Introduction to neurobiology of substance misuse and addiction Flashcards
Addiction services: drugs seen and their relative prevalence
BIGGEST
- alcohol
- opioids
- cannabis
- stims
- benzos
- nicotines
- novel psychoactive drugs
- synth cannabinoid-r agonists (e.g. Spice)
- ketamine
- GHB, GBL
- (psychadelics)
Most prevalent mental disorders
Depression is most common for females
Alcohol is most common for males
Harm from drugs to society vs individual?
Alcohol is most harmful to others
Heroin, cocaine, methamphetamine are seen as more harmful to users relatively
Definition of harmful substance use (ICD 11 criteria)?
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.
ICD 11 Criteria for Dependence Syndrome?
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.
[DSM IV vs DSM 5 slides]
[DSM IV vs DSM 5 slides]
Alcohol consumption guidelines
(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
How the speed of drug entry has changed over the years?
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
Effect of natural rewards on the brain?
Natural rewards (e.g. food/sex) -> increased DA levels in ventral striatum aka nucleus accumbens
Effect of drugs of abuse on the brain?
“hijack” natural reward pathway -> increased DA levels in ventral striatum aka nucleus accumbens
(seen in cocaine, amphetamine, alcohol, opiates, nicotine, cannabinoids, MDMA)
How different drugs of abuse specifically act with the reward pathway?
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
Experimental evidence of dopamine theory of addiction?
- 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”
DA hypothesis involvement in addiction/dependence
- seeking pleasure is less of a role; more negative reinforcement i.e. overcoming withdrawal symptoms
- “reward deficiency”
Neurobiological mechanisms of DA system in addiction
[after continuous stimulation of DA system by drugs]
brain depleted of DA -> reduced DA function -> irritability, low mood -> poor outcomes usually
Experimental evidence of reduced DA transmission underpinning addictive symptoms
[in cocaine addicts]
high DA transmission assoc w/ better treatment response
How to specifically image D2 receptors?
11C-PHNO: agonist, extra-striatal binding, DRD3 preferred
11C-raclopride: antagonist, striatal, DRD2 preferred (over DRD3)
Experimental evidence investigating DRD3 receptors?
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
How a drug can cause “cravings”?
Formation of associations between cues and contexts during drug taking and drug S/Es
Can induce drug-like or withdrawal-like effects
Experimental evidence relating DA system and reward pathway?
(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
Other modulators of the DA reward pathway?
- GABA]- inhibitory for DA
- opioids]- inhibitory on GABA-ergic neuron
GABA relation to neurotransmission?
GABA-B is key
Drugs that increase GABA action?
- baclofen: agonist]- shown to improve rate of alcohol abstinence
- others: tiagabine, vigabatrin, gabapentin, topiramate
Mechanisms of opiates?
μ-opiate receptors are inhibitory -> GABA shuts down -> increased DA firing
Pharmacological targeting of opiates?
opiate antagonists e.g. naltrexone, block μ- opiate receptor -> GABA can function -> decreased DA activity
Experimental evidence of relationship of opioids and substances of abuse?
(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
Experimental evidence linking opioid receptors on dependence
(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
Factors influencing the difference between studies on opioid receptors and dependence?
- length of abstinence (previous studies- a few days whilst newer studies were for months-years)
- scanned successul/recovered alcoholics
Other functions of the opiate system relevant to addiction
- social behaviour
- stress (via HPA-axis)
- impulsiveness (more opiate-r = more impulsive)
Proposed 4 circuit model for addiction?
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
Proposed interacting circuits underlying addiction
[see slide]
NORMAL PFC (ACC, infPFC, latOFC) interacts with NAcc, modulating it
greater influence of PFC (medial OFC), and amy&hippocamp interacting w/ VTA and NAcc
Experimental evidence of interaction between neuronal circuitry w/ 3-stage addiction cycle?
(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
SEE SLIDE 69 AND 70
SEE SLIDE 69 AND 70
