W3L1: The Pharmacology of Reward & Addiction - Dopamine & Desire

How are neuromodulators generally produced & distributed?

• Produced/generated in a bundle of nerve cells deep in the brain

• Distributed to rest of the cortex via long projections from the bundle of nerves

What are the 2 locations in which dopamine is produced, & what do these locations implicated for its functioning?

• Substantia nigra: motor coordination

  • Long projections into the basal ganglia & motor cortex

• Ventral tegmental area:

  • Motivation, emotional response, reward, desire, & addictive behaviours

Describe the process of dopamine synthesis

1. Tyrosine (amino acid) synthesised from food (cheese, nuts, avocado)

2. Tyrosine converted to L-DOPA (immediate precursor of dopamine) by tyrosine hydroxylase (synthesis enzyme)

3. L-DOPA converted to dopamine by amino acid decarboxylase (synthesis enzyme)

Why is L-DOPA particularly important for Parkinson’s disease?

• L-DOPA is found naturally in the brain but can be produced as a synthetic drug

• Give to Parkinson’s disease patients → up-regulate dopamine synthesis → improved motor control

What is Parkinson’s disease?

Loss of motor control resulting from death of dopamine cells in the Substantia Nigra

• Symptoms:

  • Resting motor tremor

  • Rigidity + being inert → difficulty initiating movements

  • Cognitive impairments & dementia

  • Reduced executive function

Describe the management of Parkinson’s disease & the implications of this treatment

• No cure BUT symptoms can be v through drugs + deep brain stimulation (^ motor activity of midbrain structures)

• Implications: impulsivity, hypersexuality, gambling, & addictive-like behaviours

What is reward prediction error?

When a reward was either more or less rewarding than what the brain predicted it to be, altering the amount of dopamine released

How does dopamine release relate to motor control?

• Dopamine is released when a muscle is moved to the correct location

• Sensory information sent to brain regarding whether the limb moved to where it was meant to go or if it needs to be adjusted

How does the timing of dopamine release change, with respect to reward & expectation?

• Reward is repeatedly given after a stimulus → reward becomes expected → no DA is released w/ reward

• DA is eventually released with the stimulus; anticipation of a reward

What happens to DA neurons if a reward is expected but not provided?

DA neurons become suppressed

Provide an example of reward prediction error

1. You unexpectedly find $50 on the ground --> you are happy

2. You receive $150 after a very long day at work when you were expecting $300 --> you are disappointed

• Even though you objectively receive more money in scenario 2, because it is not what you predicted, you are disappointed

  • Shows how dopamine is closely related to reward prediction

Describe how the value-modulated attentional capture task (VMAC) was used to display how the value of rewards & its cues can be indexed in behavioural paradigms

• People are very good @ learning what predicts a reward

  • VMAC: participants asked to identify a symbol in the target next to the distractor

    • Symbol was either a horizontal or vertical line

    • 2 types of distractors; high contrast & low contrast

    • Identify correct symbol in the target when the high contrast distractor is present --> bonus points

    • Addiction: people are distracted by high-value cue much more, @ the detriment of their performance @ identifying the target

      • Only need to stare at the target and not the distractor to perform well

      • Those that learn cues associated w/ reward more easily are very readily distracted by the distraction cue

        • Not able to ignore the reward cue, even though it is detrimental to performance

What is cognitive effort?

the brain's examination of how worthwhile it is to engage in an activity, & whether it is consistent w/ one's goals or whether one should engage in behaviour which will give more immediate gratification

How does the metabolic activity of the brain during less effortful tasks differ to the metabolic activity of the brain during more effortful tasks

It doesn’t; metabolic activity remains the same

What is a proposed explanation for why attention & cognitive task are effortful?

• Cognitive effort linked to working memory & cognitive effort

• Theory: DA codes for both goal-reward & effort costs, & the aversive feeling of cognitive effort reflects ‘opportunity cost’

  • Task persistence is justifiable only while progress outpaces accruing costs

  • Cognitive tasks w/ low success are particularly unpleasant (feels like a waste of time) → bias someone towards disengaging

What is opportunity cost & how is dopamine involved?

• Opportunity cost: the value of the next best alternative that must be given up in order to pursue a certain action

  • Role of DA: there must be a balance of task persistence (working towards a goal) vs exploring other options

  • Task persistence relies on executive control, esp. working memory

What is the proposed theory for how working memory in people w/ AUD is a predictor of relapse?

poor working memory --> poor balancing of opportunity cost ideas; they are not able to hold the potential long term outcomes of an action if they persist as opposed to seeing out immediate gratifying behaviours

What is drug abuse?

the use of illicit substances (or illicit use of legal substances) characterised by recurrent & clinically significant adverse consequence

What is drug addiction?

chronic health condition that occurs when someone is unable to stop consuming a drug or activity, even if it is causing physical & psychological harm, or affecting their life

What is drug dependence?

the state where drug taking becomes compulsive, taking precedence over other needs

How do drug additions arise & how are they perpetuated?

• Initially, taking the drug feels good. Later, after the reward-related cues of the substance have been learned, it is the anticipation of the reward which makes people take the drug, not the actual feeling of the drug itself

  • Example: seeing drug paraphernalia → ^ desire to use drugs, as opposed to wanting to experience a specific feeling

• Cravings are exacerbated under feelings of stress

  • Stress ^ cognitive load → v working memory capacity (important for long-term goals)

Describe the properties of cocaine which make it addictive

• Cocaine blocks the reuptake of dopamine from the synapse

• More dopamine remains in the synapse --> people constantly feel good --> more rewarding that what people initially expected of the drug --> addiction

Describe the properties of amphetamines which make it addictive

Blocks reuptake of dopamine AND reverses the transporter → double-action of pushing out dopamine

Compare the psychological effects of cocaine w/ amphetamine

• Cocaine: rewarding things are now more rewarding than expected

• Amphetamine: things that usually aren't rewarding are now rewarding and things that are usually rewarding are now more rewarding than expected

What is methylphenidate (Ritalin)?

Used as a treatment for ADHD

• DA & NA reuptake inhibitor

• Similar to a cocaine analog; same pharmacophore as cocaine

• Takes longer to see effects than cocaine

Not as addictive as cocaine b/c the dopamine spike following the cue isn't almost immediate

• The quicker dopamine release following a cue, the more addictive the drug is

What is the difference between ice & speed?

• Ice: most pure

  • Smoked or injected

• Speed: less pure

  • Snorted, swallowed, or injected

How does DA release differ between regular reward & addictive drugs?

• Normal: no additional DA is released when a reward is expected

• Addictive drugs: always coded by the brain as better than ex[ected

How have animal models been used to display addiction?

 

• Put an electrode into the reward centres of an animal's brain --> keeps stimulating until the animal dies

  • Dopamine is so strong that it overpowers everything, even pain

• Animal models presented w/ buttons for drugs or food --> continuously pressed level for drugs & ignored food until they died

What are the 2 problems with addiction that over-rule free will, & what is the final result of these problems?

1. Drugs initiate ‘wanting’ → drug urges/craving in addicted people which takes control over time

2. Cognitive (‘top-down’) control is v by impaired function of PFC (caused by excessive dopamine)

• Seen through PFC abnormalities in imaging studies

  • Lots of substance abuse in adolescence/young adults b/c of under-developed pre-frontal lobes

  • Stress --> v top-down control -b/c of ^ cognitive load --> ^ likelihood of acting on compulsions --> drug abuse

• Final result: addictive behaviour

  • Failures of ‘top-down’ control contribute to loss of control over urges to take drugs