Reward Physiology of Addiction Dr. Pierce Flashcards
What is the function of the nucleus accumbens and what NT is released?
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
When you do something that elicits reward VTA becomes activating inhibiting NA. How?
- Dopaminergic neurons from VTA project to NA
- DA is released to nuc Accumbens
- DA inhibitis NA
- NA decreases activity
- Decreased NA activity results in pleasure
How is VTA activated?
- 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)
What is Dynorphin?
Opioid co transmitter released by NA with GABA
What do GABA and Dynorphin do?
Function to suppress additional release of DA from VTA to halt reward process
Descrieb the path of NA back to VTA
- GABAergic neurons release GABA back to VTA
- Releases Dynorphin as co transmitter
- Acts through kappa opioid receptors
- Suppressing further DA release from VTA
Dopamine independent reward path?
- 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
How do drugs affect you at a cellular level?
- alter expression of TF and a wide variety of proteins involved in neutotransmission in brain regions regulated by dopamine
At NT level how do drugs affect you?
addiction releated adaptations have been documented for dopamine, glu, GABA,opioids, serotonin, and neuropepetides
What role does the amygdala play in regards to addiction?
Mediates cravings
Orbitofrontal cortex role with addiction?
- when person encounters associated people or things they are driven to make bad decisions or seek out more drugs despite obstacles
Memory mechanisms in reward and addiction?
- 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
What does CREB do within locus ceruleus?
- 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
Creb within NA target and function
Prominent target is Dynorphin and it is short acting and returns to nromal levels after cessation of rewarding stimulus
DeltaFosB and AP-1?
Transcription factors that upregulate structural proteins EAA receptor expressions, elementso f signal transduction paths and promote drug seeking behavior and locomotion
What NT can induce associative learning?
dopamine in large bursts such as those from drugs in nucleus Accumbens
How does dopamine release compare with drugs vs natural pleasure such as food or sex?
Natural reinforcers cease phase firining of dopamine when event ends, but drug abuse continues increasing dopamine release
What is the role of Dopamine with fear.
- 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
Acute stress releases ___.
- 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
Severe chronic stress
- 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
VTA role in fear stress memory and reward?
- SIgnals prediction error btw expected outcome and actural reward experienced
Hippocampus role in fear stress memory and reward?
Provides place and direction contextural info about environment which stimuli is experienced
Substantia nigra and dorsal striatum role in fear stress memory and reward?
motor responses with navigating environment towards a desirable cue with goal of engaging in activity that gives the reward
Amygdala role in fear stress memory and reward?
Retrieval of fear memories
Non addicvted brain vs Addicted brain?
- 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
Reward Prediction Error? What is a positive one and a negative one?
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)
