7 - Neurophysiology of Reward & Addiction Flashcards
This is the term for a process that mediates goal-directed responses or goal-seeking behavior to changes in the external or internal environment.
Motivation
This is the consequent of operant (learned) behaviors that alters the probability that a behavior will be repeated under similar conditions each time.
Reinforcement
This is the term for something important in the surrounding environment worth paying attention to.
Saliency
These are objects, stimuli, or activities that have positive value.
Rewards
This is a negative reinforcement of behavior that the individual will learn to avoid future encounters.
Aversion
This is a positive sensation often referred to as euphoria or hedonia.
Pleasure
The physiologic purpose of pleasure is to promote behaviors that are consistent with survival of self and the species. These natural rewards are elicited by behaviors such as…
Caring for young
Palatable food
Mating
Exercise/activity
_______ 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.
Dopaminergic (DA)
An unpredicted reward elicits an activation of DA neurons, this known as a…
Positive Prediction Error (Positive RPE)
A fully predicted reward elicits no response, this means there is no _______. This happens because you got what you were expecting to get, so there is no negative or positive.
RPE
Omission of a predicted reward induces a _________. This is known as Negative Prediction Error (Negative RPE).
Depression
Events that reliably precede reward delivery assigns value to the reward itself, rather than just registering when the reward has occurred. Over repeated drug use, the repetition of these ________ signals would continue to reinforce drug-related cues and behaviors.
RPE
Natural rewards produce error-correcting _______ signals only until the predictions match the actual events. This is different from drug-related awards that repeatedly use the signals to further induce drug use.
DA-RPE
T/F. As a result, when given the choice between drug and natural reward (more exactly, a choice between a state leading to drug and a state leading to natural reward), the individual develops a bias towards drugs that strengthens with each drug use.
True
_________ has been consistently associated with the reinforcing effects of most drugs of abuse. Drugs of abuse increase extracellular _________ concentrations in limbic regions, including the ________ ________.
Dopamine
Dopamine
Nucleus Accumbens
T/F. Drugs of abuse provide equal amounts of dopamine release as natural reinforcers such as food and sex.
False. Drugs of abuse provide longer and larger increases in dopamine than natural reinforcers such as food and sex.
Some drugs increase dopamine directly, by inhibiting dopamine reuptake or promoting dopamine release. What are examples of these drugs?
Cocaine
Amphetamine
Methamphetamine
Ecstasy
Some drugs work indirectly via other neuron receptors that modulate and increase dopamine levels. What are examples of these drugs?
Nicotine
Alcohol
Opiates
Marijuana
Dopamine is involved in many aspects of reward and pleasure, including the prediction of reward and _________.
Salience
This refers to stimuli or environmental changes that are arousing or that elicit an attentional-behavioral switch. It affects the motivation to seek the anticipated reward and facilitates conditioned learning.
Salience
T/F. Salience suggests that drug-induced increases in dopamine will inherently motivate further procurement of more drug (regardless of whether or not the effects of the drug are consciously perceived to pleasurable).
True
Salience also leads to a situation in which sensory stimuli (sights, sounds, etc.) that are associated with the drug or with drug taking can increase _________ by themselves and elicit the desire for the drug. This explains why an addicted person is at risk of relapsing when exposed to an environment where he or she has previously taken the drug.
Dopamine
The mesolimbic system consists of a network containing…
Nucleus Accumbens
Ventral Tegmental Area (VTA)
Limbic System
Pre-frontal Cortex
The mesolimbic system utilizes _________.
Dopamine
In addition to dopamine, what are other neurotransmitters involved in the mesolimbic system?
GABA Opioids EAAs (i.e., Glutamate) Dynorphin Orexin
The main function of this is to suppress sensations of pleasure/reward.
Nucleus Accumbens
By default, the Nucleus Accumbens is constitutively activated by a constant trickle of ________ like ________ from the hippocampus, amygdala, or even the pre-frontal complex.
EAAs
Glutamate
Nucleus Accumbens neurons themselves are _________, meaning that activation of these neurons stimulate them to release ________.
GABAergic
GABA
T/F. For Nucleus Accumbens neurons, since they release GABA when activated and GABA is inhibitory, the projections of these neurons will inhibit their target.
True
In this case, the GABAergic NA neurons project to the ______. Constitutive inhibition of the _______ targets keeps the brain in a reward-neutral state (no pleasure sensed).
PFC
PFC
Describe the basic circuit of NA to PFC.
Hippocampus, Amygdala, or PFC release EAAs (like glutamate) that activate the NA —
Once activated, the NA is GABAergic and its neurons release GABA —
GABA is inhibitory, so it goes to the PFC and inhibits or prevents pleasure
When you do something that elicits a reward, the _______ becomes activated.
