Addiction Flashcards
How much can addiction cost per year?
9 Billion
Outline what addiction is
- Addiction is a treatable brain disorder or disease which causes dysfunctional decision making, loss of control of taking a drug and continued seeking behaviour
- Not all those that take drugs become addicted
- It has underlying genetic, neural, developmental, environmental and social causes
- Where an individual uses substances or engages in behaviours that become compulsive and often continue despite harmful consequences
What are two reasons people take drugs?
- To enduce positive feeling
- To self-medicate and feel better
- May be an accumulation of these factors
What are the 3 biggest questions in addiction?
- What determines vulnerability compared to resilience to develop a SUD
- How can research address these issues?
- How do we look at comorbidity with otehr mental health conditions?
How many criteria in the DSM5 is needed for a mild disoder?
2
How many criteria in the DSM5 is needed for a moderate disoder?
6
How many criteria in the DSM5 is needed for a severe disoder?
7-11
What are the 11 DSM5 addiction criteria?
- Taking more drug than intended
- Unsuccessful efforts to cut down
- Strong urges and cravings for the drug (cues)
- Excessive time spent acquiring the drug
- Activities given up due to use of drug
- Failure to fulfil major role obligations
- Use despite negative effects
- Recurrent use in hazardous situations
- Continued use despite consistent social or interpersonal problems
- Tolerance to drug effect
- Withdrawal signs
What are the 5 mos addictive substances?
- Heroin (1 in 4 who try it become addicted)
- Alcohol (death rate of over 3 mill a year
- Cocaine (bill dollar industry- 21% who try may become addicted)
- Barbiturates
5 Nicotine
How does the dopamine reward pathway work?
Mesolimbic system
- VTA projects to NA (part of the striatum)
- Dopiminergic neurons project to and determinate in the NA
- NA binds to D1 and D2 receptors on the MSN which are GABAergic
- Influences these neruons which projects to other areas of the basal ganglia, PFC, amygdala and hippocampus
What is the addiction cycle?
- Initial use /experimentation/continued use/abuse (flooding of dopamine in NA)
- Tolerance/dependence (come down as the stress system becomes activated leading to…)
- Withdrawal/negative affect (depends on the drug and the amount we take)
- Addiction
- Craving/Impulsivity/compulsivity/preoccupation/anticipation. Anticipation of taking the drug again- Amygdala and hippocampus are activated
- Relapse (reward pathway brcomes tolerant- need more drug for th same effect)
What neuroadaptations occur with repeat drug exposure?
- Changes in receptor senstivity
- Changes in neurotransmitter release
- Changes in neural circuitary
How does tolerance occur?
The brian becomes less responsive and needs greater amounts to produce the same feeling
When does dependence develop?
Results in withdrawal symptoms if substance not taken (overarching driver within the cycle)
What leads to craving, stress and negative affect?
Dysregulation of dopamine system leading to increased reliance on substance for pleasure
What does relapse involve?
The reactivation of neural pathways involved in addiction and is triggered bby exposure to the substance, or cues/contexts associated with the substance
Outline the neurobiology of the addiction cycle
- Incentive salience- refers to what were neural stimuli becoming impaired with and attaching importance to specific stimuli
- Reward defecits and increased stress- Reward prediction with cues after repeated exposure shifts change in reward neurocircuitary in VTA, NA to substantia nigra, pars compacta and dorsolateral striatum
- Extends to the amygdala which receives input from the HPA Axis. Associated with negative reinforcement associated with withdrawal
- Exectuive function defecits- Craving controlled by the PFC which affects the ability ti make deicisions and organise activities. Cnages in the circuitary cannot apply brakes to behaviours. Anterior cingulate cortex constantly assesses value of stimuli and the orbitofrontal cortex- all impaired
Essentially what is the driving factor of neurobiology of addiction?
LTP and formation of drug-related memories
What is incentive salience related to?
- Positive reinforcement
- This is stronger when a drug releases a rapid and intense release of dopamine in the accumbens/striatum
What are the dopamine circuits dissociable roles with repeated exposure?
- Mesolimbic- gives motivational pull to cues and the rewards they predict
- Nigrostriatal- gives a push towards invigorative or arousing behaviours
How does the mesolimbic and the nigrostriatal system influence self-administration behaviours?
