Neurophysiology of Reward and Addiction (Pierce) Flashcards
1
Q
- process that mediates goal-directed responses or goal-seeking behavior to changes in exeternal/internal environment
- reinforcement: consequence of operant behaviors that alters probability that behavior will be repeated under similar conditions each time
A
motivation
2
Q
- something important in surrounding environment worth paying attention to
- attention-grabbing feature of rewarding objects
- heightens perception and focuses attention toward the particular sights, sounds, and smells associated with these rewards in a way that normally promotes well-being and survival
- triggered by encounters with reward-related cues and experienced as surges of motivation to obtain and consume the reward that can last beyond the time the individual is exposed to the cue
- something that has value to the individual so they want it
- can make the cues a/w drug use wanted almost as much as drug itself
A
salience
3
Q
involves
1) hedonic effect of pleasure
2) motivation to obtain reward b/c its value (salience)
3) associated learning
A
reward
4
Q
negative reinforcement of behavior that the individual will learn to avoid future encounters
A
aversion
5
Q
- subjectively positive sensation often referred to as euphoria
- think of as “liking” something
A
pleasure/hedonia
6
Q
What is the physiological purpose of pleasure?
A
- to promote behaviors that are c/w survival of self/species
- natural rewards elicited by behaviors may include caring for young, palatable food, mating, exercise/activity
7
Q
- lack of interest, or no longer liking something previously liked
- component of depression
A
anhedonia
8
Q
What neurons encode the discrepancy between reward predictions and info about actual reward received and send signal to the brain regions involved in reward learning?
A
dopaminergic (DA) neurons
9
Q
- mismatch between events and reward elicited
- positive: unpredicted reward elicits an activation
- negative: omission of a predicted reward induces depression
- neutral: full predicted reward elicits no response (events that reliably precede reward delivery assigns value to reward itself, rather than just registering when reward has occurred)
A
reward prediction error (RPE)
10
Q
What are the differences between drug and natural reward predictions and what do these differences lead to?
A
- repeated drug use: repetition of RPE signals continues to reinforce drug-related cues/behaviors
- natural rewards: produce error-correcting DA-RPE signals only until predictions match actual events
- result: when given a choice between state leading to drug or state leading to natural reward, individual develops bias toward drugs that strengthens w/ each use
11
Q
- increase extracellular dopamine conc in limbic regions, including nucleus accumbens (NA)
- provide longer and larger (5-10x) increases in dopamine than natural reinforcers such as food or sex
- some increase dopamine directly (inhibit uptake or promote release) and some indirectly (other neuron receptors that modulate dopamine levels)
A
drugs of abuse
12
Q
What is the relationship between reward prediction, salience, and dopamine?
A
- salience affects motivation to seek anticipated reward and facilitates conditioned learning
- suggests: drug-induced increases in dopamine will inherently motivate further procurement of more drugs (regardless of whether the effects of drug are consciously perceived to be pleasurable)
- salience also leads to situation where sensory stimuli a/w drug/drug intake can increase dopamine by themselves and elicit desire for drug (explains why addicted persons are more at risk of relapsing when exposed to an environment where they had previously taken the drug)
13
Q
What are the important brain regions and NT’s a/w reward/addiction?
A
- mesolimbic system, dopamine
- nucleus accumbens (NA), GABA
- ventral tegmental area (VTA), opioids
- prefrontal cortex (PFA), EAA’s (glutamate)
- limbic system, dynorphin and orexin
14
Q
What is the pathway for the reward-neutral state (no pleasure sensed)?
A
- main function of NA is to suppress sensations of pleasure/reward
- by default, it is constitutively activated by constant trickle of EAA’s (glutamate) from hippocampus, amygdala, or PFC
- NA neurons are GABAnergic (inhibitory), thus they inhibit their target regions, in this case they project to PFC
- constitutive inhibition of PFC targets keeps brain in reward-neutral state
15
Q
What is the pathway for the reward state (pleasure sensed)?
