Lecture 44: Neurophysiology of Reward and Addiction

Question 1

Saliency and importance in Reward system (Drug Use)

Answer 1

something important in the surrounding environment worth paying attention to

• affects motivation to seek anticipated reward and facilitates conditioned learning
• sensory stimuli associated w/drug can increase dopamine lvls by themselves (elicit drug desire)

Question 2

Motivation

Answer 2

a process that mediates goal-directed responses or goal-seeking behavior to changes in external/internal environment

Question 3

Pleasure

Answer 3

• positive sensation (euphoria or hedonia)

- promotes behaviors that are consistent with survival or self and species

Question 4

Dopamine and Drug Use

Answer 4

• associated with reinforcing effects of most drugs of abuse (inc. extracellular dopamine concentrations in limbic regions –> NUCLEUS ACCUMBENS)
• provide longer and larger inc. in dopamine than natural reinforcers

Question 5

What makes up the Mesolimbic System and what does it utilize?

Answer 5

• Nucleus Accumbens, Ventral Tegmental Area (VTA), Limbic System, Pre-Frontal Cortex (PFC)
• utilizes DOPAMINE

Question 6

Basic Circuit (Mesolimbic System) and Nucleus Accumbens main function

Answer 6

• Nucleus Accumbens –> Pre-Frontal Cortex
• NA function: suppress pleasure/reward sensations

NA constantly active by EAA trickle, causing it to release GABA into the Pre-Frontal Cortex (keeps PFC in reward-neutral state = NO PLEASURE)

Question 7

Reward Circuit (Mesolimbic System)

Answer 7

• VTA –> NA (doing something that elicits a reward)

VTA releases Dopamine into NA (inhibiting NA), decreasing NA activity = sense of plesure

Question 8

Why and how is the Ventral Tegmental Area (VTA) activated in the Reward Circuit?

Answer 8

• engaging in reward activity/behavior causes VTA activation

- activated by EAA (PFC), Acetylcholine (Dorsal Tegmental Area), Orexin (hypothalamus - food)

Question 9

Reward Feedback Circuit (Mesolimbic System)

Answer 9

• NA halts reward process via GABA and Dynorphin

- Dynorphin binds kappa-opioid receptor (VTA) and w/GABA suppresses additional Dopamine release

Question 10

VTA activation by Opioids (Dopamine-Independent Reward Pathway)

Answer 10

• opioids bind MU-receptors
• inhibit VTA interneurons, activate NA interneurons, and activate PFC itself
• results in PROFOUND sense of pleasure (EUPHORIA)

Question 11

Chronic drug exposure alters…..

Answer 11

the morphology of neurons in dopamine-regulated circuits

Question 12

Where are abnormal neurotransmitters found in addicts and what structures are affected?

Answer 12

• found in mesocortical region of the brain

- includes orbitofrontal cortex (compulsive behavior), cingulate gyrus (regulates disinhibition)

Question 13

Memory (“Conditioned Association”) and Drug Use

Answer 13

• creates memory via circumstance/environment event occurred (hippocampus), utilizing craving (amygdala) when abuser encounters people/things (orbitofrontal cortex) and is drive to make seek drug/poor choices

Question 14

CREB and Physical Dependency

Answer 14

CREB = cAMP response-element binding protein (targets CPE)

NA = upregulates Dynorphin

Locus Coeruleus –> mediates physical dependency

• works for days then becomes normal after drug
• physical dependence = excessive noradrenergic ouput and CREB-dependent upregulation of target genes

Question 15

deltaFosB and AP-1

Answer 15

• upregulated by drugs of abuse and stress
• upregulates expression of:
  1. EAA receptor expression
  2. cell signal transduction pathways
  3. factors promoting drug seeking, motivation, locomot.

LONG-TERM STRUCTURAL CHANGES (months-years)

Question 16

Drug Conditioning

Answer 16

• DA inc. that are sufficiently large = condition learning
• trigger phasic DA firing in VTA = large, fast, short-lived inc. of DA in NA
• natural reinforces cease firing after event, but drugs continue releasing DA

Question 17

Drug Associated Cues

Answer 17

• cues can elicit drug urges and physiologic responses
• can also activate reward circuits in addicted human subjects
• conditioning to fear of drug withdrawal lead to source of stress/frustration –> cue for drug use

Question 18

How can Dopamine alter conditions through which fear occurs? (2)

Answer 18

1. alter association itself (associate dopamine w/previous fearful stimuli)
2. alter the expression of the memory (fearful stimuli now associated with euphoria)

Question 19

Non-addicted Brain

Answer 19

• saliency of substances and substances cues should be low in brain (brain inhibits seeking drive)
• saliency of natural rewards greatly overrides the saliency of drugs (conditioned cues have no influence)

Question 20

Addicted Brain

Answer 20

• saliency of substances and related cues increased
• overrides PFC behavior control (conditioned cues reinforce saliency and override saliency of natural rewards –> No longer influence behavior)