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Flashcards in Physiology of Addiction Deck (21)
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1
Q

Physiologic purpose of pleasure

A

To promote behaviors that are consistent with survival of self and species

Examples — caring for young, experiences, palatable food, stress

2
Q

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

A

Mesolimbic

3
Q

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

A

Inhibitory; decreases

4
Q

What 3 things activate the ventral tegmental area?

A

Prefrontal cortex (EAA)

Other tegmental nuclei (ACh or EAA)

Lateral hypothalamic nucleus (orexin) — food

5
Q

The nucleus accumbens projects neurons that release ______ in the prefrontal cortex. Activation of the nucleus accumbens __________ pleasure

A

GABA; inhibits/prevents

6
Q

3 areas that activate the nucleus accumbens

A

Hippocampus
Amygdala
PFC itself

[EAA]

7
Q

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

A

Dynorphin; suppresses

8
Q

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?

A

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

9
Q

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?

A

An unpredicted reward elicits an activation (positive prediction error)

A fully predicted reward elicits no response

Omission of a predicted reward induces a depression

10
Q

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

A

Prelimbic cortex

Amygdala

Orbitofrontal

11
Q

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?

A

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

12
Q

Compare/contrast the normal activation of the pleasure pathways with that produced by drugs of addiction

A

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

13
Q

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

A

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]

14
Q

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

A

Dynorphin

Locus ceruleus

Shorter

15
Q

_____ 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

A

FosB; AP-1

Long

16
Q

________ may be induced within NA and promotes growth of dendritic spines, increased drug reward, interacts with FosB and is thought to correlate with addiction and depression comorbidity

A

NF-kB

17
Q

What is the mechanism of physical dependence?

A

Physical dependence is due to excessive noradrenergic output from the locus ceruleus

Due to CREB-dependent upregulation of target genes in LC

18
Q

Dopamine increases that are sufficiently large to activate D1R, such as those induced by drugs in the NA, can induce associative learning (conditioning). What effect does this have on the brain?

A

Conditioning triggers phasic DA firing in the VTA, resulting in large, fast, short-lived increases of DA in the NA, reflecting an expectation of reward

Natural reinforcers cease phase firing when the event concludes, but drugs of abuse CONTINUE increasing DA release

19
Q

What role do conditioned responses, drug-associated cues, and fear of drug withdrawal have on addiction?

A

Conditioned responses provide powerful cues to drug-taking in specific social circumstances, and this conditioning is reinforced by aspects of the drug-taking process

Drug-associated cues (persons with whom the drug was used or drug paraphernalia) elicits drug urges and physiologic responses (sympathetic activation) as well as activation of reward circuits in addicted human subjects

Eventually, becoming conditioned to fear drug withdrawal effects that can be relieved by the drug may lead to any source of stress or frustration becoming a cue for drug use

20
Q

Define conditioned-place preference and the relation to drug-seeking behavior in humans

A

Conditioned place preference is an observable correlate of drug-induced plasticity

Animals prefer the environment associated with reward; implications for social surroundings of addiction relevent to drugs of abuse, gambling, gaming, eating, and other addictions

21
Q

Define self-administration of addictive drugs and the relation to drug-seeking behavior in humans

A

Self-administration is a function of the reinforcement value of the drug