- Mesolimbic- drug reward, drug cue motivation, drug seeking renewal
- Nigrostriatal- escalated drug use and rigid drug seeking
How does the mesolimbic and the nigrostriatal system influence social interactions?
- Mesolimbi- social reward, affiliative behaviours, defeat-enhanced motivation
- Nigrostriatal- Social recognition, social withdrawal
How does the mesolimbic and the nigrostriatal system influence risky decision making?
- Mesolimbi- motivational conflice, loss sensitivity, impulsive choice
- Nigrostriatal- punishment ersistance, reward memory, feedback insensitivity
How is the PFC involved in addiction?
Is involved in decision making and inhibtory control and shows impairment in addiction
How is the amygdala involved in addiction?
Processes the emotional response, including those related to stress and craving
How is the hippocampus involved in addiction?
In forming and consolidation (drug related) memories that contribute to craving and stress
Outline synaptic plasticity in the addiction cycle
- Tonic to phasic firing of dopamine neurons LTP in VTA and NA medium spiny neurons of the direct pathway (D1 receptors)
- Can cause long term depression in the medium spiny neurons of the indirect pathway (D2 receptors)
What does LTD in NAcc lead to?
- Increased trafficking of AMPA receptors
- Increased cAMP production
- Increased CREB phosphorylation
- Reduction in the sensitivity of the reward pathway and dopamine
What synaptic changes ultimately cause executive functioning defecits in addiction?
- Changes in (stress associated) CRF, noradrenaline and dynorphin
- Balance between glutamate and dopiminergic neurons in the VTA and amygdala also underly the chnages in executive function
Is the pattern of altered activity due to drugs global?
No, each drug has its own pattern of activity
What does long-term potentiation of GABAergic synapses onto VTA DA neurons cause?
Leads to disinhibition of DA neurons in VTA
What does synaptic plasticity in the VTA trigger?
- Triggers subsequent synaptic plasticity in other parts of the mesocorticolimbic pathway
- The accumbens receives glutamatergic inputs from cortical (PFC) and limbic (amygdala) brain regions
- LTP in glutamaterfic activity between PFC and striatal medium spiny neurons occurs after repeated exposure to a substance
- Subunit changes in NMDA/AMPA receptors as well as the shift in balance of currents, Ca sensitivity of subunits etc all contribute to changes in synaptic activity
What changes occur at the individual neuron level in addiction?
Changes occur in the NA and VTA neurons and these can be the size of the dopaminergic neurons (decrease) or increased dendritic branching
What are some unique pharmacological and pharmodynamic properties which can be drug specific?
- Receptor binding
- Signalling profiles
- Cellular localisation
What do spatial aspects of localisation lead to in terms of different pharmacological effects at the plasma membrane?
- MOP ligands (mu opioid ligands))
- 5HT2A ligands
What are three common hedonic effects associated with NA dopamine influx?
- Stimulation and/or sedation
- Mood elevation
- Intense euphoria (initially acute rush- then prolonged high)
What are 4 psychostimulants?
- Cocaine
- Amphetamines
- MDMA
- Cathinones (bath salts)
Where does cocaine act?
Inhibit noradrenaline (NAT/NET), serotonin (SERT) and dopamine (DAT) transporters
What effects does cocaine cause?
- Pleasure- DAT and SERT
- Stimulant effect- NAT/NET
What happens when smoking crack cocaine?
- Rapid rush within seconds
- Rapid intense crash
Where does amphetamine act?
- Inhibits DAT
- Taken up into the presynpatic terminal and inhibits VMAT and the filling of vesicles with transmitter
- Reversal of DAQT direction and cytoplasmic DA released into synapse (increase EC dopamine)
- Also has effects on NAT/NET and SERT
What are MDMA’s actions?
- Inhibits DAT, NAT/NET/ SERT
- Primary effects through the release of 5HT
- Can cause serotonin syndrome
What is serotonin syndrome?
- Profound hyperthermia
- Altered mental states
- Movement disorders
What is the cathinones method of action?
- Increase release of NA, DA and 5HT
- Inhibit transporters NAT/NET, DAT, SERT
- Not easily detected in urine and toxicology screens
Through what methods do cannabinoids work?
Modulate mesolimbic DA through CB1 and CB2 receptors
How does D-9THC work?
