Addiction 2

Question 1

How is dopamien usually released in response to rewards? Outline an experiment

Answer 1

• Dopamine is released in resposne to reward-prediction errors
  
  • Under normal conditions, mesostriatal dopamine neurones act to improve the detection and learning of salient environmental information to promote efficient goal motivated behaviour by signalling the error between the predicted and actual reward.
• Hollerman and Schulz in 1998
  
  • They recorded dopamine neurones of the ventral tegmental area in monkeys undergoing a task in which a visual stimulus is presented and pressing a lever delivers a reward
  • There is increased dopamine release as the monkey receives the reward which then disappears during learning as the association between the stimulus and reward is made.
    
    • After this association is made, firing increases in response to either visual stimulus (reward predicting cue) or an unexpected reward
      
      • This suggests dopamine release signals reward-prediction errors.

Question 2

What evidence do we have that addictive drugs increase dopamine concentrations?

Answer 2

• Di Chiara et al (1988)
  
  • ​The experimenters utilised a microdialysis catheter was used to measure [DA] in the NAc and caudate nucleus of rats
  • The administration of various addictive drugs such as opiates, ethanol, and cocaine was associated with an increase in [DA] in both areas, most prominently the NAc.
  • By contrast, non-addictive drugs (e.g. neuroleptics, antimuscarinics) and drugs with aversive properties (e.g. k opioid receptor antagonists) showed no [DA] increase
  • Addictive drugs therefore interfere with the reward system because they generate a positive error signal and thus always increase DA, regardless of conditioning.

Question 3

What evidence is there that cocaine addiciton occurs through the mesolimbic dopamine neural circuit?

Answer 3

• Recent optogenetic study by Pascoli et al in 2015 revealed that cocaine addiction occurs through the mesolimbic dopamine neural circuit
  
  • They also showed that optogenetic mesolimbic activation of the dopamine neurones in mice with channel rhodopsin in their dopamine neurons is sufficient for progression to addiction
  • Optogenetic self-stimulation of these neurons (through lever press) was shown to strongly reinforce the response of self-stimulation.
  • The number of presses required for stimulation was gradually increased and met by the mice indicating increased craving
  • The mice also demonstrated additional addiction behaviours such as cue-associated drug seeking upon withdrawal, synaptic plasticity and resistance to punishment
  • Furthermore, cocaine infusion limited the self-stimulation indicating that optogenetic self-stimulation and reinforcement by cocaine share underling neural circuits.

Question 4

Explain the mechanism of short-term changes in plasticity

Answer 4

• Synaptic plasticity in the ventral tegmental area
  
  • In 2001, Ungless et al conducted a landmark experiment in which they demonstrated synaptic plasticity in vivo as a consequence of drug administration.
    
    • At that time, changes in plasticity of the ventral tegmental area were only shown in vitro.
    • They compared the relative contribution of AMPARs and NMDARs to excitatory postsynaptic potential (EPCSs) recorded in dopamine cells in midbrain slices from naïve mice, mice injected with saline the previous day and mice injected with cocaine (15 mg k^-1) the previous day.
    • EPSCs were evoked whilst holding neurone in voltage clamp at +40mV in the absence and then in the presence of an NMDAR antagonist (AP5)
      
      • This allowed them to quantify the relative contribution of NMDAR and AMPAR to the EPSC.
    • Mice injected with a single dose of cocaine exhibited significantly larger AMPAR/NMDAR ratio than mice injected with saline.
      
      • However, these changes are shown to be transient, being abolished after 5 days, suggesting it is important in the initial stages of addiction development.

Question 5

Explain the epigenetic changes underlying long-term plasticity

Answer 5

• The activation of dopamine and glutamate can result in the stimulation of multiple intracellular secondary messengers which can in turn upregulate growth factors, transcription factors and chromatin regulators such as BDNF and CREB that can mediate long-term changes lasting several months
• One of these transcription factors, FosB has been coined the addiction switch
  
  • It increases most notably in the NAc and dorsal striatum in response to addictive drugs
  • It regulates the expression of genes related to dendritic spine architecture, AMPAR submits and CAMKII subunits – all of which mediate actions associated with plasticity.

Question 6

What evidence is there of the role of FosB?

Answer 6

• The role of FosB in addiction behaviour was demonstrated by Peakman et al in 2003 who utilised transgenic mice with selective overexpression of FosB in the dynorphin-containing medium spiny neurones in the NAc and dorsal striatum
  
  • The researchers observed enhanced sensitivity to the rewarding effects of cocaine and self-administration of lower doses compared to littermate controls.
  • Additionally, inducible antagonists to FosB as well as knockout models produces opposite behavioural effects and prevent sensitisation.
  • Figure 1 shows the increased levels of FosB transcription factors after doses of cocaine. Due to FosB being biochemically stable, it gradually accumulates.

Question 7

Outline the evidence for maldaptive reinforcement learning? Where does this primarily take place?

Answer 7

• Behavioural habits are initially goal-directed but become habitual when the stimulus leads to behaviour automatically through dopamine-mediated plastic changes. Unlike the acquisition of initial drug seeking behaviour, drug seeking habits are dependent on dopamine in the dorsal striatum, released by the nigrostriatal dopamine neurones.
• In 2006, Volkow et used dopamine-sensitive radioligands in PET imaging of cocaine addicts to illustrate the link between craving and increased dopamine in the dorsal striatum .
  
  • The experimenters observed increases in dorsal striatum dopamine release when subjects were shown videos of cocaine behaviour e.g. a visual cue, compared to a nature videos (neutral).
    
    • This increase correlated with subjects reporting a “craving”.
    • This shows the importance of the environment in behavioural conditioning.
      
      • However, the experiment only shows association and not causation; the experimenters also did not show repeat the experiment in non-addicts and therefore we do not know if the increased dopamine is due to the craving or simply the cue of any addictive drug.
    • They did infuse antagonists to AMPA receptors in the dorsal striatum which did successfully block drug seeking behaviour in response to cocaine associated cues.
      
      • This is consistent with the hypothesis that once cue activated drug seeking and taking becomes well established, action-outcome becomes the stimulus-response and is dependent on the dorsal striatum.