A
- TLDR: VTA becomes activated and inhibits NA
1. DA neurons from VTA project to NA
2. DA is released into NA
3. DA inhibits neurons in NA
4. NA activity decreases
5. decreased NA activity results in sensation of pleasure (target areas in PFC are no longer inhibited)
16
Q
In the reward-circuit, how is VTA activated in the first place?
A
by behavior/activity that results in reward VTA is activated by EAA’s (PFC), acetylcholine (other tegmental nuclei like dorsal tegmental area), and orexin (hypothalamus w/ food consumption)
17
Q
How is the reward process halted within the reward-circuit?
A
- NA has projections back to the VTA
- NA sends GABAnergic neurons to VTA as well as neurons that release co-transmitter, dynorphin (opioid, binds kappa-opioid receptor in VTA)
- both GABA and dynorphin function to suppress additional release of dopamine from VTA to halt the reward process
18
Q
- the system by which the NA is inactivated via dopaminergic neurons from VTA
- many drugs of abuse activate the mesolimbic DA-system and result in associated hedonic effect
A
dopamine-hypothesis of reward
19
Q
- exercise, ethanol, and other activities increase endogenous opioid signaling at all levels of reward network (VTA, NA, PFC)
- via activation of mu-receptors, opioids activate: 1) dopaminergic neurons in VTA, 2) local interneurons in NA (inhibit GABAergic neurons locally), 3) the PFC itself
- net result: profound euphoria
A
dopamine-independent reward pathway
20
Q
Compare normal reward stimuli vs reward due to drugs of abuse:
A
- normal reward: due to release of dopamine from VTA; purpose is to reinforce behaviors c/w health, longevity, and otherwise don’t seem to have an immediate benefit; reward for these behaviors is sense of pleasure that is derived
- drug reward: many drugs enhance dopamine release from VTA; dopamine signal in NA is not proportional to stimuli; “reward” for this is enhanced euphoria and an exaggerated reward to an otherwise mild stimulus
21
Q
How does chronic drug use lead to addiction?
A
- chronic drug use alters morphology neurons in dopamine-regulated circuits
- cellular level: drugs alter expression of certain transcription factors and proteins involved in NTmission in brain regions regulated by dopamine
- NT level: addiction-related adaptations have been documented for dopamine, glutamate, GABA, opioids, serotonin, and neuropeptides
- adaptations are believed to play a role in aberrant adictive behaviors (compulsive drug administration, poor inhibitory control, relapse)
22
Q
What role does memory play in addiction?
A
- hippocampus: lasting mem is created that associates rewarding feelings w/ circumstance and environment where they occur (conditioned associations)
- amygdala: mediates craving
- orbitofrontal cortex: when abuser encounters associated persons or things and then is driven to make poor decisions/seek out drugs in spite of obstacles
- learning/memory: persistent increase in synaptic strength following high-freq stim of chemical synapse
- large DA increases (such as those induced by drugs in the NA) can induce conditioning, which triggers phasic DA firing in VTA to NA (large, fast, short-lived) reflecting expectation of reward compared to nautral reinforcers (food, sex, exercise) cease phase firing when event concludes (drugs of abuse continue increasing DA release)
- conditioned responses: provide powerful cues to drug-taking in specific social circumstances and is reinforced by aspects of drug-taking process
23
Q
What is the mechanism for memory in reward/addiction?
A
- requires a strong stimulus
- 3 mechanisms based on timing:
1) short term: increased phosphorylation of AMPA receptors by kinases in post-synaptic membrane, phosphate removed by phosphatases when reward signaling is diminished
2) moderate term (days-weeks): activation of calcium-calmodulin-CREB mechanism
3) life long: signaling cascades involving ΔFosB and AP-1 - examples: dynorphin feeds back to NA (helps suppress dopaminergic signaling from VTA) and certain ion channels/glutamate receptor subunits which control NA excitability
24
Q
Describe calcium-calmodulin-CREB mechanism in terms of moderate-term addiction:
A
- Ca2+ binds to calmodulin > activates cAMP > activates PKA > activates CREB (transcription factor) > alters DNA within nucleus > produces more dynorphin
- faily short acting (days-weeks) and returns to normal levels after cessation of rewarding stimulus
25
Describe calcium-calmodulin-CREB mechanism in terms of locus ceruleus:
- within locus ceruleus calcium-calmodulin-CREB mechanism mediates **physical dependency**
- LC has excessive noradrenergic output (involved in arousal and vigilance) and CREB-dependent upregulation of target genes in LC leads to increase in structural proteins involved in learning/memory
26
How does fear conditioning play a role in addiction?
