Addiction Flashcards
relationship between the access and use of a drug
Easier access to drug = greater use of the drug (think about the rates of alcohol use below, the lower rates are in Islamic countries where it is illegal to drink).
What is a ‘safe’ level of alcohol consumption?
- Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden Study 2016
- Common alcohol consumption: Griswold et al. 2016
- None is the ‘safe’ level of alcohol consumption!
alcoholism in England stats
o 1 million people
o 4% of the adult population
2% of women, 6% of men (3x more common in men)
Most (90%+) not receiving treatment
o 24% of adults consume in excess of recommended limits
o 27% binge drink
o Alcohol misuse is the biggest risk factor for death, ill health and
disability among 15-49 year-olds in the UK
How does alcohol (ethanol) work?
- Weak and dirty drug
- No specific receptor?
- Affects ion channels
o GABA receptor (inhibitory) – turns them up
o NMDA receptors (excitatory) – turns them down (hyperpolarisation)
o Calcium channels (excitatory) – turns them down (so less AP fired and NT released)
o Many other molecular effects - 2 major functional neuronal targets (see right)
o GABA receptor potentiates inhibition
o VOCC (Ca) receptor and NMDA receptor reduces excitation
GABA receptors role
- Effect of GABA is potentiated by positive (makes GABA receptor work more efficiently) allosteric (binds elsewhere to where GABA binds) modulators
- GABA binds at the surface, other drugs bind elsewhere
- Makes GABA more effective (more GABA comes in when alcohol binds)
o BZs have the same effect
o Additive effects (it is why you often cannot drink when taking medication) - Chloral hydrate (one of the first positive allosteric modulators)
Acute pharmacodynamics of ethanol:
- Increase inhibitory pathways (GABA)
o EtOH allosterically potentiates GABA receptors
o EtOH + benzodiazepine effects additive
o Important for acute intoxication - Decrease excitatory pathways (Glutamate)
o EtOH inhibits NMDA receptor activity
most sensitive ethanol effect-
important in acute intoxication, memory loss (blackouts)
o Calcium channels - These increases/decreases occur everywhere in the brain!
o Impaired functioning in the cerebellum
Loss of coordination, including speech (ataxia)
o Impaired functioning in the prefrontal cortex
Working memory impaired
Executive functioning (inhibition of decision-making, reduces social inhibitions – makes decisions quicker (impulsivity))
parts of brain damaged in wernickes encephalopathy
o Medial thalamus (memory problems)
o Hypothalamus (basic physiology)
o Mamillary bodies (memory problems)
o Cerebellum (Ataxia)
o Prefrontal Cortex (Executive Function and memory)
causes of wernickes encephalopathy
- Most common cause is vitamin B1 deficiency
o Chronic alcoholism
Unable to absorb vitamin B1 (thiamine)
Direct toxicity of alcohol
treatment for wernickes encephalopathy
IV thiamine (if caught early enough)
- Korsakoff’s psychosis
o Consequence of Wernickes Encephalopathy
o Irreversible damage to Medial thalamus + Mamillary bodies
o Anterograde AND retrograde amnesia
o Confabulation (Confusion between memory and imagination)
o Little or no recovery
Alcohol flush reaction: ‘Asian Flush’
- ~40% of East Asians
- Aldehyde Dehydrogenase does not work as well (remove this from the diagram above between aldehyde and acetate), so acetaldehydes cannot be metabolised
- Acetaldehyde accumulates
- Alcohol very aversive
- Lower rates of alcoholism
tolerance
- Tolerance: Decreased response to set drug concentration after continued use
o Compensatory homeostatic systems adapt to drug
dependence
- (physical) Dependence: Stopping drug causes withdrawal, via compensatory homeostatic systems.
o Can occur with non-addictive drugs (eg; vasoconstrictors)
addiction
- Addiction: Continued drug use despite known adverse consequences.
o Compulsive drug-seeking behaviour
relapse
- Relapse: Resumption of (problematic) drug use after trying to stop taking drugs.
