Introduction to neurobiology of substance misuse and addiction

Question 1

Addiction services: drugs seen and their relative prevalence

Answer 1

BIGGEST

• alcohol
• opioids
• cannabis
• stims
• benzos
• nicotines
• novel psychoactive drugs
• synth cannabinoid-r agonists (e.g. Spice)
• ketamine
• GHB, GBL
• (psychadelics)

Question 2

Most prevalent mental disorders

Answer 2

Depression is most common for females

Alcohol is most common for males

Question 3

Harm from drugs to society vs individual?

Answer 3

Alcohol is most harmful to others

Heroin, cocaine, methamphetamine are seen as more harmful to users relatively

Question 4

Definition of harmful substance use (ICD 11 criteria)?

Answer 4

ICD 11 Criteria

Pattern of use causing damage to physical/mental health or has resulted in behaviour leading to harm to the health of others

Pattern of use over at least 12 months if substance use is episodic or at least 1 month of continuous use

Harm to to health from one or more of:

• behaviour related to intoxication;
• direct or secondary toxic effects on body organs and
  systems; or
• a harmful route of administration.

Question 5

ICD 11 Criteria for Dependence Syndrome?

Answer 5

Disorder of use regulation from repeated/continuous use. Characteristic feature is a strong, internal drive to use. Increasing priority given to use over other activities and persisitence of use despire harm/consequences

2 of:
Impaired control over substance use
in terms of the onset, level, circumstances or termination of use, often but not necessarily accompanied by a subjective sensation of urge or craving.
Substance use becomes an increasing priority in life
takes precedence over other interests or enjoyments, daily activities, responsibilities, or health or personal care. Substance use takes an increasingly central role in the person’s life and relegates other areas of life to the periphery; continues despite the occurrence of problems.
Physiological features (indicative of neuroadaptation to the substance) as manifested by
(i) tolerance, (ii) withdrawal symptoms following cessation or reduction in use of that substance or (iii) repeated use of the substance (or pharmacologically similar substance) to prevent or alleviate withdrawal symptoms.

Question 6

[DSM IV vs DSM 5 slides]

Answer 6

[DSM IV vs DSM 5 slides]

Question 7

Alcohol consumption guidelines

Answer 7

(2016)

14 units per week]- this was used to increased risk of breast cancer in women

NB: 1 unit = 8g of alcohol
NB II: binge = double the daily recommended guidelines
NB III: if alcohol is excessive on multiple days w/ days completely without it is NOT binging but alcohol dependence

Question 8

How the speed of drug entry has changed over the years?

Answer 8

HEROIN
opioid -> morphine -> heroin -> snorted heroin -> IV/smoked heroin

COCAINE
coca leaves -> coca paste -> cocaine -> crack

CIGARETTES
chewing tobacco -> snuff -> cigarettes

NB: faster brain entry = more “rush” and more addiction

Question 9

Effect of natural rewards on the brain?

Answer 9

Natural rewards (e.g. food/sex) -> increased DA levels in ventral striatum aka nucleus accumbens

Question 10

Effect of drugs of abuse on the brain?

Answer 10

“hijack” natural reward pathway -> increased DA levels in ventral striatum aka nucleus accumbens

(seen in cocaine, amphetamine, alcohol, opiates, nicotine, cannabinoids, MDMA)

Question 11

How different drugs of abuse specifically act with the reward pathway?

Answer 11

Increase DA neuron firing in VTA (consequently more DA is released): alcohol, opiates, nicotine

Enhances DA release that is released from vesicles: amphetamine

Block re-uptake: cocaine, amphetamine

Question 12

Experimental evidence of dopamine theory of addiction?

Answer 12

• increased DA levels in striatum associated w/ reinforcing effects of stimulants in man
• amphetamines increase DA release “really well”
• alcohol involved in change in DA levels in brain “less well”
• cannabis might or might not be involved in this hypothesis “unconvincing”

Question 13

DA hypothesis involvement in addiction/dependence

Answer 13

• seeking pleasure is less of a role; more negative reinforcement i.e. overcoming withdrawal symptoms
• “reward deficiency”

Question 14

Neurobiological mechanisms of DA system in addiction

Answer 14

[after continuous stimulation of DA system by drugs]

brain depleted of DA -> reduced DA function -> irritability, low mood -> poor outcomes usually

Question 15

Experimental evidence of reduced DA transmission underpinning addictive symptoms

Answer 15

[in cocaine addicts]

high DA transmission assoc w/ better treatment response

Question 16

How to specifically image D2 receptors?

