Neurobiology of Addiction

Question 1

mesocortical DA pathways in the brain + functions (2)

Answer 1

1. VTA -> PFC (executive functions)
2. VTA -> NAcc (motivation)

Question 2

what do commonly abused drugs all have in common

Answer 2

all stimulate DA transmission one way or another (at synapse level)

Question 3

ways drugs increase DA signalling and at which part of the neuron (2)

Answer 3

1. activating or disinhibiting VTA DA cell firing (at cell body level)
2. increasing amount of synaptically released DA (at synaptic level)

Question 4

ex of drugs that activate or disinhibit VTA DA cell firing (4)

Answer 4

1. morphine
2. heroin
3. alcohol
4. nicotine

Question 5

ex of drugs that increase DA release at synapse (4)

Answer 5

1. amphetamine
2. cocaine
3. methamphetamine
4. phencyclidine

Question 6

DA synthesis steps & enzymes (4)

Answer 6

phenylalanine -> tyrosine (hydroxyalse)
tyrosine -> L-DOPA (hydroxylase)
L-DOPA -> DA (L-AA decarboxylase)

Question 7

synaptic DA transmission (9 elements)

Answer 7

axon terminal:
1. DA production
2. encapsulation of DA vesicles by vesicular transporters
3. voltage-gated calcium channels opened due to AP (increase in intracellular calcium)
4. vesicular fusion/exocytosis of vesicle + release of DA from vesicle in synaptic cleft
postsyn neuron:
5. DA in synaptic cleft bind to DAr on postsynaptic neuron
6a. activation of 2nd messenger processes
6b. COMT (on postsyn neuron) binds unbound extracellular DA and metabolizes it into 3-methoxytyramine
6c. DAT reuptakes into presyn neuron unbound DA from cleft
7c. DA binds to MAO and metabolizes it into DOPAC (inactivated); DOPAC -> HVA

Question 8

role of MAO and COMT

Answer 8

MAO: inactivates DA (deamination) that is pumped from synaptic cleft via DAT
COMT: binds unbound DA from synaptic cleft and inactivates it (methylation)

Question 9

amphetamine synaptic transmission (5 elements)

Answer 9

1. vesicular transporter (axon terminal) prefer amphetamine over DA (internalizes more amphetamine molecules than DA)
2. DA not taken up by vesicles floats around in presynaptic axon terminal
3. increased [DA] in presynaptic axon terminal reverses the effect of DAT: instead of DA reuptake from synaptic cleft, DA release into synaptic cleft
4. high amphetamine doses inhibit MAO in presynaptic axon terminal (no DA inactivation)
5. increased unbound DA in synaptic cleft

Question 10

cocaine synaptic transmission (3 elements)

Answer 10

1. vesicular transporter not affected
2. exocytosis not affected
3. DAT blocked -> prolongs time that DA spends in synaptic cleft, increases DA binding to DAr on postsynaptic neuron

Question 11

opiate (heroin, morphine) synaptic transmission (no drug vs with drug)

Answer 11

1. no drug: GABA interneuron in VTA releases GABA that binds to DA neurons and stops neuron from firing too fast (inhibition)
2. with drug: GABA interneuron inhibited (disinhibition) so decreased GABA binding to DA neuron and DA neuron fires faster

Question 12

where do morphine and heroin bind (2)

Answer 12

u receptors on VTA GABA interneurons and NAcc GABA neurons that feedback to VTA cell bodies

Question 13

what determines the level of sensitization

Answer 13

length of the off period

Question 14

what is acute tolerance

Answer 14

decrease of NAcc DA levels and behavioral response with each dose (closely spaced repeated administration; 1-2 per day)

Question 15

how long does sensitization last

Answer 15

months, years (maybe permanent) -> neuroadpative alterations to circuitry mediating actions of drugs

Question 16

what is cross-sensitization

Answer 16

repeated administration of drug #1 will later sensitize to effects of different drug (even if never taken it before)

Question 17

lever experiments: what happens with DAr blocker

Answer 17

animal presses the lever more often: like reducing the dose of the drug

Question 18

liking vs wanting vs learning

Answer 18

liking: pleasurable experience from rewards
wanting: motivation (willingness) to pursue rewards (how much effort willing to put to get the reward?)
learning: cues and events associated with rewards acquire predictive and incentive motivational properties

Question 19

motive circuit plays role in (2)

