Physiology of Addiction Flashcards
Physiologic purpose of pleasure
To promote behaviors that are consistent with survival of self and species
Examples — caring for young, experiences, palatable food, stress
One of the major systems that uses dopamine is the ______ system, consisting of ventral tegmental area to nucleus accumbens; this system is central to pleasure, reward, and addiction
Mesolimbic
Projections from the ventral tegmental area (VTA) to the nucleus accumbens (NA) release dopamine in the NA, which has _________ effect and NA activity _________, leading to pleasure
Inhibitory; decreases
What 3 things activate the ventral tegmental area?
Prefrontal cortex (EAA)
Other tegmental nuclei (ACh or EAA)
Lateral hypothalamic nucleus (orexin) — food
The nucleus accumbens projects neurons that release ______ in the prefrontal cortex. Activation of the nucleus accumbens __________ pleasure
GABA; inhibits/prevents
3 areas that activate the nucleus accumbens
Hippocampus
Amygdala
PFC itself
[EAA]
The nucleus accumbens also projects GABAergic neurons that release GABA back to the VTA. It also releases ______ as a co-transmitter which binds kappa-opioid receptors and plays a role with CREB. This interaction ______ further DA release from VTA neurons
Dynorphin; suppresses
The dopamine hypothesis of reward relates to the pleasure-related (hedonic) effect resulting from activation of the mesolimbic dopamine system.
However, reward can be induced (at the VTA) via dopamine-independent mechanisms — what system falls into this category and how does it do this?
The endogenous opioid system
[Opioids increase dopamine in the VTA by disinhibition of GABAergic neurons locally through mu-receptors — this allows increased dopamine in the NA —> pleasure/reward]
Operates like a positive feedback loop
Dopaminergic neurons encode the discrepancy between reward predictions and information about the actual reward received and broadcast this signal to downstream brain regions involved in reward learning.
What is the difference in response with an unpredicted reward, a fully predicted reward, and an omission of a predicted reward?
An unpredicted reward elicits an activation (positive prediction error)
A fully predicted reward elicits no response
Omission of a predicted reward induces a depression
The VTA to _____ _____ promotes attention toward cues that are good predictors of an outcome relative to other rewards
The VTA to the ________ promotes attention to cues that inconsistently predict an outcome, uncertain predictors
The VTA to the _____ _____ promotes attention toward cues that are particularly noticable even if they are inconsistent predictors
Prelimbic cortex
Amygdala
Orbitofrontal
Dopaminergic neurons encode the discrepancy between reward predictions and information about the actual reward received and broadcast this signal to downstream brain regions involved in reward learning.
How is this system impacted by addictive drugs?
Over repeated drug use, the repetition of reward prediction error (RPE) signals continues to reinforce drug-related cues and behaviors
This is in contrast to natural rewards that produce error-correcting DA-RPE signals only until the predictions match the actual events
As a result, the individual develops bias towards drug that strengthens with each use
Compare/contrast the normal activation of the pleasure pathways with that produced by drugs of addiction
Normal reward stimuli — due to release of dopamine in the NA. Purpose is to reinforce behaviors consistent with health, longevity, and otherwise don’t seem to have an immediate benefit. The reward for these behaviors is the sense of pleasure that is derived.
Drugs of addiction — many drugs lead to enhanced dopamine in the NA. Dopamine signal in the NA is not proportional to stimuli. The “reward” for this is enhanced euphoria and exaggerated reward to an otherwise mild stimulus
Long-term potentiation = a persistent increase in synaptic strength following high-frequency stimulation of a chemical synapse; requires repeated strong stimulation.
The mechanism of LTP involves increased _______ of AMPA receptors and insertion of additional AMPA receptors into post-synaptic membrane. Eventually, activation of the __________ mechanism
Phosphorylation
Calcium-calmodulin-CREB
[increase signaling via LGIC, GPCR, and VGCC results in trascription factors FosB, CREB, NF-kB, and JUN which impact BDNF, cytoskeleton structural proteins, synapse and growth formation, enzymes for NT synthesis, and NT receptors]
CREB is cAMP response-element binding protein targeting CRE (cAMP response elements). CREB within the nucleus accumbens involves _____ as a prominent target.
CREB within the _____ ______ mediates physical dependency.
This is a _____-acting response and returns to normal after drug cessation
Dynorphin
Locus ceruleus
Shorter
_____ and _____ are TFs upregulated by stress and drugs of abuse; they upregulate the expression of EAA receptors (AMPA/NMDA), elements of cell signal transduction pathway, and factors promoting drug seeking, motivation, and locomotion. These are ______-term (structural) changes that last months to years
FosB; AP-1
Long
