Addiction

Question 1

relationship between the access and use of a drug

Answer 1

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).

Question 2

What is a ‘safe’ level of alcohol consumption?

Answer 2

• 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!

Question 3

alcoholism in England stats

Answer 3

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

Question 4

How does alcohol (ethanol) work?

Answer 4

• 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

Question 5

GABA receptors role

Answer 5

• 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)

Question 6

Acute pharmacodynamics of ethanol:

Answer 6

• 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))

Question 7

parts of brain damaged in wernickes encephalopathy

Answer 7

o Medial thalamus (memory problems)
o Hypothalamus (basic physiology)
o Mamillary bodies (memory problems)
o Cerebellum (Ataxia)
o Prefrontal Cortex (Executive Function and memory)

Question 8

causes of wernickes encephalopathy

Answer 8

• Most common cause is vitamin B1 deficiency
  o Chronic alcoholism
   Unable to absorb vitamin B1 (thiamine)
   Direct toxicity of alcohol

Question 9

treatment for wernickes encephalopathy

Answer 9

IV thiamine (if caught early enough)

Question 10

• Korsakoff’s psychosis

Answer 10

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

Question 11

Alcohol flush reaction: ‘Asian Flush’

Answer 11

• ~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

Question 12

tolerance

Answer 12

• Tolerance: Decreased response to set drug concentration after continued use
  o Compensatory homeostatic systems adapt to drug

Question 13

dependence

Answer 13

• (physical) Dependence: Stopping drug causes withdrawal, via compensatory homeostatic systems.
  o Can occur with non-addictive drugs (eg; vasoconstrictors)

Question 14

addiction

Answer 14

• Addiction: Continued drug use despite known adverse consequences.
  o Compulsive drug-seeking behaviour

Question 15

relapse

Answer 15

• 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

Question 16

chronic tolerance

Answer 16

• 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

Question 17

acute tolerance

Answer 17

• 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

Question 18

Himmelsbach hypothesis:

Answer 18

• 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

Question 19

Alcohol withdrawal syndrome:

Answer 19

• 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.

Question 20

withdrawal

Answer 20

• 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

Question 21

• 2 major types (Ball, 1996) of alcoholism

Answer 21

Type A/1 Type B/1

• Type 2/B is harder to treat

Question 22

• Treatments used in the management of alcoholism:

Answer 22

o Acamprosate
o BZs
o CBT
o Disulfiram (blocks alcohol metabolism to make them less likely to drink)
o Naltrexone (reduced addiction cravings)

Question 23

nocotine addiction

Answer 23

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

Question 24

• Psychostimulant ‘empathogens’ addiction

Answer 24

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?

Question 25

replacement therapy

Answer 25

• 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

Question 26

Mesolimbic dopamine pathway:

Answer 26

• Dopamine neurons in Ventral Tegmental Area
  o Part of midbrain (A)
• Project to Ventral Striatum
  o Nucleus Accumbens
  o Via Medial Forebrain Bundle

Question 27

Intracranial self-stimulation: short-circuiting reward:

Answer 27

• 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

Question 28

Reward circuit (motivation circuit): Schultz, 2016

Answer 28

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

Question 29

Reward and endogenous opioids:

Answer 29

• 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

Question 30

gambling addiction comorbidity

Answer 30

50%+ seeking treatment for gambling disorder screen positive for substance use disorder (Grant and Chamberlain 2016)