L2 - INTRODUCTION TO THE NEUROBIOLOGY OF ADDICTIVE DRUGS

Question 1

What are the principal output(s)/input(s) of the mesocorticolimbic dopamine pathway?

Answer 1

Output: VTA
Inputs: NAcc (also projecting back to VTA) and PFC

Question 2

What are the two common ways drugs of abuse stimulate dopamine transmission?

Answer 2

1. Activating (or disinhibiting) VTA DA cell firing.
2. Increasing the amount of DA released at synaptic terminals.

Question 3

What drugs from the list below are stimulating dopamine transmission by activating (or disinhibiting) VTA DA cell firing? By increasing the amount of DA released at synaptic terminals?

Cocaine, Heroin, Morphine, Amphetamine, Nicotine, Phencyclidine, Alcohol, Methamphetamine.

Answer 3

By activating (or disinhibiting) VTA DA cell firing:

Heroin
Morphine
Alcohol
Nicotine

By increasing the amount of DA released at synaptic terminals:

Cocaine
Amphetamine
Methamphetamine
Phencyclidine

Question 4

Generally explain how the synaptic DA transmission occurs.

Answer 4

1. Phenylalanine is converted to dopamine
2. DA sequestered in vesicles (picked up by vesicle transporter)
3. Opening of voltage-gated Ca++ channels
4. Vesicles migrating to membrane for fusing
5. DA molecules are liberated in the synaptic cleft and bind
   D1 receptors
   D2 receptors
6. Postsynaptic potential is created (can be either IPSP or EPSP, depending on receptor)DA is re-uptaken by protein transporters (DAT)
7. MAO breaks down dopamine → deamination → DOPAC (secreted in the extracellular space) → HVACOMT converts unbound DA to 3-MT (COMT is not present at the same levels in every area of the brain)

Question 5

Describe the neurobiological effects of amphetamine on the synaptic transmission of dopamine.

Answer 5

Amphetamine consequences on DA trans.
- Displaces DA in vesicles (competitive)
- DAT is reversed bc. of higher DA intracellular concentration → synaptic cleft is filled with more DA
- MAO inhibition → accumulation of DA

Question 6

Describe the neurobiological effects of cocaine on the synaptic transmission of dopamine.

Answer 6

Blocks DAT reuptake.

Question 7

Describe the neurobiological effects of opiates on the synaptic transmission of dopamine.

Answer 7

Inhibits GABA neurons (in VTA and NAcc) = disinhibitation = increased DA release from axon terminal

Question 8

True or false: some neurons of the NAcc project back on the dopaminergic neurons of the VTA.

Answer 8

True.

Question 9

How are the dopaminergic neurons of the VTA regulated?

Answer 9

By (1) GABA neurons from VTA (interneuron) and (2) GABA neurons from NAcc (forming a negative feedback loop)

Question 10

To what kind of receptor does bind heroin and morphine on the GABAergic neurons of the mesocorticolimbic dopamine pathway?

Answer 10

The μ-opioid receptors.

Question 11

What phenomenon would be observed after repeated, closely spaced administration of an addictive drug concerning its effects?

Answer 11

Tolerance.

Question 12

After a drug-free period, what phenomenon can be observed subsequently to drug administration?

Answer 12

Sensitization.

Question 13

How long does last sensitization to an addictive drug?

Answer 13

Months, years, permanently perhaps.

Question 14

Liking, wanting and learning are interdependant processes elicited in response to what?

Answer 14

Rewards.

Question 15

How does one learn from rewards?

Answer 15

Reward-associated cues acquire PREDICTIVE and INCENTIVE properties.

Question 16

How are the predictive and incentive properties of a reward differentiating?

Answer 16

The incentive properties drive the compulsion to seek the reward while the predictive properties stress the reward availability.

Question 17

What is the role of the motive circuit?

Answer 17

Assigning predictive and incentive properties to reward-associated cues.

Question 18

Regarding incentive and predictive properties of a reward, what can a Pavlovian Conditioned Approach (PCA) be used for?

Answer 18

Dissociating incentive and predictive properties of a reward, which are normally strongly associated.

Question 19

What does PCA reveal concerning individual differences in response to reward cues?

Answer 19

Dissociating the predictive and incentive motivational properties of reward cues shows that some individuals are sign trackers (STs) and others goal trackers (GTs).

Question 20

How do sign trackers and goal trackers differ?

Answer 20

The conditioned stimuli (CS) associated to the reward has predictive value for both STs and GTs. However, only the STs show that the CS gained incentive salience (work will be done to earn CS presentations).

Question 21

In regards to DA levels in the NAcc, how are STs and GTs differentiating?

Answer 21

STs show a high DA response to CS, but no DA response to reward. GTs show a moderate DA response to CS, but a higher DA response to reward.

Question 22

What is neurobiologically necessary for processing the emergent incentive salience of reward cues?

Answer 22

Release of DA NAcc.

Question 23

Concerning behavior in relation to reward cues, what would be the consequence of a DA receptor blockade in NAcc?

Answer 23

Impairing the acquisition and expression of sign-tracking behavior (GT behavior would be sensibly the same).

Question 24

DA receptor blockade in NAcc impairs ST behavior but not GT behavior. Provide a hypothesis to this observation.

Answer 24

Since the receptor blockade acts probably on one specific type of receptor, it is possible that the medium spiny neurons of the NAcc that are either D1 or D2-prominent correspond to a ST or GT behavioural profile.

Question 25

What unintuitive relationship holds between stress and dopamine? What preconceived popular idea can this fact dissolve?

Answer 25

Stress potently activates DA transmission in PFC and in the NAcc. The popular idea that dopamine is the “pleasure” molecule in the brain.

Question 26

True or false: stress and how we cope with it can influence our sensitivity to addictive drugs.

Answer 26

True. Stress impacts DA transmission, just like addictive drugs.

Question 27

To what kind of response lead glucocorticoid receptors?

Answer 27

Inhibitory response upon binding to corticosteroids (CORT).

Question 28

What is the pathway leading to CORT secretion?

Answer 28

Hippocampus and PFC - + >Hypothalamus of PVN - + > Anterior Pituitary - + > Adrenal Cortex - + > CORT

Question 29

What kind of loop is forming the Hypothalamic-Pituitary-Adrenal (HPA) axis?

Answer 29

A negative feedback loop.

Question 30

How are high levels of cortisol affecting the NAcc DA response to stimulants?

Answer 30

Potentiation of the DA response.

Question 31

True or false: psychostimulant drugs activate the HPA axis.

Answer 31

True.

Question 32

What impact can psychostimulant or stress-induced increases in CORT have on the PFC?

Answer 32

CORT induces GR-dependent inhibition of PFC GABA interneurons limiting inhibitory control over PFC pyramidal GLU-containing neurons involved in regulating DA transmission in subcortical regions such as the NAcc.

Question 33

In what PFC neuroadaptation(s) does result chronic stress?

Answer 33

-Dendritic retraction and spine loss in pyramidal (Glu) neurons.
-Dendritic/spine proliferation in GABA interneurons.

Question 34

What are the prominent factors precipitating relapse (for substance use)?

Answer 34

Drug, drug-associated cue and stress.

Question 35

True or false: early life stressors, such as maternal separation, can affect the HPA axis even once in the adulthood?

Answer 35

True. Maternally separated individuals have much more chance to develop an abnormally responsive HPA axis.