucleus
What are the neurotransmitters associated with the reward pathways?
- dopamine - serotonin
Why are there reward pathways?
To reward us for signals that promote survival e.g. food consumption, drinking water, procreation child nutrition
What is the common pathway of addiction?
- dopamine released into nucleus accumbens - control of dopamine release by GABA neurones= inhibited by opiates - VTA and nucleus accumbens mostly targeted
How do drugs over-ride in-built controls?
- drugs over-ride top-down control (control and self-regulation) - salience= motivational component to a rewarding stimulus (a drug)
What areas do drugs over-ride?
- amygdala and hippocampus (memories of pleasurable events) - orbitofrontal cortex (fuels drive) - prefrontal cortex and cingulate gyrus (weakened control)
What is the physical dependence of addiction?
- resetting homeostatic mechanisms in response to repeated drug use - withdrawal syndrome (sign of physical dependence) - withdrawal arises due to abrupt termination of drug use
What is the psychological dependence of addiction?
- motivational component, craving for the drug - not always associated with physical dependence - persists longer than physical dependence
What is innate tolerance?
Genetically determined sensitivity i.e. occurs after first dose
What is acquired tolerance?
- pharmacokinetic= changes in metabolism and absorption reduce systemic blood concentration - pharmacodynamic= adaptive changes within the system resulting in altered response to the drug i.e. receptor desensitisation
What is cross tolerance?
Resistance to the effects of a substance because of exposure to a pharmacologically similar substance e.g. cocaine and amphetamines
Describe pharmacodynamic tolerance
- GPCR activation occurs - phosphorylation of receptors occurs - arrestin binding= prevent receptor signalling - endocytosis of receptors
Would you expect a larger or smaller number of GPCRs in long-term addicts?
Smaller number of GPCRs because of endocytosis
How does tolerance occur in cocaine addicts?
- prevents dopamine and 5-HT uptake - cycle between euphoria and dysphoria (can lead to paranoia and psychosis) - chronic use= speed to dysphoria increases - memory increases drive to increase euphoric state
How does cocaine modulate reward pathways?
Blocks uptake transporters for dopamine and 5-HT= increases levels of extracellular dopamine and 5-HT
How does cocaine modulate synaptic properties?
- changes in AMPA receptor levels= related to glutamatergic transmission - impaired cytosine-glutamate exchange - changes in intrinsic membrane excitability of medium-spiny neurones
How does cocaine affect the morphology of medium-spiny neurones?
- increases spine numbers - increases synapse synapse numbers within nucleus accumbens
How do we measure study brain circuit changes using animal models?
- choice as a method of measuring drug addiction - sweet vs drug solution - food, ethanol and intracranial self-administration - forced swim test
What are the principles for the effective treatment of drug dependence?
- quick and easy access to treatment - addresses all of the patients’ needs, not just drug use - patient must stay long enough in treatment - requirement for counselling and other behavioural therapies - medication in combination with behavioural therapies - drug use during treatment must be monitored - test for HIV/AIDS
What are the pharmacological approaches to treating drug dependence?
- alleviate with withdrawal symptoms e.g. methadone, nicotine patches - long term drug substitution - block drug response e.g. naltrexone - aversive therapies e.g. disulfiram - treat underlying mental health problems e.g. antidepressants
Disulfiram (antabuse) as an aversive therapy
- small amounts of alcohol can precipitate a reaction - nausea, vomiting, sweating - confusion - hypotension - blurred vision
What are the stages of cocaine withdrawal?
- crash= hunger, anxiety, fatigue, extreme depression - withdrawal= dysphoria, anxiety, depression, paranoia - extinction= low mood, episodic cravings
What are the methods of treating cocaine addiction?
- no specific pharmacological interventions - contingency management= reward-based system on the basis of free urine tests - CBT= recognise situations in which they are likely to relapse
What are the stages of opioid intoxication?
- rush= pleasure, facial flushing, resistance to tolerance - nod= sleepiness, virtual unconsciousness, detached - high= feeling of well-being (shows tolerance) - being straight= no high but no withdrawal
What are the mechanisms of opioid action?
- activate opioid receptors on GABA neurons in VTA - increased dopamine release into nucleus accumbens - reduced cAMP= when opioid are stopped cAMP rebounds leading to hyperactivity
What are the treatments of opioid addiction and how do they work?
- methadone, buprenorphine or legal heroin - alleviate withdrawal symptoms - long-term susbtution
Why are addicts at risk of overdose if they miss their methadone prescription?
Loss of tolerance
Why is buprenorphine used?
- precipitates opiate withdrawal - aimed to deter misuse - ineffective if taken orally but if crushed, dissolved or injected= naloxone blocks buprenorphine
Why would you use naltrexone?
- opioid receptor antagonist - in case of accidental overdose - BUT poor adherence limits effectiveness
Where does nicotine act in the brain?
- hippocampus - VTA - amygdala - nucleus accumbens - prefrontal cortex
What are the symptoms of nicotine withdrawal?
- headache - nausea - constipation or diarrhoea - anxiety - depression - insomnia
What are the methods to treat nicotine addiction?
- nicotine replacement e.g. gum - transdermal patches - e-cigarettes - varenicline= partial nicotine agonist - bupropion= nicotine antagonist
What are the pharmacological treatments for alcohol addiction?
- acamprosate calcium SR tablets - disulfiram - alleviate withdrawal symptoms= benzodiazepines, clonidine - opioid receptor antagonists= reduces endorphin effects in reward properties
How are acomprosate calcium SR tablets used to treat alcohol addiction?
- weak NMDAR antagonist reduces craving - used with counselling after abstinence