- Binds to CB1 receptors in VTA GABAergic neurons or their afferents (disinhibition of DA release)
- Binds to CB1 receptors in VTA glutamatergic neurons or their afferents or CB1 receptors on DA neurones (decreased DA release)
- And/or CB2 on dopamine neurons
How does ethanol work?
- Increased GABA release
- Inhibition of NMDA receptors on GABA neurons in VTA
- Increased release of b-endorphin to act on mu receptors on GABA neurons in VTA
- Leads to increased DA release in NAc
Through what methodology do opioids act?
GPCR (Gi)
What occurs when an opioid is taken?
- Reduced adenylate cyclase activity reducing cAMP production
- Closure of voltage-sensitive calcium channels
- Hyperpolarisation of neurons through potassium efflux
- Reduced neuronal excitability
- Activation of mu receptors on GABAergic neurons in VTA leads to disinhibition of DA neurons
Where are peptide agonists for MOR signalling?
- Plasma membrane
- Endosomes following receptor internalisation
Where are non-peptide agonists for MOR signalling?
- Plasma membrane
- Golgi-localised MOR
What are the patterns of abuse for psychostimulants?
- Very intense binge/intoxication
- Intense withdrawal (depends on length of binge)
- Eventually intense craving can develop
What are the patterns of abuse for cannabis?
- Significant intoxication (during waking hours)
- Craving is not too intense
What are the patterns of abuse for Ethanol?
- Less intense binge and withdrawal effect
- Repeated over extended periods
- Intensifies over time
What are the patterns of abuse for opioids?
Have an intense affect at all stages
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What are 5 ways in which addiction can be measured?
- The extent to which the drug activates the brain’s dopamine system
- How pleasurable people report the drug to be
- The degree to which the drug causes withdrawal symptoms
- How easily a person trying the drug will become hooked
- How much physical and cognitive harm the drug causes
How have animal models of addiction been helpful?
Understanding of neurobiologial brain function and psychiatric disorders has increased dramatically
Why are new, clinically useful treatments limited due to animal studies?
- Due to the lack of predictive power of animal models and the varyability between humans and animals
- We have known treatments that we can use in models to see how they work rather than developing new drugs
What are the best animal models for face validity?
- Drug self-administration (Used to asses binge/intoxication phase of the cycle)
- Deprivation-effect model (used to assess the withdrawal/relapse phase of the cycle)
- Reinstatement of drug-seeking (used to assess the craving phase of the cycle)
What are three ways of modelling the binge and intoxication stage of addiction?
- Self administration
- Lowering of reward thresholds
- Conditioned place preference
How is self administration normally administered?
- IV
- Oral
- Lever pressing
- Nose pokes
How is lowering of the reward theshold measured?
- Intracranial self stimulation
- ICSS thresholds are lowered by drugs of abuse
- Less electrical stimulation is required to perceive it as a reward
How does conditioned place preference work?
- Based on classical Pavlovian conditioning
- Pairing of distinct environments with drug/non-drug states
- Conditioned to prefer side paired with drug of abuse
What are 6 things to consider when deciding on an animal model for binge/intoxication?
- Cost of equiptment
- Length of training involved
- Ease of qualification
- Sensitivity to dose
- Effect of drug on motor activity, sedation
- Drug administration regime
Outline a self administration study using cocaine
- Panlilio and Goldberg 2007
- Infusion implanted into the animal to get the delivery of the substance whenever it is needed
- Press lever either nothing (saline) or cocaine (reward)
RESULTS
- Will rapidly keep pressing the reward lever to get the pleasurable effect, slowly administering more and more of the drug
- Learns the saline does nothing so ignore the lever
What is continuous reinforcement?
Press the lever and get the drug every time
What is intermittent reinforcement?
