Lecture 2 - Tolerance, mechanisms of action and features of addiction Flashcards
What are agonists and antagonists?
Agonists = activate receptors by mimicking a neurotransmitter or by increasing the existing neurotransmitter
Antagonists = block the activation of receptors
What is downregulation and upregulation?
Downregulation = the cellular decrease in the number of receptors to brain chemicals, such as hormones or neurotransmitters, which reduce the cell’s sensitivity to that chemical.
Upregulation = an increase in the number of receptors on the surface of target cells, making those cells more sensitive to a hormone or another agent
These processes are ways of maintaining homeostasis
What is serotonin responsible for?
- Arousal
- Emotion and mood
- Body temperature
- Sensory perception
What is dopamine responsible for?
- Arousal
- Emotion
- Motivation
- Positive reinforcement
- Reward
- Sexual arousal
What is noradrenaline responsible for?
- Anxiety
- Cognition
- Nociception (perception of pain)
What is acetylcholine responsible for?
- Arousal
- Motivation
- Learning
What is glutamate responsible for?
- Learning
- Memory
- Emotions
- Sensory information
- Motor coordination
What is GABA responsible for?
- Sleep and circadian rhythms
- Anxiety
- Memory and learning
What is adenosine responsible for?
- Sleep and alertness
- Stress
What is endocannabinoids responsible for?
- Mood
- Memory
- Pain sensation
- Anxiety
- Appetite
- Reward
What are opioids responsible for?
- Analgesia (pain relief)
- Reward
- Emotion
- Stress
How does drug tolerance et established?
- The effects of a drug diminish when you use it repeatedly
- We need more to get to the same effect as when we first used it
- Applies to almost all drugs of abuse
- Happens at different rates and varying extents
What is metabolic tolerance (pharmacokinetic tolerance)?
Body becomes better and more efficient at breaking the drug down - small effect
What is cellular tolerance (pharmacodynamic tolerance)?
Change in number of receptors (downregulation), in receptor function and/or post-synaptic function - large effect
What is the effect of caffeine on adenosine?
- Acts as an antagonist to adenosine by blocking its receptors
- Creates behavioural stimulation (arousal)
What are the positive effects of caffeine?
Smith, Kendrick & Maden, 1992 - Increased alertness and wakefulness
Horne & Reyner, 1996 - caffeine during a driving break reduces driver impairments and sleepiness when driving resumes
What are the effects of nicotine on acetylcholine transmitters?
- Stimulates nicotinic receptors of acetylcholine (Ach) neurones
- Most negative effects of smoking come from the inhalation of tobacco rather than nicotine
- Positive effects such as improving attention and concentration
- Protective attributes against health conditions like Alzheimer’s and ADHD
- Regular smoking mostly negatively reinforced (governed by withdrawal)
What are the effects of alcohol?
- Effects include sedation, relaxation, euphoria and disinhibition
- Acts on multiple neurotransmitters
- Crosses BBB very quickly and can be detected in the brain within minutes
- Has specific and non-specific actions on brain
- Non-specific actions include acting as a depressant on all brain neurons
- Disturbs neuronal membrane lipids - membrane fluidisation
- Inhibits glutamate activity and stimulates GABA release - additional effects on endorphin and dopaminergic systems and serotonin receptors
How do alcohol and sugar interact?
- Sugar-dependent rats increased intake of alcohol when denied access to sugar (Avena et al., 2004)
- Access to alcohol (ethanol) increase sugar intake in rats
- Authors concluded that bingeing on either sugar or alcohol fostered intake of the other
- Implications for human diet and alcohol intake
- E.g., ‘Alcopops’ targeted as adolescents and young people
- Alcohol use - risk of less health diet
What are the effects of cannabis (THC and CBD)?
- Diverse effects according to individual, mood and species of plant
- Including relaxation, happiness, increased laughter, increased chattiness, lack of motivation, lethargy, drowsiness, nausea, anxiety, confusion and paranoia
- Only THC is psychoactive - CBD is legal in the UK
What are the effects of synthetic cannabinoids (e.g. Spice)?
- Act similarly to cannabis
- Different effects on specific receptors
- THC is a weak CB1 agonist, whereas synthetic cannabinoids tend to be full CB1 agonists
- Increased adverse reactions compared to THC
- Lack of CBD appears to prevent mediating and relaxing effects in comparison to natural cannabis - more negative effects and less pleasant effects
- Synthetic cannabinoids cause agitation, irritability, confusion, hallucinations, delusions and psychosis
What are the effects of heroin and opioids?
- Appears to be very addictive in both physical and psychological sense
- Effects include relaxation, euphoria, sleepiness, happiness, less sensitive to pain and trauma
- Specific opioid receptors were identified in the 1970s by Pert & Snyder
- Leading to the discovery of endogenous opioids (endorphins)
- Opiates such as heroin and morphine mimic endorphins - sit in the receptor sites
- Synaptic dopamine levels (due to disinhibition of dopaminergic neurons) involved in the reward mechanism of the drugs
How does tolerance to heroin occur?
- Quick tolerance to nausea
- No tolerance ever to constipation or ‘pinpoint’ pupils
- Cross tolerance = once you are tolerant to heroin you are also tolerant to morphine, codeine and methadone - one drug in a class leads to tolerance to other drugs in the class
Why does overdose often occur during recovery?
Because tolerance has gone down but the individual uses a habitual amount and that amount is too much following abstinence or reduction (White & Irvine, 1999)
What are the effects of cocaine?
- Confidence, euphoria, alertness, energy and excitement
- Cocaine blocks the reuptake of dopamine, noradrenaline and serotonin
- This acts as an agonist to increase these transmitters
- Addictive potential correlated with increased dopaminergic activity in the mesocorticolimbic pathways, with predominance in the ventral tegmental area (VTA) and projection to other brain locations e.g., nucleus accumbens
What are the effects of amphetamines?