VTA (Ventral Tegmental Area)
The VTA ultimately inhibits the ______ because this usually inhibits reward/pleasure, and the VTA wants this to occur.
NA
Explain the steps of the reward circuit, involving the VTA and NA.
Dopaminergic neurons from the VTA project to the NA —
DA is released into the NA —
DA inhibits neurons in the NA —
NA activity decreases —
Decreased NA activity results in sensation of pleasure
Upon engaging in a behavior or activity that results in reward, the VTA is activated by…
EAAs
Orexin
ACh
The NTs used to activate the VTA (EAAs, Orexin, or ACh) may arise from where?
Pre-frontal Cortex (EAA)
Other tegmental nuclei like the Dorsal Tegmental Area (ACh)
In the case of consumption of food – from Hypothalamus (Orexin)
There is also a feedback circuit to consider. There exist projects from the NA back to the VTA. Recall the NA contains _________ neurons, so if they project back to the VTA, they will inhibit the VTA.
GABAergic
In the reward feedback circuit (NA back to VTA), in addition to releasing GABA, the NA-neurons also release a co-transmitter called _________. This is an opioid that binds to the _______-opioid receptor in the VTA.
Dynorphin
Kappa
Together, _______ and _______ from the NA function to suppress additional release of dopamine from the VTA as a means to halt the reward process.
GABA
Dynorphin
Describe the reward feedback circuit from the NA to the VTA.
GABAergic neurons (from NA) release GABA back to VTA —
Na also releases Dynorphin as co-transmitter —
Dynorphin binds to Kappa-opioid receptors and CREB —
The GABA and Dynorphin suppress further DA release from VTA neurons
Together, the inactivation of the Nucleus Accumbens via dopaminergic neurons from the VTA is termed the…
Dopamine-Hypothesis of reward
Many drugs of abuse activate this, and the associated hedonic effect is a result.
Mesolimbic-DA system
There is also another mechanism to activate the reward pathway, which utilizes endogenous opioids. This is called the…
Dopamine-Independent reward pathway
The VTA can be activated by EAA, ACh, Orexin, and ________.
Opioids
Exercise, ethanol, and other activities increase endogenous opioid signaling at all levels of the reward network: the VTA, NA, and PFC. Via activation of ______ receptors, they activate _________ neurons in the VTA (via inhibiting local VTA interneurons that would normally suppress ________ activity: therefore, opioids dis-inhibit ________ neurons).
Mu
Dopaminergic
Dopaminergic
Dopaminergic
Besides activating dopaminergic neurons in the VTA, endogenous opioids also activate local interneurons in the ______ (which inhibit GABAergic neurons locally), and they activate the ______ itself. The net result is a profound sense of pleasure (or even euphoria).
NA
PFC
________ increase DA in the VTA by inhibition of GABAergic neurons locally through mu-receptors. This allows increased DA in the NA, which leads to pleasure/reward.
Opioids
From a neurobiologic perspective, addiction probably results from neurobiologic changes that are associated with recurrent supraphysiologic perturbations in the ________ system. Chronic drug exposure alters the morphology of neurons in ________-regulated circuits.
Dopamine
Dopamine
At a cellular level, drugs have been reported to alter the expression of _______ _______, as well as a wide variety of proteins involved in neurotransmission in brain regions that are regulated by dopamine.
Transcription factors
At the neurotransmitter level, addiction-related adaptations have been documented not only for dopamine but also for…
Glutamate GABA Opioids Serotonin Various other neuropeptides
In people with addictions, abnormal neurotransmitter levels are found in the mesocortical region of the brain. This brain regions contains the ________ _______, which is involved in compulsive behavior, as well as the ________ ________, which regulates disinhibition. These adaptations are believed to play a significant role in aberrant addictive behaviors such as compulsive drug administration and poor inhibitory control, as well as relapse.
Orbitofrontal Cortex
Cingulate Gyrus
A lasting memory is created that associates these good feelings with the circumstance and environment in which they occur (hippocampus). These memories called “_________ ________” utilize circuitry that also mediates craving (amygdala) when the abuser encounters those persons or things (orbitofrontal cortex) and is then driven to make poor decisions or seek out more drugs in spite of obstacles.
Conditioned Associations
This type of learning and memory development occurs from a persistent increase in synaptic strength following high-frequency stimulation of a chemical synapse. It requires repeated, long stimulation.
Long-term Potentiation (LTP)
What is the short-term mechanism of LTP?
Increased phosphorylation of AMPA receptors and insertion of additional AMPA receptors into the post-synaptic membrane.
What is the long-term mechanism of LTP?