- Sometimes if press get the reward
- Need to keep doing, gets harder and harder to get the reward (progressive ratio)
- Measures how much they will persevere to get the reward
Outline a study into intracranial self-stimulation with cocaine
- Nose poke through a hole where there is an infared beam (when beam is broken they will get reward)
- Electrode can be implanted into different brain regions
- Normally medial forebrain bundle (white matter tract for neurons connecting VTA to NA)
- Stimulation mimics the release of DA into NAcc
RESULTS
- With saline, flat line
- Dose dependent effect on lowering the threshold for cocaine
- The more cocaine, the more depressed as its mimicking self-stimulation
- Wears off over time
- The greater the depression, the greater the abuse potential
Outline a condition placed preference study using cocaine
- Three chambers where the mouse can freely pass through will different surroundings
- One chamber with neutral stimuli training
- One chamber trained with the drug
- Train animals in different sides (so no physical dependence on where it is- balance the design)
- Inject the mouse with cocaine and place in a chamber (block off other areas so it learns this chamber is the pleasurable one)
- When test, open up the chambers, put mouse in middle one and see how long it spends in th drug chamber
RESULTS
- Spends more time in the associated chamber, the more time they spend there we get a quantifiable idea of the positive effect the animal gets from the drug
How is withdrawal normally measured in animal models?
Characterised by physical signs of withdrawal:
- Standard rating scales available
- Telemetry devices can wirelessly monitor BP, HR and temp
- Piloerection, tremor, seizures can be visually monitored
How can we use animal models for binge/intoxification stage in withdrawal models?
- Usually the opposite to those seen with acute initial actions of drug abuse
- Disruption of operant responding
- Condidtioned place aversion
- ICSS: increases in threshold observed
What is the general patterr of ICSS and withdrawal from different drugs of abuse?
- When withdraw there is an increase in threshold, so more self stimulation
- Different drugs have different potentials, and can link to abuse potential
- Can rank these and then compare how treatments help lessen the effects.
What are 3 animal models of the craving stage of addiction?
- Drug-induced reinstatement
- Cue-inuced reinstatement
- Stress-induced reinstatement
Outline drug-induced reinstatement
- Drug is removed
- Extinction of drug-seeking behaviour occurs
- Drug reintroduced and drug-seeking behaviour increases again
Outline cue-induced reinstatement
- Cue used to train self-administration stopped (e.g. lever doesn’t deliver drug)
- Exinction occurs
- Cue presented and dug given by lever pressing
Outline stress-induced reinstatement
- Extinction of behaviour established
- Stressor used (eg footshock)
- Drug-seeking restarts
How can animal model techniques be combined to study addiction?
- Use of microdialysis probe into the brain region (NA to look at DA)
- Can take samples of perfuse neurotransmitter levels from this area
- Can measure the amount with stimulation and self-administration
- Gives us a measure of behaviour and the amount of dopamine
How can animals be used to assess addiction ex vivo?
- Post-mortem examination of:
- Brain morphology
- Gene expression (immunohistochemistry)
- Signalling changes (neurobiology)
How can addiction be looked at in animal models in vivo?
- Lesioning of pathways to see the involvement, recruitment and importance of these pathways
- Knockout proteins or change the gene expression using CRISPR/CAS9
- How much the environmental context influences them
- Imaging
What type of disorder is alcohol use disorder (AUD)?
Heterogenous disorder
- Complex artiologies and mechanisms
How does strain of animal affect AUD?
Different strains have different sensitivities in taking alcohol, some strains are genetically bred to consume high levels of alcohol
Why is palatability an issue in animal models of alcohol
Ethanol is not very palatable
Normally give in orally water and perhaps with sucrose
What occurs in pre-clinical studies for alcohol addiction medication?
- Investigation of many different aspects
- lots of different manipulations can be carried out and combined
What occurs in human studies for medication into alcohol addiction?
- Investigation of alcohol pharmacodynamics and pharmacokinetics
- Behavioural assessment
What can happen if we can bridge the gap between human studies and pre-clinical animal studies?
In clinical trials there is better predictability for treatments
What are three treatments for AUD?
- Acamprosate
- Naltrexone
- Disulfram
Outline acamprosate’s mechanisms
- NMDA receptor antagonist
- Acts on Ca channels
- Acts via GABA A and B receptors
- Restores glutamatergic activity
Outline naltrexone’s mechanisms
- Mu-opioid antagonist
- Blocks effects of ethanol-induced b-endorphin release
Outline the mechanisms of disulfram
- Irreversibly inhibits ALDH
- Prevents conversion of acetaldehyde to acetate
- Discourages alcohol intake (makes feel very ill)
How is CPP translatable to humans using alcohol?