o Can occur in the absence of tolerance + dependence, months/years after stopping
chronic tolerance
- Results from long-term ethanol exposure
- Higher dose required to achieve same effect
- Significant increase in number and activity of enzymes that metabolise ethanol
- Long-lasting changes in abundance and function of those targets affected by acute ethanol exposure
acute tolerance
- Drinking yourself sober (clinically and legally important)
- Occurs ‘within-session’
o Same basic mechanisms as chronic tolerance – changes in function of GABA/NMDA receptors - Consequences of acute functional tolerance:
o Not good because they may feel fine but blood alcohol would still be too high
Himmelsbach hypothesis:
- Mechanisms of tolerance and withdrawal
o Withdrawal happens when adaptions that cause tolerance are expressed without drug on board
o Crudely; symptoms of withdrawal are opposite of acute drug effects
Alcohol withdrawal syndrome:
- Can be fatal
- Many alcoholics are very afraid of withdrawal
- Abrupt cessations after chronic use:
o motor agitation, anxiety, insomnia, reduction in seizure threshold (after acute use)
o delirium tremens (after going into withdrawal)
Hallucinations, tremor, hyperpyrexia, sympathetic hyperactivity, death - Treatment options: ‘hair of the dog’ – works (Himmelsbach hypothesis), BZs most commonly used in the clinic instead (chlordiazepoxide).
o BZs work to treat alcohol withdrawal in the same way as the hair of the dog principle and can be explained by the Himmelsbach hypothesis. - Hangover is basically a mild case of alcohol withdrawal syndrome.
o Have become acutely tolerant and feel a reduction in anxiety and seizure threshold, and then the next day you go into withdrawal.
withdrawal
- Most physical withdrawal syndromes resolve quickly (under 2 weeks)
o Alcohol, opiates, nicotine, benzodiazepines
o “Getting clean” or “detox” is relatively straightforward - Relapse possible months or years later
o Stress, cues associated with drug use - Some highly addictive drugs have no obvious physical withdrawal syndrome
o psychostimulants
- 2 major types (Ball, 1996) of alcoholism
Type A/1 Type B/1
- Type 2/B is harder to treat
- Treatments used in the management of alcoholism:
o Acamprosate
o BZs
o CBT
o Disulfiram (blocks alcohol metabolism to make them less likely to drink)
o Naltrexone (reduced addiction cravings)
nocotine addiction
o More people addicted to nicotine than anything else
o Stimulant and depressant
o Effects mediated by nicotinic acetylcholine receptors
Many different subtypes
CNS and PNS
- Psychostimulant ‘empathogens’ addiction
o MDMA (Ecstasy), 4-MMC (Mephedrone)
o Mixed psychostimulant and ‘hallucinogen’ properties
o Legal until recently
o Addictive profiles uncertain; MDMA probably not
o Overdose possible?
replacement therapy
- Replace a fast-acting drug/prep with a slow one:
o Addictive drugs
Fast on, fast off (e.g. cigarettes)
Short duration
Strong
Route of admin affects all four
o Replacement therapy
Replace with slow on/off
Nicotine, opioids, BZs
Doesn’t work very well
Mesolimbic dopamine pathway:
- Dopamine neurons in Ventral Tegmental Area
o Part of midbrain (A) - Project to Ventral Striatum
o Nucleus Accumbens
o Via Medial Forebrain Bundle
Intracranial self-stimulation: short-circuiting reward:
- Olds and Milner, 1954
- Stimulating electrodes in Medial Forebrain Bundle
o Activated when rat presses lever - Rats learned to press lever to stimulate MFB
- Once learned, did not stop
- Deprioritised all other behaviours
- Similar findings in humans
Reward circuit (motivation circuit): Schultz, 2016
Dopamine neurons – reward prediction error
- “Rewards” stimulate release of dopamine
o Unexpected rewards are most potent
o More unexpected rewards = more dopamine
- Dopamine acts as a learning signal
o Environmental cues which predict reward will cause dopamine release
o (reward itself does not cause dopamine release)
o If reward is not obtained, dopamine neurons are inhibited
- The actions of this circuit ensure
o We learn about rewards
Especially the environment in which they may be found
o We are highly motivated to obtain them
- Dopamine neurons are activated by molecular correlates of reward
Reward and endogenous opioids:
- Endogenous Opioids are Peptide Neuromodulators
- Tonic firing of dopamine neurons is subject to inhibition from GABAergic interneurons
- Endorphins inhibit GABA release from interneurons
- Less inhibition of dopamine neurons
o Double negative
o Dopamine neurons fire more often
o equals more dopamine release
gambling addiction comorbidity
50%+ seeking treatment for gambling disorder screen positive for substance use disorder (Grant and Chamberlain 2016)