- FC is learning that a behavior is associated with or leads to something unpleasant or aversive (e.g. the sound of a bell always pairs with an electric shock, subject begins to fear the bell sound itself)
- drug-associated cues (persons w/ whom drug was used or drug paraphernalia) elicits drug urges and **physiologic responses** (sympathetic activation) and activation of reward circuits in addicted human subjects
- **becoming addicted to fear drug withdrawal effects** (that can be relieved by drug) might lead to any source of stress/frustration also becoming cue for drug use
27
Describe ΔFosB and AP-1 system in terms of reward/addiction:
- these are transcription factors that, when altered by drugs, can have **lifelong (permanent)** implications in terms of addiction
- mechanism: drugs of abuse, chronic stress, and other factors \> trigger signaling cascades \> ΔFosB and AP-1 \> alter genes within nucleus \> **targets structural proteins, EAA receptor expression, elements of cell signal transduction pathways, and factors promoting drug seeking, motivation, and locomotion**
28
How does dopamine alter fear response?
- dopamine release within reward circuitry alters subjective value assigned to fearful stimuli and directly affects memory consolidation
- it can **alter the association itself**: attaching rewarding hedonic value to previously fearful stimuli; e.g. pairing the sound of a bell w/ euphoria of cocaine use (may be an explanation as to why an addict might engage in self-destructive behaviors despite the known risk b/c they are seeking the reward)
- it can **alter the expression of the memory**: e.g. sound of bell was a/w electric shock but is now a/w euphoria
- dopamine has the ability to modulate many learned experiences due to the myriad of dopamine-receptors and their individual signaling cascades
- conditioning is also relevant to other addictions (gambling, gaming, eating, etc.)
29
What is the role of the NA in fear, stress, memory, and reward?
- assigns salience to certain stim and mediates decisions that seek a desirable outcome or avoid aversive situation
- **acute stress**: (CRF) usually increases dopamine release in NA in short term in response to pleasurable stimulus
- **severe, chronic stress**: results in CRF inducing a dopamine release that was once a/w pleasurable results switches to aversive results (switches emotional response to acute stressors due to divergent action of CRF1 vs CRF2 sub-type receptors in NA)
30
What is the role of the VTA, hippocampus, substantia nigra/dorsal striatum, and amygdala in fear, stress, memory, and reward?
- **VTA**: signals prediction error between expected outcome and actual award experienced
- **hippocampus**: provides place and direction-contextual info about environment in which stim is experienced
- **substantia nigra and dorsal striatum**: motor reponse a/w navigating the environment toward a desirable cue w/ the goal of engaging in activity that elicits reward
- **amygdala**: retrieval of fear memories
31
Compare a non-addicted brain vs an addicted brain:
- **non-addicted**: saliency of substances (the thing to which one is *not addicted*) and substances cues are **low** b/c the brain **inhibits the drive** to seek such substances; conditioned cues have l**ittle or no influence** on the saliency of drug-substances; **saliency of natural rewards greatly overrides the saliency of drugs**
- **addicted**: saliency of substances (the thing to which one *is addicted*) and substance-related cues is **increased;** overrides the PFC’s control of behavior and PFC can **no longer inhibit the drive** to seek substances; conditioned cues **reinforce** the saliency of substances, further increasing substance-seeking behavior; **saliency of substances overrides the saliency of natural rewards, which no longer influence behavior**