- Associate one room with no reward and the other with alcohol
- Similar effects between animals and humans
- But humans need a lot of time and space
- VR developed to make alcohol/cue pairing
- Nieto et al 2021
How does acamprosate interfere with animal models of AUD in CPP?
- Dose dependent reaction in animals with the paired chambers
- Highest dose get no preference anymore for either chamber
- So interferes with the positive reinforcement effect
- No effect on its own (only with AUD)
- McGeehan A.J, Olive MF 2003
How is the alcohol deprivation effect in animal models translatable to humans?
- Conditioning established in rodents using ethanol vapour in chamber
- Two bottle choice given intermittently (24hr access; 3 days per week)
- In humans, give alcohol then take it away to see if they return to it or have withdrawal effects
- Similar effects seen for both- more of an effect for AUD than a light drinker
- Nieto et al 2021
What is the effect of acamprosate and naltrexone in animal models of the alcohol deprivation effect?
- Dampens the want to take alcohol again after abstained (acamprosate) (Spangel et al 2014)
- Depends on the dose and how it was administered however (naltrexone) (Simms et al 2008)
How are animal models of drug-primed reinstatement translatable to humans?
- Models craving and loss of control over ethanol consumption
- See how much reintroduction the exposure is as to how much it will increase the amount of ethanol taken
- Ultamatum for humans, money or ethanol
- Similar effect inn humans and animals
- Nieto et al 2021
How do treatments using acamprosate and naltrexone affect drug primed reinstatement?
- Acamprosate reduces reinstatement (Bachteler et al 2005)
- Naltrexone reduces reinstatement much more when the stimulus is present than when it is not (Burratini et al 2006)
Outline methadone as a treatment for opioid addiction
- Opioid full agonist
- Slower onset of action; longer hald-life than heroin
- Addictive/abuse potential
- Side-effects
Outline buprenorphine as a treatment for opioid addiction
- Partial agonist; long half life
- Still reinforces and so keeps patient in treatment
- Produces less neuroadaptation
- Safer; higher doses can be given
Outline varenicline as a treatment for nicotine addiction
- Alpha 4 beta 2 partial nicotinic agonist
- High density of alpha 4 beta 2 in the VTA
- Pushes receptor into desensitised state
- Reduces DA in the NAc; reduces cravings and withdrawal
Outline memantine as a common approach for treating addiction
- Low affinity, non-competative NMDA receptor antagonist
- Transiently blocks the channel without interfering with normal synaptic transmission
- May help where addiction results in hyperglutamatergic states but not hypoglutamatergic
- Different results between drugs and animal/human studies
What 4 things need to be considered when evaluating new treatments?
- Use of appropriate animal models
- Knowledge of what these models show with drugs of abuse
- Are these models translatable
- How do existing treatments work in these models
What adverse effects does cannabis have the potential to cause?
Physical and mental effects
What is an example of a high potency cannabinoid?
Spice
What is the main high of cannabis through?
THC (partial agonist) via CB1 receptors on brain dopamine reward system
How can cannabis differ in terms of abuse potential and withdrawal?
- Strains of high potency cannabis
- Synthetic cannabinoid drugs (spice)
- Full agonists at CB1 receptor
What treatments are available for cannabis use disorder?
- None
- But recognised by DSM5
What are the aims of cannabis use disorder treatments?
To provide treatments that can help decrease or stop cannabis use, reduce withdrawal symptoms, and prevent craving and relapse
What is a problem of using rats in cannabis studies?
- Low reproducability
- Use squirrel monkeys instead
What animal models may be most translatable for cannabis use disorder?
CPP, drug discrimination, reinstatement models
What is the main potential treatment for cannabis use disorder?
Rimonabant- CB1 antagonist
What happens to self administration of cannabis when paired with Ro 61-8048?
Pleasurable effects decrease and less self administration (not completely gone)
What does Ro 61-8048 do?
- Prevents the conversion of L-kynurenine to 3 hydroxykynurenine
- More Kynurenine which is a glutamate receptor antagonist and a nicotinic alpha 7 negative allosteric modulator
What does Rimonabant do when given to THC self-administering monkey?
Reduces the pleasureable effect, do not self-administer as much
What happens when treat THC-administering monkeys with dronabinol?
- Decreases withdrawal
- Is a synthetic THC used to treat loss of appetite in people living with AIDS