- Include high energy, excitement and chattiness
- Amphetamines stimulate release of DA and act as DA agonists
- Also stimulate release of noradrenaline
- Methamphetamine increases synaptic levels of monoamines (noradrenaline, dopamine and serotonin)
- Impairs the active transport of the monoamines into the synaptic vesicles - it can also slow down catecholamine metabolism and inhibits DA synthesis
- MDMA increases the levels of DA and NA but also have hallucinogenic effects
What are the effects of ecstasy/MDMA?
- Extreme happiness, energy, feeling love for people around them
- Classed as a hallucinogen due to effect on perception of reality
- MDMA stimulates release of noradrenalin and is a NA agonist
- Also stimulates the release of serotonin
- Stimulates DA but main effects are on 5HT and NA
What are the effects of hallucinogens?
- Tryptamines are tryptaminic hallucinogens (most popular being LSD)
- LSD, magic mushrooms and other hallucinogens are psychedelic drugs
- Powerfully alter cognition, mood and perception
- Serotonin agonists as main action, specifically 5HT-2A seems implicated
- Novel psychoactive substances (NPS) - ‘legal highs’ or designer drugs - synthetic or plant based (can include cannabinoids, cathinone, hallucinogens, synthetic opioids, phenethylamines, piperazines and synthetic benzodiazepines)
What are benzodiazepines?
- Prescription medication with addictive properties - abused on the streets
- Agonist for GABA - leading to anxiolytic and muscle relaxant action (type 2 site)
- Leads to sedation, amnesia and anticonvulsant action (type 1 site)
- Can also block adenosine reuptake decreasing arousal & increasing sleepiness
What are the most common benzodiazepines?
- Diazepam
- Alprazolam
- Lorazepam
- Temazepam
- Flunitrazepam
Study: Volkow et al., 2019
- Addiction is increasingly regarded as a chronic relapsing disorder
- Characterised by an urge to consume drugs, by progressive loss of control over, and escalation in, drug intake
- Despite repeated (unsuccessful) attempts to resist doing so
- Addiction emerges in context with complex biopsychosocial interactions between the pharmacological effects of a drug and individual vulnerabilities, inadequate social connectivity and other sociocultural factors
What are the features of addiction?
- Tolerance
- Withdrawal
- Compulsive engagement with drug
- Neural mechanisms
- Craving/obsessive focus on drug
- Relapse
What is physical withdrawal syndrome?
- Due to neuroadaptation
- As drug wears off, uncomfortable symptoms occur
- E.g., for heroin = cramps, convulsions, sweating, goose flesh (‘cold turkey’), flu-like symptoms
- Alcohol withdrawal for heavy, chronic drinkers = tremors, fever, seizures, hallucinations, fatigue, nausea, vomiting, headaches, increased heart rate, sweating and high blood pressure
- Reversed by administering drug (negative reinforcement)
What are the 11 criteria in the DSM-5 for addiction (Substance-use disorder)?
- Taking larger amounts or for longer than you are meant to
- Not being able to cut down or stop even when wanting to
- Cravings and urges to use substance
- Not being able to do what you should at work, home, etc due to the substance use
- Continuing use even when causing problems with relationships
- Giving up important activities because of substance use
- Using substance even when putting you in danger
- Continued use even when know it has caused psychological or physical issues or made them worse
- Tolerance
- Withdrawal symptoms when not using the substance
How does the DSM-5 measure the degree of the addiction?
2/3 of the criteria = mild
4/5 = moderate
6+ = severe addiction
What are the three ICD-11 criteria for substance dependence?
- Impaired control over substance use
- Substance use becomes an increasing priority in life
- Physiological features
What are the three factors that make up the addiction cycle?
- Preoccupation anticipation
- Binge intoxication
- Withdrawal negative affect
What occurs in the preoccupation/anticipation stage of the addiction cycle?
- Drug addiction is a chronic, relapsing disorder
- Key stage in cycle as it precedes drug use
- Although it’s assumed this stage involves craving, this is difficult to measure in human PTs and does not correlate well with relapse (Tiffany et al., 2000)
What are the major factors which can contribute to relapse of drug use?
- A priming dose of the drug - administration of a small dose of the target drug can induce craving and drug-seeking behaviour for the drug
- Drug-associated cues - places, objects and stimuli associated with the drug induce craving and preoccupation
- Exposure to stressors - long-understood anecdotally in humans, this has also been experimentally demonstrated in animals
What occurs in the binge/intoxication stage of the addiction cycle?
- Immediate positive drug reinforcement
- Drugs of abuse have powerful reinforcing properties
- Behavioural measures of drug use is that drugs of abuse are their own reinforcers
- Conditioned place preference - animals exhibit conditioned place preference for an environment previously associated with drugs
- DoA decrease thresholds for brain stimulation reward and there is a correlation between this effect and abuse potential of the drug
- Drug is associated with activation of neural reward pathways in the brain - biology of reinforcing properties of drugs
- Positive reinforcement also associated with social and cultural practice of drug use
What occurs in the withdrawal/negative affect stage of the addiction cycle?
- For heavy/dependent users this is a highly uncomfortable psychological and/or physical state that typically leads to marked increase of drug-seeking
- Conditioned place preference (Pavlovian conditioning) - animals avoid environments associated with withdrawal
- Reward thresholds increase in this stage - reversal of tolerance and possible link to craving
- Changes to neuronal reward pathways contribute to negative motivational state associated with this stage, and the negatively reinforcing properties of drug-seeking behaviour
