Neurophysiology of Reward and Addiction (Pierce) Flashcards
What is motivation?
A process that mediates goal-directed responses or goal-seeking behavior to changes in the external or internal environment
What is saliency?
Something important in the surrounding env. worth paying attention to; the attention-grabbing feature of rewarding objects.
What does reward involve?
- hedonic effect of pleasure
- motivation to obtain the reward because of its value
- Associated learning
What is aversion?
A negative reinforcement of behavior that the individual will learn to avoid future encounters
What is pleasure?
A subjectively positive sensation
What is the purpose of pleasure?
To promote behaviors that are consistent with survival of self and the species.
What NT plays a role in pleasure reward seeking behavior?
Dopamine
What do DA neurons encode
The discrepancy between reward prediction and information about the actual reward received and broadcast the signal to downstream brain region involved in reward learning.
How do drugs of abuse affect dopamine concentration?
Will increase extracellular concentration of dopamine in limbic regions, including the nucleus accumbens (NA) and prevent reuptake of dopamine
How do drugs increase dopamine and by how much?
- Directly: Inhibiting dopamine reuptake or promoting dopamine release
- Indirectly: Using other neuron receptors that modulate dopamine levels
5-10 fold increase than natural reinforces such as food and sex
What is salience?
A stimuli or environmental changes that are arousing or that elicit an attentional behavioral switch
Why are addicts at a great risk for relapse when they visit places they had taken drugs at?
The stimuli around them are salient (noticeable). The stimuli itself can increase dopamine and elicit desire for drugs.
What are important brain regions in the mesolimbic system
Nucleus Accumbens (NA)
Ventral tegmental area (VTA)
Prefrontal cortex (PFC)
Limbic system
What is the main function of the nucleus accumbens?
Suppress sensations of pleasure and reward
What structures constitutively activate (via EAA like glutamate) nucleus accumbens?
Hippocampus
Amygdala
Prefrontal cortex (PFC)
What type of neurons does the nucleus accumbens release?
GABA (inhibitory)
What is the basic/default circuit of pleasure
- Hippocampus, amygdala & prefrontal cortex release constant trickle of EAA to NA
- NA neurons release GABAergic (inhibitory) neurons to PFC
- Constituitive inhibition of PFC targets keeps the brain in a reward-neutral state (no pleasure)
What pathway occurs when you do something that elicits a reward?
- Dopamine neurons synthesized in VTA project to nucleus accumbens.
- Dopamine released into NA inhibits it.
- NA activity decreases, resulting in a sensation of pleasure
When NA actvity decreases, it can’t inhibit targets in the prefrontal cortex
What stimulates the VTA when you engage in behavior or activity that results in rewards?
Pre-frontal cortex: EAA
Dorsal Tegmental area: ACh
Hypothalamus: Orexin (from food)
What suppresses the VTA to prevent additional release of dopamine and halt the reward process
Projections from the NA back to the VTA which release GABA and a opiod co-transitter called dynorphin
What is the dopamine-hypothesis of reward?
Inactivation of Nucleus Accumbens via dopaminergic neurons from VTA
What is the dopamine-independent reward pathway
Utilizing endogenous opiods to activate the reward pathway
What activities can increase endogenous opioid signaling?
Exercise
Ethanol
Other activities
What receptors do opioid signaling utilize to activate dopaminergic receptors at VTA?
Mu receptors
How does opioid signaling work?
- Inhibit local VTA interneurons that normally suppress dopaminergic neurons in VTA
- Disinhibit dopaminergic neurons
- Activate nucleus accumbens local interneurons to inhibit the release of GABA
- Activate pre-frontal cortex
What is the result of endogenous opioid signaling?
Pleasure
Euphoria
From a neurobiological perspective, what does addiction probably result from?
Recurrent supraphysiologic perturbations in dopamine system. Chronic drug exposure alters the morphology of neurons in dopamine-regulated circuits
How can drugs change things at a cellular level?
Alter expression of certain transcription factors and proteins involved in neurotransmission in brain regions regulated by dopamine
How can drugs change things at a neurotransmitter level?
Abnormal NT levels for dopamine, glutamate, GABA, opioids, serotonin
Where are lasting memories of the good feelings associated with drugs created?
Memories made in hippocampus
What brain region mediates craving?
Amygdala
When the abuser seeks out drugs, what structure is involved in the poor decision making?
Orbitofrontal cortex
What is the short term mechanism of memory in reward and addiction
Increased phosphorylation of AMPA receptors in the post-synaptic membrane
What is the long term mechanism of memory in reward and addiction
Activation of calcium-calmodulin-CREB mechanism
What is the life long mechanism of memory in reward and addiction
Signaling cascade involving transcription factors - change FosB and AP-1
How does the activation of calcium-calmodulin-CREB mechanism work?
Promotes production of dynorphin in nucleus accumbens to shut off VTA and dopaminergic signaling
What is physical dependency?
Chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms
Why does physical dependency occur?
Excessive noradrenergic output from the locus ceruleus (involved in arousal and vigilance), and CREB dependent up-regulation of target genes in locus ceruleus.
When are the FosB and AP-1 genes up-regulated?
Chronic Stress
Drugs of Abuse
How do natural reinforcers (food, sex, exercise) differ from drugs?
Natural Reinforcers: Firing of neurons stop when event concludes
Drugs: Dopamine release continues after activity
How does dopamine change the reward circuitry?
Dopamine can alter a fearful stimuli to a pleasurable one Ex: Before hearing a bell could be scary, but now hearing a bell is associated with euphoria from drugs
How do addicted brains differ from non-addicted brains?
Conditioned cues reinforce saliency of substances, increasing behavior to find and consume drugs. These cues override prefrontal cortex’s control of behavior
What role does the substantia nigra and dorsal striatum play in pleasure/reward-seeking behavior?
Control motor response associated with navigating the environment for desirable activity
What are differences between conditioned responses and drug-associated cues?
Conditioned responses: cues to drug-taking in specific social circumstances
Drug-associated cues: powerful cues that can elicit drug urges and physiologic responses w/o taking drug
What role does the locus ceruleus play?
- Involved with physiological responses to stress and panic
- Synthesis of norepinephrine
What does CREB mediate in the locus ceruleus?
Physical dependency due to excessive noradrenergic output from locus ceruleus
How does dopamine alter the conditions through which fear occurs
- Alters the association itself - attaching rewarding hedonic value to previously fearful stimuli
- Alters the expression of the memory
