Pharm - Reward pathways

Question 1

What are neural substrates? (brain reward pathways)

Answer 1

• Set of interconnected forebrain structures that underlie the perception of reward and the phenomenon of positive reinforcement.
• Nucleus accumbens (major component of the ventral striatum)
• Amygdala
• Hippocampus
• Lateral hypothalamus
• Prefrontal cortex
○ All of these receive DA from neurons in the ventral tegmental area

Question 2

What do the VTA and Nac do?

Answer 2

• VTA = ventral tegmental area
  
  • Nac = nucleus accumbens
  • Function in reward and reinforcement as part of a neural circuit that interfaces between limbic emotional-motivational information and extrapyramidal regulation of motor behavior

Question 3

What does the amygdala do?

Answer 3

• Critical integrative structure projecting to the VTA and nac
• Thought to be important to the formation of stimulus-reward associates
○ Remembering the pairing of stimulus with reward
What does the hippocampus do for reward pathways?
• Memory circuit involved in mediating associaitons between biologic stimuli (or drugs of abuse) and environmental cues

Question 4

What does the prefrontal cortex do in reward pathways?

Answer 4

• Certain regions are critical for executive function in providing control over impulses from destructive behavior
  
  • Their impairment in humans following chronic drug abuse appears to be an important mediator in the loss of control over drug intake

Question 5

What’s the normal reward pathway function?

Answer 5

• Normal function - mediate pleasure (reward) and the strengthening of behaviors (reinforcement) associated with natural reinforcers such as food, water, and sexual contact
  
  • Pathway produces motivational states, shaped by natural selection, that allow modulation of physiological and behavioral responses ensuring survival and reproduction
  • Think of this as complementary to survival networks in the brain that mediate learning about dangerous and harmful stimuli (fear-conditioning)

Question 6

What is a reinforcing stimulus?

Answer 6

• One that increases the probability that behaviors paired with it will be repeated
  
  • Not all reinforcers are rewarding, some can reinforce avoidance
  • Positive reinforcement might involve the alleviation of unpleasant symptoms

Question 7

What is meant by reward?

Answer 7

• Stimulus that the brain interprets as intrinsically positive or something to be approached
  
  • Drug-induced pleasurable states are important motivators of initial drug use

Question 8

What is the final common pathway for reward signaling?

Answer 8

• Dopamine release from VTA into NA
○ Ventral tegmental area into nucleus accumbens
○ Mesolimbic dopamine pathway
○ Used to be the “pleasure center” of brain with DA as “pleasure NT”
• Better thought- DA may affect motivation and attention to salient stimuli, including reward

Question 9

What are the stimuli coming onto the VTA neurons?

Answer 9

• 5HT - from raphe nuclei (which also project to NA directly)
• GABA input from interneurons
○ These are Ach and enkephalin responsive, release GABA on the VTA neurons projecting to NA
• GABA input from NA neurons (feedback loop)
• Glutamate input from PFC, amygdala and hippocampus
• Ach input from PPT/LDT
○ Final pathway - DA release onto NA neurons

Question 10

Neurons from the PFC, amygdala, and hippocampus release what NT onto NA neurons?

Answer 10

• Glutamate. All these areas project excitatory stimuli to NA
  
  • Can be blocked by cannabinoids
  • NA neurons will release GABA on VTA and (-) reinforce the excitation of NA neurons

Question 11

What pathway do drugs of abuse all converge on?

Answer 11

• The final common pathway of DA release onto NA neurons from VTA
• Increasing synaptic dopamine levels in the nucleus accumbens via interactions either directly with dopamine neurons or indirectly with other NT systems
• The more intense and more direct the effect of the drug on dopamine neurons, the greater the addiction potential
○ Cocaine, methamphetamine, nicotine

Question 12

What does the reactive reward system exist to do?

Answer 12

• Functions to signal the immediate prospect of either pleasure (positive) or pain (negative)
• Provides the motivational and behavioral drive to achieve that pleasure or avoid the pain
○ VTA, NA, amygdala

Question 13

Drugs tend to mimic the natural reinforcement pathway. What’s different about drug induced DA activity?

Answer 13

• Drug-induced DA release in NA is more explosive and pleasurable than that occurring with natural reinforcers
• Repeated exposures to drugs of abuse results in pathologic learning to trigger drug seeking behaviors
○ When presented with internal or external cues
○ Craving, withdrawal, environmental associations with past drug use

Question 14

As far as neurocircuitry is concerned, what’s the end result of drug addiction?

