Addiction

Question 1

What is a drug?

Answer 1

A drug is any substance that can have an effect on a biological system.

Question 2

What is addiction?

Answer 2

Have to have the drug, and cannot function without it. Once we have developed a dependency, it is a chronic condition - can never be cured, and becomes a constant battle to remain off the drug.

Question 3

What are substance use disorders in DSM 5?

Answer 3

Impaired control, social impairment, risky use, and pharmacological criteria.

Question 4

What is impaired control?

Answer 4

The individual may take the substance in larger amounts/over a longer period of time that was originally intended. May express a persistent desire to cut down/regulate use, but be unsuccessful. May spend a great deal of time obtaining the substance. Craving is most likely when in an environment when the drug was previously obtained/used.

Question 5

What is social impairment?

Answer 5

Recurrent substance use may result in a failure to fulfil major role obligations at work, school or home. Continue substance use despite having persistent social/interpersonal problems. Activities may be given up and the individual may withdraw from activities to use the substance.

Question 6

What is risky use of the substance?

Answer 6

Recurrent substance use in situations in which it is physically hazardous. May continue substance use despite recurrent physical or psychological problems.

Question 7

What is tolerance?

Answer 7

Signaled by requiring a markedly increased dose of the substance to achieve the desired effect. Degree to which tolerance develops varies greatly across different individuals. Tolerance is not necessary for the person to be considered as having a substance use disorder.

Question 8

What is withdrawal?

Answer 8

A syndrome that occurs when blood or tissue concentrations of a substance decline in an individual who had maintained prolonged heavy use of the substance. Our body attempts to adapt & get used to the substance - because of this adaption, it creates withdrawal symptoms. This is the opposite symptoms of the effect the drug has. This is not necessary for a diagnosis of a substance use disorder.

Question 9

Why have substance use disorders been placed on a continuum?

Answer 9

Substance use disorders occur in a broad range of severity, from mild to severe, with severity based on the number of symptom criteria endorsed. Mild disorder is suggested by the presence of 2-3 symptoms, moderate by 4-5 symptoms, severe by 6+ symptoms.

Question 10

What is the mesocorticolimbic dopamine system?

Answer 10

Dopamine neurons projecting from ventral segmental area (VTA) to nucleus accumbens (NAc) and prefrontal cortex (PFC). Natural reinforcers (e.g. food & sex) increase extracellular dopamine in the nucleus accumbens. All known addictive drugs also activate this system. Have large release of dopamine (10x the amount released for a natural pleasure) - the reinforcing aspect is a need for it again, due to the magnitude of reinforcement. Therefore very easy for us to get addicted.

Question 11

What are direct mechanisms by which addictive drugs increase dopamine availability/release in Nucleus Accumbens (NAc)?

Answer 11

Cocaine/amphetamine - increase availability at synapse by blocking or reversing dopamine transporters. If block dopamine transporter you don’t do the reuptake, and therefore have more dopamine in the synapse to act on the postsynaptic cell.
Nicotine - direct excitation of VTA neurones by action at nicotinic receptors.

Question 12

What are indirect mechanisms by which addictive drugs increase dopamine availability/release in Nucleus Accumbens (NAc)?

Answer 12

Opioids/Cannabinoids - action at opioid or cannabinoid receptors indirectly leads to modulation of VTA activity. e.g. inhibition of GABAergic projections onto VTA neurons allows them o fire resulting in increase in DA release.

Question 13

What is associative learning?

Answer 13

“Cells that fire together wire together” (D.O.Hebb). Sensory information: people, places, emotions etc present at the time when DA release occurs will become associated with reward (salience). Coincident firing in NAc will induce LTP & strengthening of synaptic connections. Reward associated cues will trigger reward seeking behaviour & pause problems associated with relapse.

Question 14

How does dopamine enhance LTP?

Answer 14

Synaptic re-modelling - increases spines & dendritic branching. Long-term molecular & cellular changes. Memories in these pathways may trigger relapse years later.

Question 15

How is the frontal system dysfunctional in chronic substance abuse?

Answer 15

PET study showing reduced glucose metabolism in brain of a cocaine addict. Hypoactivity in these brain areas may underlie some of the behaviours associated with addiction - loss of motivational control and compulsive drug taking, loss of inhibitory control & inability to restrain when exposed to drugs.

Question 16

What are binding sites of cocaine following acute administration?

Answer 16

Striatum contains the nucleus accumbent. The brain quickly uptakes the substance, and subsequently feels pleasure quickly afterwards.

Question 17

How do we know this pathway is involved in reward?

Answer 17

Damage to the nucleus accumbens decreases self-administration of heroin. Mesocorticolimbic pathway needed for drug to have a rewarding effect.

Question 18

What are psychomotor stimulants?

Answer 18

Cocaine and amphetamines. Potentiate monoaminergic transmission by inhibition of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters. Cocaine blocks & inhibits transporter to prolong pool of extracellular DA. Amphetamine reverses transporter to increase extracellular DA levels. Action at dopamine transporter (DAT) most directly related to reinforcing effects.

Question 19

What have animal studies found about psychomotor stimulants?

Answer 19

Subjective effects such as feelings of euphoria are probably mediated by action of drugs at other sites. In animal studies: DAT transporter knockouts still show some behavioural response to cocaine. Only triple knockout (DAT, SERT and NET) show no drug action.

Question 20

What are opitates?

