Addiction, overdose, and tolerance Flashcards
Define tolerance.
o Either:
A) a need for markedly increased amounts of a substance to achieve intoxication or desired effect
B) markedly diminished effect with continued use of the same amount of substance
Define withdrawal.
o Either:
A) the characteristic withdrawal syndrome for the substance
B) the same (or closely-related) substance is taken to relieve or avoid withdrawal symptoms
In addition to tolerance and withdrawal, are the criteria for addiction as stipulated by the DSM-V?
- The substance is often taken in larger amounts or over a longer period than was intended
- There is a persistent desire or unsuccessful efforts to cut down or control substance use
- A great deal of time is spent in activities necessary to obtain the substance, use it, or recover from its effects
- Important social, occupational, or recreational activities are given up or reduced because of substance use
- The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance
• Many neurotransmitters are involved in the development, maintenance, and removal of addiction – but they all lead to an increase in [dopamine] as a final common pathway.
Give a brief overview of the molecular basis of tolerance.
• Short-term drug exposure increases firing frequency and neurotransmitter release
• This is offset in the long-term by homeostasis:
o Receptors become:
Desensitised – via altered intracellular signalling; the mechanisms differ between ionotropic and metabotropic receptors
Downregulated – receptors are removed from the post-synaptic membrane and destroyed
Rightward shift on a graph with tolerance
Briefly outline the molecular basis of withdrawal
- In the absence of a drug, down-regulation means that activity is below the normal physiologically appropriate level
- This occurs in the same systems that the drug affected – symptoms of withdrawal are often opposite to that of the drug’s effect but across a wider range
Describe the effects of withdrawal on glutamatergic, GABAergic, dopaminergic and opioidergic signalling in the brain, and the behavioural effects of these.
Glutamate Receptor antagonism and reduces release Upregulation of receptors and rebound increase in release
Extreme hyperexcitability and massive Ca2+ influx (rebound)
Memory loss
Rebound hyperexcitability of the abstinence syndrome
Brain damage
GABA
Acutely enhances GABA-induced Cl- influx to hyperpolarise
Neuroadaptive decrease in GABA function without change in receptor number
Sedative effects: anxiety reduction, sedation, incoordination, memory impairment
Tolerance and signs of hyperexcitability during withdrawal (seizures and tremors)
Dopamine
Acute increase in transmission in the mesolimbic tract
Reduced firing rate, release, and metabolism
Reinforcement
Negative affect as a sign of withdrawal
Opioids
Acute increase in endogenous opioid synthesis and release
Neuroadaptive decrease in endorphin levels
Reinforcement
Dysphoria
Briefly outline the effects of alcohol withdrawal and the associated risks to health.
• Acute alcohol withdrawal is one of the leading causes of death in the UK
o Issue with alcoholism is legality and accessibility, as well as ‘sudden stops’
o Sudden stops –> seizures of large intensity and duration, usually –> cardiovascular issues due to excitability
• 30% of people in ED have a diagnosable addiction-related condition
o Standard approach – make them withdraw
This actually makes them worse because of kindling –> epilepsy
When you remove a tolerated compound you get rebound excitation (more excitation than there was before) –> epilepsy as a result of withdrawal, memory impairments
o Brain structure of those who withdraw is impaired vs those who are just addicted for life
Explain the effects of withdrawal on cocaine addiction
• Craving can be triggered 10-20 years after last usage; doesn’t just apply to cocaine. Can be triggered by anything
• When withdrawing from cocaine, there is long-term downregulation of dopaminergic neurons in the VTA – in rats this occurs within 10 days
o At the population level, the circuit has reduced spontaneous activity – yet firing rate is unchanged if the cell is still active
o Cells that aren’t firing have either reduced firing completely or died
How do the principles of withdrawal apply to other drugs?
- Other drugs – different details but similar principles across a range of drugs
- Behavioural principles are the same
How might withdrawal lead to relapse?
• Abstinence –>withdrawal, may –>relapse
• Negative reinforcement of operant conditioning –>pre-emptive drug use to terminate withdrawal
o The unpleasantness of withdrawal is sufficient enough to cause drug use again in order to escape the unpleasant effects
o May not use the same drugs as they used prior to withdrawal – e.g. preventing alcohol withdrawal by smoking
Why does relapse occur so long after withdrawal?
• Relapse occurs after withdrawal due to Pavlovian (classical conditioning) – everything familiar about using the drug becomes a hazard:
o Alcoholics can’t walk by bars they drank at/listen to music/watch TV they were near when they withdrew – it recreates feelings of withdrawal so forces them to relive it –> reuse and relapse
o O’Brien (1975) – cold turkey study: PPs given saline, then naloxone with a sound tone played and the smell of peppermint; then given saline with a sound tone played and peppermint smell –> same response regardless of whether or not naloxone is in their system
• However: relapse is typically evoked by cues associated with drug use; not those associated with withdrawal – this is due to homeostasis and the opponent process theory:
o The body will undergo changes to oppose those brought about by the drug – desensitise neurons and downregulate processes: conditions the body to counteract the drugs. Thus cues associated with drug use elicit a drug-opposing conditioned opponent-process which feels like withdrawal
Even though you take the drug there’s no effect (eventually)
Give a real-world example of conditioning on drug efficacy and relate this to any relevant study.
• This is best exemplified by the case of Davide, a man who had end-stage terminal cancer; his son administered strong painkillers and sat him outside as it was sunny (end-of-life); Davide died and his son was arrested for murder (Davide couldn’t self-administer) – the change of the environment from Davide’s normal one (his bedroom when taking the painkillers) reduced his compensatory response overdose and death
o Relates to the work of Subkov and Zilov:
Injected a dog with adrenaline increased heart rate; effect decreases with successive doses: this is tolerance
When given a placebo, the dog’s heart rate decreased (this is the conditioned compensatory response)
• If you give a placebo (thus causing the conditioned compensatory response), you only get the compensatory response negative physiological effects (e.g. slower heart rate) instead of no net change as the drug tolerated isn’t administered
o If the response is absent, standard dose becomes overdose
• This formed the basis of the defence for Davide’s son
How many people worldwide die every hour from addiction?
• 42694 worldwide people die every hour from addiction
o More people in one hour than were killed in the first day of the Battle of the Somme
Why is addiction hard to treat? What are the consequences of this?
• Don’t understand biology of addiction well
o Not more than 30% of people achieve full abstinence
o Treatments are dangerous and often lead to relapse