Answer 14

○ NET RESULT - development of drug addiction produces changes whereby the reactive reward system hijacks the normal reward circuitry

Question 15

What’s up with the REFLECTIVE reward system?

Answer 15

• A complementary and potentially competitive component of the reactive reward system with connections from the prefrontal cortex to the nucleus accumbens
  
  • OFC = orbitofrontal projections
  • DLPFC = dorsolateral prefrontal cortex projections
  • VMPFC = ventromedial prefrontal cortex
  • OFC projections may be involved in regulating impulses
  • DLPFC is involved in the analysis of situation
  • VMPFC is involved in integration of impulsiveness and cognitive flexibility with its regulation of emotions

Question 16

In the prefrontal cortex, how would the VMPFC projections be representative of what the WHOLE PFC was thinking?

Answer 16

• OFC and DLPFC projections will stimulate the VMPFC neurons
  
  • Essentially the VMPFC would be stimulated to release glutamate onto NA neurons more if there is concomitant stimulation by the OFC and DLPFC

Question 17

What inputs go into forming the normal reflective reward pathway?

Answer 17

• Over time
  
  • Genetics, neurodevelopment, experience, peer pressure, learning social rules
  • All go together to focus the final output of the reward system into beneficial long-term goal-directed behavior
  • The balance between reactive reward ddrives and reflective reward decisions determines whether the output of the reward circuity will be converted into short-term rewards (drug seeking) or long-term behaviors (delayed gratification)

Question 18

What’s the neurocircuitry of addiction?

Answer 18

• Repetetive drug-induced rewarding experiences alter the reward circuits so that not only will drug ingestion itself cause mesolimbic dopamine release
○ But also cues that merely predict pleasure
• The amygdala has learned that a drug causes pleasure and has associated drug cues with pleasure and may also signal relief from craving
• These cues lead to DA release in NA, triggering GABA output from NA to thalamus to PFC
• Balanced by reflective reward system, so in hypoactive reflective systems there is little to break the cycle of addictive short-term drug seeking behavior

Question 19

What are the “stimulants”?

Answer 19

• Cocaine
		○ Target = DAT, SERT-NET
		○ Inhibitor
		○ Blocks DA uptake
		○ Very addictive
	• Methamphetamine
		○ Target = DAT, SERT-NET, VMAT
		○ Reverses transporter
		○ DA releaser
		○ Very addictive

	• Nicotine
		○ Target = nicotine receptor
		○ agonist
		○ Excitation of DA neurons
		○ 4/5 addictive

	• MDMA (ecstasy)
		○ Target = SERT> DAT, NET
		○ Reverses transporter
		○ 5HT releaser - so stimulatory on DA in NA?
		○ UNKNOWN addictive potential

Question 20

What drugs work by disinhibtion of the DA neurons in the NA?

Answer 20

• Opioids
	• CNS depressants
		○ Alcohol
		○ Benzodiazepines
	• cannabinoids

Question 21

Rate in order the fastest routes of administration for drugs of abuse

Answer 21

• Inhalation
○ Cocaine, nicotine, cannabis
○ Within 7 seconds they can feel the effects
○ Synthetic THC (dronabinol) can be delivered by nasal spray
• Intravenous
○ 15-30 seconds onset
○ Similar to orgasm in the dose that hits the brain all of a sudden
• Mucous membrane
○ Most commonly by insufflation (snorting)
○ 3-5 minutes and intense b/c bypass first pass metabolism
• Oral
○ Delayed effects, 20-30 minutes

Question 22

Do drugs with longer 1/2 lives or shorter 1/2 lives tend to be more addictive?

Answer 22

• Shorter 1/2 lives
  
  • Acutely, quick offset of drug action is more likely to lead user to frequent administrations tha tincrease likelihood of loss of control over consumption

Question 23

What does the amygdala necessarily do to create patterns of drug-seeking behavior?

Answer 23

• Once learning ahs been conditioned in the amygdala, connections back to the VTA act as a detector for anything relevant to previous drug abuse experience
• Projections from amygdala to nucleus accumbens signal that emotional memories have been triggered by internal or external cues
• Initiate impulsive-automatic-obligatory actions to find and take more drugs (like a reflex almost)
○ NET RESULT - development of drug addiction produces changes whereby the reactive reward system hijacks the normal reward circuitry

Question 24

What two mechanisms of action in addictive drugs will have the greatest potential for addictive behaviors?

Answer 24

• Increased release of dopamine

* Block of dopamine transporter