Reward Physiology of Addiction Dr. Pierce

Question 1

What is the function of the nucleus accumbens and what NT is released?

Answer 1

Suppress sensations of pleasure/reward

• it is always activated by default from constatn trickle of EAA’s
• The NA is GABAergic
• GABA is inhibitory and projects to prefrontal cortex
• Constitutive inhibition of PFC targets keeps brain in reward neutral state

Question 2

When you do something that elicits reward VTA becomes activating inhibiting NA. How?

Answer 2

1. Dopaminergic neurons from VTA project to NA
2. DA is released to nuc Accumbens
3. DA inhibitis NA
4. NA decreases activity
5. Decreased NA activity results in pleasure

Question 3

How is VTA activated?

Answer 3

• Engating in reward behavior VTA is activated by EAA Orexin or Ach
• NT come from PFC (EAA)other tegmental nuclei like dorsal tegmental area (ach release), or with food consusmption from hypothalamus (Orexin)

Question 4

What is Dynorphin?

Answer 4

Opioid co transmitter released by NA with GABA

Question 5

What do GABA and Dynorphin do?

Answer 5

Function to suppress additional release of DA from VTA to halt reward process

Question 6

Descrieb the path of NA back to VTA

Answer 6

• GABAergic neurons release GABA back to VTA
• Releases Dynorphin as co transmitter
• Acts through kappa opioid receptors
• Suppressing further DA release from VTA

Question 7

Dopamine independent reward path?

Answer 7

• Excercise, ethanol, and other activities increase endogenous opoid signaling at all levels of VTA NA and PFC activating:
  
  • Dopaminergic neurons in VTA
  • Local interneurons in NA which inhibit GABAergic
  • PFC itself
• Resulting in profound euphoria

Question 8

How do drugs affect you at a cellular level?

Answer 8

• alter expression of TF and a wide variety of proteins involved in neutotransmission in brain regions regulated by dopamine

Question 9

At NT level how do drugs affect you?

Answer 9

addiction releated adaptations have been documented for dopamine, glu, GABA,opioids, serotonin, and neuropepetides

Question 10

What role does the amygdala play in regards to addiction?

Answer 10

Mediates cravings

Question 11

Orbitofrontal cortex role with addiction?

Answer 11

• when person encounters associated people or things they are driven to make bad decisions or seek out more drugs despite obstacles

Question 12

Memory mechanisms in reward and addiction?

Answer 12

• Short term: increased phosphorylation of AMPA in post syn mem
• Long term: activation of Ca-Calmodulin-CREB mechanism
• Life long: signaling cascade involving deltaFosB and AP-1

Question 13

What does CREB do within locus ceruleus?

Answer 13

• Mediates physical dependency-reason for withdrawl
• Due to excessive noradrenergic output from LC and CREB dependent upreg of target genes in LC
• Creb targets the structural proteins involved in learning and memory in the LC that mediate physical dependency

Question 14

Creb within NA target and function

Answer 14

Prominent target is Dynorphin and it is short acting and returns to nromal levels after cessation of rewarding stimulus

Question 15

DeltaFosB and AP-1?

Answer 15

Transcription factors that upregulate structural proteins EAA receptor expressions, elementso f signal transduction paths and promote drug seeking behavior and locomotion

Question 16

What NT can induce associative learning?

Answer 16

dopamine in large bursts such as those from drugs in nucleus Accumbens

Question 17

How does dopamine release compare with drugs vs natural pleasure such as food or sex?

Answer 17

Natural reinforcers cease phase firining of dopamine when event ends, but drug abuse continues increasing dopamine release

Question 18

What is the role of Dopamine with fear.

Answer 18

• Alters association and memory expression of the fear- it can make a normally negative stimulus become positive
  
  • you are aware that the drug is bad for you, but you know the euphoria that comes with it so you do it anyways
  • Example of the dogs with bell and electric shock and cocaine. The animal learns the bell is accompanied by something negative but if it is paired with cocaine after the shock the animal determines it is worth the euphoria and seeks it out

Question 19

Acute stress releases ___.

Answer 19

• Corticotrophin releasing factor increasaes dopamine release in nucleus accumbuns in the short term
  
  • ex: during acute stress if you eat candy, it makes the candy taste even better than normal

Question 20

Severe chronic stress

Answer 20

• CRF inducing dopamine release that was once associated with pleasure switching to aversive results
  
  • Switches the emotional response to acute stress
  • Caused by the divergent action of CRF1 vs CRF2 subtype receptorss in the NA

Question 21

VTA role in fear stress memory and reward?

Answer 21

• SIgnals prediction error btw expected outcome and actural reward experienced

Question 22

Hippocampus role in fear stress memory and reward?

Answer 22

Provides place and direction contextural info about environment which stimuli is experienced

Question 23

Substantia nigra and dorsal striatum role in fear stress memory and reward?

Answer 23

motor responses with navigating environment towards a desirable cue with goal of engaging in activity that gives the reward

Question 24

Amygdala role in fear stress memory and reward?

Answer 24

Retrieval of fear memories

Question 25

Non addicvted brain vs Addicted brain?

Answer 25

• Saliency of substances and substance cues are low in non addicted brain while an addicted brain his high substance cues and saliency
• In non addicted brain the PFC inhibits drive to seek out destructive substances but addicted brain the PFC can’t inhibit the drive
• Conditioned cues have little influence on saliency of drugs in non addiction- saliency of natural rewards overrides drugs, but in addicted brains conditioned cues reinforce saliency of substances increasing the substance seeking behavior. Saliencey of substances overrides natural rewards

Question 26

Reward Prediction Error? What is a positive one and a negative one?

Answer 26

Mismatch btw events and reward elicited

• unpredicted reward elicits activation (Positive prediction error)
• Fully predicted reward gives no response
• Omission of predicted reward induces depression (negative PE)