Neurobiology of Addiction Flashcards
mesocortical DA pathways in the brain + functions (2)
- VTA -> PFC (executive functions)
- VTA -> NAcc (motivation)
what do commonly abused drugs all have in common
all stimulate DA transmission one way or another (at synapse level)
ways drugs increase DA signalling and at which part of the neuron (2)
- activating or disinhibiting VTA DA cell firing (at cell body level)
- increasing amount of synaptically released DA (at synaptic level)
ex of drugs that activate or disinhibit VTA DA cell firing (4)
- morphine
- heroin
- alcohol
- nicotine
ex of drugs that increase DA release at synapse (4)
- amphetamine
- cocaine
- methamphetamine
- phencyclidine
DA synthesis steps & enzymes (4)
phenylalanine -> tyrosine (hydroxyalse)
tyrosine -> L-DOPA (hydroxylase)
L-DOPA -> DA (L-AA decarboxylase)
synaptic DA transmission (9 elements)
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
role of MAO and COMT
MAO: inactivates DA (deamination) that is pumped from synaptic cleft via DAT
COMT: binds unbound DA from synaptic cleft and inactivates it (methylation)
amphetamine synaptic transmission (5 elements)
- vesicular transporter (axon terminal) prefer amphetamine over DA (internalizes more amphetamine molecules than DA)
- DA not taken up by vesicles floats around in presynaptic axon terminal
- increased [DA] in presynaptic axon terminal reverses the effect of DAT: instead of DA reuptake from synaptic cleft, DA release into synaptic cleft
- high amphetamine doses inhibit MAO in presynaptic axon terminal (no DA inactivation)
- increased unbound DA in synaptic cleft
cocaine synaptic transmission (3 elements)
- vesicular transporter not affected
- exocytosis not affected
- DAT blocked -> prolongs time that DA spends in synaptic cleft, increases DA binding to DAr on postsynaptic neuron
opiate (heroin, morphine) synaptic transmission (no drug vs with drug)
- no drug: GABA interneuron in VTA releases GABA that binds to DA neurons and stops neuron from firing too fast (inhibition)
- with drug: GABA interneuron inhibited (disinhibition) so decreased GABA binding to DA neuron and DA neuron fires faster
where do morphine and heroin bind (2)
u receptors on VTA GABA interneurons and NAcc GABA neurons that feedback to VTA cell bodies
what determines the level of sensitization
length of the off period
what is acute tolerance
decrease of NAcc DA levels and behavioral response with each dose (closely spaced repeated administration; 1-2 per day)
how long does sensitization last
months, years (maybe permanent) -> neuroadpative alterations to circuitry mediating actions of drugs
what is cross-sensitization
repeated administration of drug #1 will later sensitize to effects of different drug (even if never taken it before)
lever experiments: what happens with DAr blocker
animal presses the lever more often: like reducing the dose of the drug
liking vs wanting vs learning
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
motive circuit plays role in (2)
- ability to predict reward availability
- attributing motivational value to cues
challenge in studying motive circuit
predictive and incentive motivational properties of cues acquired together -> dissociating them is difficult
how overcome challenge of studying motive circuit
pavlovian conditioned approach -> cue (lever) predicting reward is separated in space from location of reward (separate wanting from liking)
2 types of rats observed in PCA
- sign trackers (want the reward)
- goal trackers (like the reward)
behavior of STs (3)
- persistently engage with lever that predicts reward
- retrieve reward after lever is retracted
- treat the lever as ‘highly desirable’ (has incentive value) -> willing to work for reward
behavior of GTs (3)
- rarely interact with lever
- lever gains predictive value (animal waits for the reward where it will be delivered)
- don’t find lever attractive
conclusions from PCA concerning the lever (2)
- lever (CS) predictive of reward and evokes conditioned response in STs and GTs
- lever has incentive salience only for STs
PCA mirrored to drug addicts
drug-associated cues have predictive value and incentive value -> drives compulsive drug-seeking behavior
NAcc DA release in STs: PCA session 1 vs 5
session 1: DA release when get reward (US)
session 5: DA release when press lever (CS)
NAcc DA release in GTs: PCA session 1 vs 5
session 1: DA release when get reward (US)
session 5: DA release when get reward (and a bit when lever activated)
what does differential release of DA in STs vs GTs indicate
NAcc DA is necessary to process incentive salience of reward cues, but not to encode their predictive value
DAr blockade in STs and GTs
impaired acquisition and expression of STs; little effect on behavior of GTs
how does stress impact drug use (4)
- exposure to stressors = risk factor in drug addiction
- increases abuse liability of drugs (increases likelihood of engaging in drug-taking)
- contributes to escalation from recreational use to compulsive drug-seeking
- increases likelihood of relapse in abstinent drug addicts
HPA axis
5 elements
higher order brain areas (hippocampus & PFC) -> PVN releases CRH -> AP releases ACTH -> adrenal cortex releases CORT -> CORT negative feedback at all levels
how does constant stress influence drug taking (3 elements)
constant stress -> less effective at turning off HPA axis -> CORT levels stay high -> prolonged brain exposure to CORT (bad) -> influences drug taking
relationship between stress, HPA axis and DA transmission (2)
- NAcc responses to stimulants is sensitized in stressed animals
- stimulant-induced DA release in NAcc depends on HPA axis
DA release in (a) stressed animals (b) ADX animals (c) animals treated with CRH
(a) sensitized response/DA release
(b) low DA release
(c) potentiated DA release (as if stressed)
morphological remodeling in PFC following chronic exposure to stress (2)
- dendritic retraction + spine loss in pyramidal glutamatergic neurons (decreased excitatory input)
- dendritic/spine proliferation in GABA interneurons (increased inhibitory input)
events that precipitate relapse to drug-taking (sufficient for relapse; wanting) (3)
- drug itself -> drug-induced relapse
- conditioned stimuli -> reward cue-induced relapse
- stress -> stress-induced relapse
brain circuitry implicated stress-induced relapse (4)
- VTA DA projection to PFC
- NE projection from LTN to CeNA
- CRH in BNST
- HPA axis
meaning of (a) VTA (b) PFC (c) LTN (d) CeNA (e) BNST
(a) ventral tegmental area
(b) pre-frontal cortex
(c) lateral tegmental nucleus
(d) central nucleus of the amygdala
(e) bed nucleus of stria terminalis
effect of maternal care on HPA axis stress response during adulthood (3)
- maternally separated when pups -> high stress response + impaired negative feedback when adults
- early life adversity -> increased stress responsivity -> increased vulnerability to disease (including to drug addiction)
- maternally separated when pups -> willing to work a lot more for reward