Answer 19

1. ability to predict reward availability
2. attributing motivational value to cues

Question 20

challenge in studying motive circuit

Answer 20

predictive and incentive motivational properties of cues acquired together -> dissociating them is difficult

Question 21

how overcome challenge of studying motive circuit

Answer 21

pavlovian conditioned approach -> cue (lever) predicting reward is separated in space from location of reward (separate wanting from liking)

Question 22

2 types of rats observed in PCA

Answer 22

1. sign trackers (want the reward)
2. goal trackers (like the reward)

Question 23

behavior of STs (3)

Answer 23

1. persistently engage with lever that predicts reward
2. retrieve reward after lever is retracted
3. treat the lever as ‘highly desirable’ (has incentive value) -> willing to work for reward

Question 24

behavior of GTs (3)

Answer 24

1. rarely interact with lever
2. lever gains predictive value (animal waits for the reward where it will be delivered)
3. don’t find lever attractive

Question 25

conclusions from PCA concerning the lever (2)

Answer 25

1. lever (CS) predictive of reward and evokes conditioned response in STs and GTs 2. lever has incentive salience only for STs

Question 26

PCA mirrored to drug addicts

Answer 26

drug-associated cues have predictive value and incentive value -> drives compulsive drug-seeking behavior

Question 27

NAcc DA release in STs: PCA session 1 vs 5

Answer 27

session 1: DA release when get reward (US) session 5: DA release when press lever (CS)

Question 28

NAcc DA release in GTs: PCA session 1 vs 5

Answer 28

session 1: DA release when get reward (US) session 5: DA release when get reward (and a bit when lever activated)

Question 29

what does differential release of DA in STs vs GTs indicate

Answer 29

NAcc DA is necessary to process incentive salience of reward cues, but not to encode their predictive value

Question 30

DAr blockade in STs and GTs

Answer 30

impaired acquisition and expression of STs; little effect on behavior of GTs

Question 31

how does stress impact drug use (4)

Answer 31

1. exposure to stressors = risk factor in drug addiction 2. increases abuse liability of drugs (increases likelihood of engaging in drug-taking) 3. contributes to escalation from recreational use to compulsive drug-seeking 4. increases likelihood of relapse in abstinent drug addicts

Question 32

HPA axis | 5 elements

Answer 32

higher order brain areas (hippocampus & PFC) -> PVN releases CRH -> AP releases ACTH -> adrenal cortex releases CORT -> CORT negative feedback at all levels

Question 33

how does constant stress influence drug taking (3 elements)

Answer 33

constant stress -> less effective at turning off HPA axis -> CORT levels stay high -> prolonged brain exposure to CORT (bad) -> influences drug taking

Question 34

relationship between stress, HPA axis and DA transmission (2)

Answer 34

1. NAcc responses to stimulants is sensitized in stressed animals 2. stimulant-induced DA release in NAcc depends on HPA axis

Question 35

DA release in (a) stressed animals (b) ADX animals (c) animals treated with CRH

Answer 35

(a) sensitized response/DA release (b) low DA release (c) potentiated DA release (as if stressed)

Question 36

morphological remodeling in PFC following chronic exposure to stress (2)

Answer 36

1. dendritic retraction + spine loss in pyramidal glutamatergic neurons (decreased excitatory input) 2. dendritic/spine proliferation in GABA interneurons (increased inhibitory input)

Question 37

events that precipitate relapse to drug-taking (sufficient for relapse; wanting) (3)

Answer 37

1. drug itself -> drug-induced relapse 2. conditioned stimuli -> reward cue-induced relapse 3. stress -> stress-induced relapse

Question 38

brain circuitry implicated stress-induced relapse (4)

Answer 38

1. VTA DA projection to PFC 2. NE projection from LTN to CeNA 3. CRH in BNST 4. HPA axis

Question 39

meaning of (a) VTA (b) PFC (c) LTN (d) CeNA (e) BNST

Answer 39

(a) ventral tegmental area (b) pre-frontal cortex (c) lateral tegmental nucleus (d) central nucleus of the amygdala (e) bed nucleus of stria terminalis

Question 40

effect of maternal care on HPA axis stress response during adulthood (3)

Answer 40

1. maternally separated when pups -> high stress response + impaired negative feedback when adults 2. early life adversity -> increased stress responsivity -> increased vulnerability to disease (including to drug addiction) 3. maternally separated when pups -> willing to work a lot more for reward