Activation of the calcium-calmodulin-CREB mechanism
Describe the activity of CREB in the NA.
When there is reward stimulation (either natural or drug-related) then there is activation of calcium-calmodulin, which causes activation of cAMP. cAMP in turn activates PKA which leads to the up regulation of CREB (transcription factor). CREB then stimulates the production of the protein Dynorphin in the NA. Remember, Dynorphin is a co-transporter that works with GABA to suppress the release of dopamine from the VTA, thus stopping the reward process.
What are the transcription factors responsible for changing the shape, growth, dendrites, etc of neurons in order to induce learning and memory? Do they induce long-term changes or short-term?
CREB – Long-term, except when stimulated by drug use then it is short-term
Delta-FosB – Long-term
AP1 – Long-term
Physical dependence can occur due to excessive noradrenergic output from the…
Locus Ceruleus
Physical dependence can also be a component of addiction, and this can be due to ______-dependent upregulation of target genes in the Locus Ceruleus. Here, the target genes deal with learning and memory and this will change the neurons creating the physical dependence.
CREB
Describe the activity of CREB in the LC.
A reward process, usually drug-related in this case, will lead to the activation of calcium-calmodulin and then cAMP. cAMP goes on to activate PKA, which upregulates CREB. CREB goes on to promote targets such as structural proteins involved in learning and memory. This is part of why a person becomes physically dependent on a drug.
Describe the activity of the other important transcription factors, Delta-FosB and AP-1.
Drugs of abuse, chronic stress, and other factors will activate the signaling cascades to activate the upregulation of Delta-FosB and AP-1. These then will target structural proteins, EAA receptor expression, elements of cell signal transduction pathways, and factors promoting drug-seeking, motivation, and locomotion. This is what essentially makes a drug-addict relentless in their pursuit for a drug, because they have the motivation and will move (locomotion) in any way possible to get it.
DA increases that are sufficiently large, such as those induced by drugs in the NA, can induce…
Associative learning (conditioning)
Conditioning induces phasic DA firing in the _______ resulting in large, fast, short-lived increases of DA in the NA reflecting expectation of reward. Natural reinforcers (food, sex, exercise) cease phase firing when the event concludes, but drugs of abuse continue increasing DA release.
VTA
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 ________ ________ in addicted human subjects.
Reward circuits
T/F. Eventually, becoming conditioned to fear drug withdrawal effects than can be relieved by the drug might lead to any source of stress or frustration becoming a cue for drug use.
True
________ ________ is learning that one behavior is associated or leads to something unpleasant or aversive. For example, the sound of a bell always pairs with an electric shock.
Fear conditioning
In fear conditioning, _________ can alter the conditions through which the fear occurs, or alter the association itself. For example, attaching rewarding hedonic value to previously fearful stimuli. Now pairing the sound of a bell with the euphoria of cocaine administration. This alters the expression of the memory (the sound of the bell used to be associated with electric shock, now it’s associated with euphoria).
Dopamine
Why is dopamine able to modulate so many learned experiences (like in the example of the bell and electric shock/euphoria)?
Because there is countless dopamine-receptors all over and they have individual signaling cascades in different regions of the brain.
In a non-addicted brain, the _________ of substances (the thing to which one is not addicted) and substances cues should be low in the non-addicted brain because the brain inhibits the drive to seek such substances. Conditioned cues have little or no influence on the ________ of drug-substances. The ________ of natural rewards greatly overrides that of drugs.
Saliency
Saliency
Saliency
In an addicted brain, the saliency of substances (the thing to which one is addicted) and substance-related cues is increased. This overrides the _______ control of behavior, it can no longer inhibit the drive to seek substances. Conditioned cues reinforce the saliency of substances, further increasing substance-seeking behavior. The saliency of substances overrides that of natural reward, which no longer influence behavior.
PFC
This is responsible for the retrieval of fear memories.
Amygdala
This signals prediction error between the expected outcome and the actual reward experienced.
VTA
This gives the assignment of salience to certain stimuli and mediates decisions that seek (or avoid) a desirable (or aversive) situation.
NA
For acute stress, _______ usually increases dopamine release in the NA in the short term.
CRF (corticotropin releasing factor)
Prolonged, chronic, severe stress results in CRF inducing a dopamine release that was once associated with pleasurable, appetitive results to aversion. This switches the emotional response to acute stressors. This is due to the divergent action of ______ vs ______ subtype-receptors in the NA.
CRF1
CRF2
This provides place and direction-contextual information about the environment in which stimuli is experienced.
Hippocampus
These provide motor responses associated with navigating the environment toward a desirable cue with a goal of engaging in the activity that elicits reward.
Substantia Nigra
Dorsal Striatum