Answer 16

11C-PHNO: agonist, extra-striatal binding, DRD3 preferred

11C-raclopride: antagonist, striatal, DRD2 preferred (over DRD3)

Question 17

Experimental evidence investigating DRD3 receptors?

Answer 17

11C-PHNO PET imaging

Alcohol Addiction:
No differences between alcohol-dependent and control groups EXCEPT in hypothalamus where there is an INCREASE

Cocaine Addicts:
INCREASED number of DRD3 receptors

Stimulant and gambling: correlations implicate D3 receptor levels in motivation, impulsiveness and risky decisions

Question 18

How a drug can cause “cravings”?

Answer 18

Formation of associations between cues and contexts during drug taking and drug S/Es

Can induce drug-like or withdrawal-like effects

Question 19

Experimental evidence relating DA system and reward pathway?

Answer 19

(1) No prediction, then reward occurs: increase in DA neuron firing

Reward prediction, then reward occurs: increase in DA neuronal firing to cue

Reward predicted, then NO reward: decrease in DA neuron firing when reward occurs

[less DA -> dysphoria, irritability]

(2) : cocaine cues increase DA levels in dorsal striatum (but not ventral)
(3) change from involvement of ventral striatum -> dorsal striatum
(4) alcohol cue caused greater activation of ventral striatum, ACC and VM PFC in alcoholics; activation of ventral striatum correlated w/ behavioural measures and this was reduced by treatment

Question 20

Other modulators of the DA reward pathway?

Answer 20

• GABA]- inhibitory for DA

- opioids]- inhibitory on GABA-ergic neuron

Question 21

GABA relation to neurotransmission?

Answer 21

GABA-B is key

Question 22

Drugs that increase GABA action?

Answer 22

• baclofen: agonist]- shown to improve rate of alcohol abstinence
• others: tiagabine, vigabatrin, gabapentin, topiramate

Question 23

Mechanisms of opiates?

Answer 23

μ-opiate receptors are inhibitory -> GABA shuts down -> increased DA firing

Question 24

Pharmacological targeting of opiates?

Answer 24

opiate antagonists e.g. naltrexone, block μ- opiate receptor -> GABA can function -> decreased DA activity

Question 25

Experimental evidence of relationship of opioids and substances of abuse?

Answer 25

(1) : amphetamines can induce endogenous opioid release in human brain reward system
(2) alcohol consumption induces opioid release in human OF cortex and NAcc
(3) PET study: alcohol releases endorphins in ventral striatum (reduced 11C-carfentanil binding on PET)

NB: larger change in opioid releases were assoc w/ greater euphoria

Question 26

Experimental evidence linking opioid receptors on dependence

Answer 26

(1): alcoholics have more opiate receptors than controls and more receptors assoc w/ greater alcohol craving

(2)
opioids, alcohol, cocaine all assoc with greater opioid receptor number in brain AND greater problems with craings

BUT

(3): no difference in μ-opiate receptors between abstinent alcoholism w/ healthy controls i.e. less 11C-carfentanil binding

blunted amphetamine induced opioid release in abstinent alcoholism compared to healthy controls

Question 27

Factors influencing the difference between studies on opioid receptors and dependence?

Answer 27

• length of abstinence (previous studies- a few days whilst newer studies were for months-years)
• scanned successul/recovered alcoholics

Question 28

Other functions of the opiate system relevant to addiction

Answer 28

• social behaviour
• stress (via HPA-axis)
• impulsiveness (more opiate-r = more impulsive)

Question 29

Proposed 4 circuit model for addiction?

Answer 29

NORMAL
Control, drive, memory, reward all interact with each other equally

ADDICTED
Control, drive, memory, reward are enhanced particularly between control w/ reward and control w/ drive

NB: naltrexone can interact w/ this system, decreasing reward w/ drive and increasing control w/ reward

Question 30

Proposed interacting circuits underlying addiction

[see slide]

Answer 30

NORMAL
PFC (ACC, infPFC, latOFC) interacts with NAcc, modulating it

greater influence of PFC (medial OFC), and amy&hippocamp interacting w/ VTA and NAcc

Question 31

Experimental evidence of interaction between neuronal circuitry w/ 3-stage addiction cycle?

Answer 31

(1)
Binge/intoxication stage: reward systems and assoc mechanisms in NAcc- DA and opioids

Withdrawal/negative affect: key role of amyg, activation of stress system (CRF), dynorphin, NA systems

Preoccupation/anticipation (craving): processing of conditional reinforcement of amygdala and contextual info in hippocampus

Question 32

SEE SLIDE 69 AND 70

Answer 32

SEE SLIDE 69 AND 70