Answer 20

e.g. morphine & heroin. Act as endogenous opioid receptors. Inhibitory - decrease adenylyl cyclase activity, lead to open K+ channels and close Na+ channels. Subjective effects: Euphoria and intense rush with heroin compared to morphine due to route of administration and entry to brain (seconds vs minutes). Relaxing effects: inhibition of Noradrenergic pathways.

Question 21

How do opiates impact on the function of the Dopaminergic reward pathways?

Answer 21

Reward & reinforcement by: Disinhibition of DA neurons in VTA (DA neurons fire tonically but are inhibited by GABA interneurons - μ receptor activation on GABA neurons inhibits them from firing - relieving inhibition of DA neurons.
AND
Action at opiate receptors in the NAc - independent of DA release.

Question 22

What is the effect of alcohol?

Answer 22

Effects depend on ability to metabolise alcohol, & how much you have on board. Is a GABA a agonist (inhibitory) and NMDA antagonist (blocks excitation). Has effect on the cerebellum - so we lose coordination & may become sedated.

Question 23

What are subject effects of alcohol?

Answer 23

Low doses of alcohol lead to mild euphoria & anxiolytic effects. Higher doses lead to poor coordination, amnesia, and sedation. Chronic alcoholism leads to Korsakoff’s Amnesia (inability to form new memories (anterograde amnesia). Not due to specific affect of alcohol, but the malnutrition caused by the consumption of alcohol (e.g. lack of nutrients)).

Question 24

What effects does alcohol have on reward circuitry?

Answer 24

Alcohol leads to increased dopamine release in NAc - NMDA antagonism of cortical inputs to VTA may lead to increased dopamine release in NAc.
Suppression of cortical output leads to no activation of GABA interneuron, which leads to DA neurons being disinhibited in VTA and become able to fire.

Question 25

What is the involvement of the opiate system from alcohol?

Answer 25

Naltrexone (an opiate antagonist). Reduces alcohol self administration in animals. Used as a treatment to reduce alcohol consumption, relapse & craving in alcoholics (DA independent effects on reward).

Question 26

What is the effect of nicotine?

Answer 26

Action at nicotinic acetylcholine receptors. Ligand gated ion channels located pre or post-synaptically (present throughout brain, excitatory or modulatory). Unlike cocaine and opiates - powerfully reinforcing in absence of subjective euphoria. Stimulate release of acetylcholine and dopamine.

Question 27

What is the result of prolonged activation of nicotinic receptors?

Answer 27

Leads to desensitisation. First cigarette of the day - subject response (rapid desensitisation of receptors). Subsequent cigarettes - less obvious reported effects (overnight - normalisation of receptor state).

Question 28

What are the effects of nicotine on reward circuitry?

Answer 28

Nicotine treatment increase DA release in NAc. Release of DA is likely due to activation of each receptors on cell body in the VTA (increasing cell firing) and facilitation of DA release by pre-synaptic receptors in NAc.

Question 29

What is the involvement of the opiate system with nicotine?

Answer 29

Both opitate and DA antagonists can block nicotine-induced behaviours and self-administration (Naltrexone is on trial as a drug to aid smoking cessation).

Question 30

What is the Impaired Response Inhibition and Salience Attribution (I-RISA) Model of Addiction?

Answer 30

Goldstein & Volkow (2004). Weakening of top-down inhibitory control functions and strengthening of bottom-up functions are features of the addicted brain. In non-addicted brain, things like drugs are noted but are not salient – don’t go to great efforts to remember them. Have pleasure from them, but have control of frontal lobe to resist taken it again. Addicted brain - very salient because of changes made in our brain. Have powerful drive system that makes us seek this drug again. Also have inactivation of control system – unable to inhibit ourselves from taking that substance again in the future.

Question 31

Who becomes dependent?

Answer 31

A small % of people who use drugs become addicted (15%). Genetic vulnerability that allows for this addiction to take place (40-60%). How easily you can access the drug is also important. Addiction begins in adolescence - 50% of addiction cases begin between the ages of 15-18.

Question 32

What else is important in dependency?

Answer 32

Impulsivity (a behaviour that is performed with little or inadequate fore-thought). Key sub-types of behavioural impulsivity: inability to inhibit actions (motor impulsivity), inability to delay gratification, inability to reflect before making a decision.

Question 33

What is the matching familiar figures test “reflection” sub-type of impulsivity?

Answer 33

The Matching Familiar Figures Test (Kagan, 1966) has been used extensively to measure reflective processing during childhood (aid diagnosis of ADHD). Performance of healthy children was distributed bimodally on the MFFT: “impulsives” responded rapidly (less than 10 secs) but made frequent errors. “reflectives” responded slowly (30-40 secs) but with high accuracy. People who take drugs are more impulsive in this test.

Question 34

What is the association between impulsivity and addiction in these tests?

Answer 34

Chronic substance use is associated with elevated scores on measures of impulsivity (all substances not just psychostimulants). In animals: impulsive animals tend to self administer drugs more than the non-impulsive animals.

Question 35

Does impulsivity predispose later substance abuse?

Answer 35

Field et al (2013) prospectively investigated relationships between performance on several behavioural impulsivity tasks (delay discounting, risk-taking and disinhibition) and alcohol use, drunkenness and related problems in adolescents. Performance on all impulsivity tasks predicted alcohol involvement 6 months later. Importantly, the converse relationship across time was not observed: alcohol involvement did not predict future behavioural impulsivity performance.