Lecture 21: Neurobiology of Addiction

Question 1

What is addiction?

Answer 1

addition (or substance use disorder) is a chronic relapsing disorder characterized by: compulsion to seek and take the drug, loss of control in limiting intake, and emergence of a negative emotional state when access to the drug is prevented

diagnosed by 11 diagnostic criteria

severity of the substance use disorder is determined by the number of criteria the person meets: 2/11 is mild, 4/11 is moderate, 6+/11 is severe

Question 2

How is addiction a biopsychosocial disease?

Answer 2

biological factors can increase your likelihood of developing an addiction and can promote continued drug use

prolonged drug use changes the way neurons fire to promote more drug use

interventions need to target both psychosocial and biological factors

Question 3

What factors is risky drug use associated with?

Answer 3

socioeconomic status (poverty)

homelessness

social isolation

early life trauma

Question 4

What is the cycle of addiction?

Answer 4

1. initial drug use –> continued drug use (through pleasant experience) –> drug withdrawal (gets worse over time) <–> compulsive drug use (only source of pleasure is the drug)

Question 5

What is the initial use stage in the cycle of addiction?

Answer 5

several factors determine whether someone takes a drug for the first time

genetics: impulsivity, differences in monoamine neurotransmitter metabolism can cause different reactions

mood: depression and anxiety, self-medicate

Question 6

What is impulsivity?

Answer 6

a predisposition towards rapid, unplanned reactions to internal or external stimuli without regard for negative consequences

high impulsivity means more likely to try drugs

Question 7

What is the continued use stage of the cycle of addiction?

Answer 7

associated with the positive effects of the drug (euphoria, reduced anxiety, analgesia)

driven by positive reinforcement

incentive salience increases overtime = incentive sensitization (amplification of drug “wanting” triggered by drug cues)

Question 8

What is positive reinforcement?

Answer 8

presentation of a usually pleasant stimulus that increases the likelihood of response

behavioral outcome

Question 9

What is incentive salience?

Answer 9

motivation for rewards that is learned by previously learned association about a reward

pay attention to rewarding cues

Question 10

What is the drug withdrawal stage of the cycle of addiction?

Answer 10

opposite effects of acute drug use (dysphoria, increased pain, anxiety), fighting back against the drug to maintain homeostasis

unpleasant symptoms can drive craving and relapse (want to avoid the feeling)

withdrawal symptoms get worse with chronic drug use, do not develop tolerance to withdrawal

Question 11

What are some symptoms of drug withdrawal?

Answer 11

certain drugs induce lethal lethal withdrawal symptoms (e.g. alcohol)

other drugs induce long-term withdrawal that are unpleasant and promote continued drug use (e.g. opioids, nicotine)

the desire to avoid withdrawal symptoms can promote continued drug use (negative reinforcement)

Question 12

What is the compulsive drug use stage of the cycle of addiction?

Answer 12

characterized by a shift from impulsive drug use to compulsive drug use

keep using the drug even though it has a negative impact on life

characterized by a shift from positive reinforcement (I am going to keep doing this because it feels good) to negative reinforcement (I am going to do this because it stops me feeling bad)

Question 13

What is compulsivity?

Answer 13

behaviors that persevere in the face of adverse consequences

Question 14

What is the mesolimbic dopamine system?

Answer 14

dopamine containing neurons in the ventral tegmental area project to the ventral striatum (mesolimbic) and prefrontal (mesocortical)

dopamine release occurs following a salient stimuli and promotes motivated behavior

substantia nigra –> dorsal, associated with movement, reward and movement are linked

all drugs of abuse evoke dopamine release, although they do so via different mechanisms

Question 15

What functions is midbrain dopamine associated with?

Answer 15

incentive salience, invigorate goal directed activity, or activation in general

rate of dopamine increase important to determine function

“phasic burst” is associated with salience and reward

deficits in dopamine signaling are associated with depression and anhedonia (especially during drug withdrawal

Question 16

What is tonic dopamine?

Answer 16

a slow release of dopamine

Question 17

What is a phasic burst?

Answer 17

spike in dopamine

Question 18

What does phasic dopamine signal?

Answer 18

phasic dopamine signals salience of rewarding cues, but does not necessarily signal reward itself

CS could evoke dopamine, but not the reward itself

dopamine signal can shift

Question 19

What does the study measuring VTA dopamine in awake monkeys tell us about dopamine signals in the brain?

Answer 19

a reward is given, and dopamine neurons fire

monkeys are trained so that a conditioned stimulus precedes the reward, VTA dopamine neurons fire to the sound, not the reward

if the sound is given, but no reward, dopamine neurons inhibit firing around the time the reward is expected

Question 20

How do opioids evoke dopamine release?

Answer 20

heroin bind to mu opioid receptors located on inhibitory GABAergic interneurons in the VTA, mu opioid receptors are inhibitory G-protein couple receptors (inhibit neurons)

so, opioids inhibit inhibition (called disinhibition) leading to dopamine release

Question 21

How do psychostimulants evoke dopamine release?

Answer 21

cocaine blocks the dopamine transporter, inhibiting reuptake of dopamine from the synaptic cleft into the presynaptic axon terminal

increases synaptic levels of dopamine

Question 22

Which drugs require midbrain dopamine for reward?

Answer 22

midbrain dopamine is required for psychostimulant reward, but not opioid reward (and other drugs, like alcohol, nicotine, or cannabis)

Question 23

How did a study involving rats prove that midbrain dopamine isn’t involved in opioid reward?

Answer 23

a study measuring how much a rat will press a lever to receive an infusion of cocaine

some rats received a dopamine antagonist into the amygdala, others received the antagonist into the nucleus accumbens

only in the nucleus accumbens did blocking dopamine receptors block cocaine self-administration

Question 24

How did a study involving rats show that dopamine isn’t needed for morphine reward?

Answer 24

a study measuring how much time a rat will spend in the chamber previously associated with morphine

both control and dopamine-deficient mice show a preference for morphine (e.g. you don’t need dopamine for morphine reward)

Question 25

How do drugs effect the mesolimbic dopamine system?

Answer 25

salient stimuli, including all drugs of abuse, evoke dopamine release in the striatum

rapid dopamine release (phasic is associated with saliency and reward

over time, dopamine release can become tied to cues that predict oncoming reward, rather than reward itself

phasic dopamine release in the striatum is sufficient to produce reward, but not necessarily required for drug reward (depends on the drug)

Question 26

What is the neurocircuitry adaptation to the mesolimbic dopamine system that takes place in the transition to addiction?

Answer 26

compulsive drug use associated with incentive sensitization (amplification of drug “wanting” triggered by drug cues)

driven by sensitization of mesolimbic dopamine system –> the same amount of drug (or cues) evoke larger dopamine dependent behavioral responses

drives drug craving

also recalibrates dopamine thresholds for natural rewards (e.g. harder for non-drug rewards to evoke a dopamine response), leads to narrowing of focus to obtain drug-related reward

Question 27

How does withdrawal affect the mesolimbic dopamine system?

Answer 27

drug withdrawal associated with deficits in dopamine tone

lower tonic dopamine associated with anhedonia (inability to feel pleasure) and depression

contributes to the negative affective state of drug abstinence

Question 28

What is the prefrontal cortex?

Answer 28

glutamate afferents project from cortex to the striatum and increase dopamine release

drug cues activate orbital frontal cortex in addicted, but not non-addicted individuals

glutamate release increase glutamate receptor expression (AMPA) and long-term potentiation (LTP) at dopamine synapses in the striatum = increased dopamine signaling

Question 29

What kind of activity does a fMRI show in cocaine addicted brains?

Answer 29

people addicted to cocaine and non-addicted controls presented with a drug cue

brain activity measured with fMRI

only those with a cocaine addiction showed activation in the orbital frontal cortex

Question 30

What is the central amygdala?

Answer 30

central amygdala is a nucleus in the limbic brain associated with fear and anxiety

neopeptide release (especially corticotropin releasing factor, CRF) in the central amygdala causes anxiety

Question 31

How does drug withdrawal impact the central amygdala?

Answer 31

drug withdrawal is associated with increase CRF levels in the central amygdala

increased CRF in the central amygdala associated with aversive states of withdrawal

it also contributes to increased drug-seeking behavior in dependent animals

blocking CRF signaling is effective at reversing symptoms of drug withdrawal and drug seeking behavior

CRF doesn’t influence initial drug use phase

Question 32

What do pharmacological interventions seek to treat in addiction?

Answer 32

biological, psychological, social

block the positive effects of the drug: no longer motivated to take it

make withdrawal easier: relieve negative reinforcement

Question 33

What are partial dopamine agonists?

Answer 33

chronic drug use impacts dopamine in two ways: sensitized drug-evoked phasic release, decreased tonic levels during withdrawal

partial dopamine agonists can normalize both these adaptions to bring dopamine levels back to a homeostatic level

Question 34

How do partial dopamine agonists treat addiction?

Answer 34

blunts drug-evoked dopamine effect (antagonist-like)

restores dopamine deficit during withdrawal (agonist-like)

Question 35

How do partial dopamine agonists treat withdrawal symptoms?

Answer 35

partial agonists are drugs that only partially activate a receptor, even at very high doses (lower efficacy)

during drug withdrawal, when tonic dopamine levels are low, a partial dopamine agonist will gently activate dopamine receptors

alleviates symptoms of withdrawal like negative affect and anhedonia

Question 36

How do partial dopamine agonists act like antagonists?

Answer 36

partial agonists can act as antagonists when competing for receptor binding with full agonists (like dopamine)

therefore partial agonists will reduce drug or cue evoked dopamine activity and improve drug craving

Question 37

What do treatments of drug withdrawal try to achieve?

Answer 37

treatment of withdrawal symptoms can help maintain drug abstinence and may be a necessary step to safely and effectively stop drug abuse

treatment involves treatment with a drug that targets the same receptor as the drug of abuse, but with safer therapeutic profile

Question 38

What are treatments for opioid withdrawal?

Answer 38

agonist replacement therapy is a comprehensive treatment approach including maintenance on an opioid agonist and cognitive behavioral therapy

agonist therapy blunts the symptoms of opioid withdrawal

replacement agonists have longer half-lives, so avoid the repeated high/crash cycle

methadone and buprenorphine: safer, less likelihood of addiction, longer half life means it lasts longer

Question 39

What are the advantages to agonist replacement therapy?

Answer 39

reduces drug cravings

better participation in addiction treatment (behavioral therapy) since withdrawal symptoms aren’t a distraction

improved social functioning

reduction in infectious disease/death associated with illicit drug use (particularly injection drug abuse), know that it is not laced

Question 40

What factors improve the effectiveness of addiction treatment?

Answer 40

not all substance use disorders are the same and effective treatments are likely different between different drugs of abuse (cocaine versus opioids)

treatments for substance use disorder most effective when behavioral and pharmacological interventions are combined

drug treatments must be voluntary for them to be effective, mandatory drug treatments are not effective and increase harms

risk or relapse is 2-20x higher then those without forced abstinence