Pathophysiology of Substance Abuse

Question 1

Define Abuse

Answer 1

self-administration of any drug in a culturally disapproved manner that causes adverse consequences

Question 2

Define Addiction

Answer 2

a behavioral pattern of drug abuse characterized by compulsive use of the drug and strong tendency to relapse after discontinuation

Question 3

Define Tolerance

Answer 3

state of physiologic adaptation to a drug such that higher than usual dosages are required to achieve the usual effect

Question 4

Define Sensitization

Answer 4

increased response arising from chronic use of initial withdrawal

Question 5

Define Physical Dependence

Answer 5

state of physiologic adaptation to chronic use of a drug such that abrupt reduction or cessation results in a characteristics abstinence or “withdrawal” syndrome

Question 6

Define Psychological Dependence

Answer 6

Syndrome where one feels a strong urge or “craving” for the drug to achieve or maintain the altered mood or feeling state

Question 7

Variables that influence the likelihood of a person becoming a drug abuser:

Answer 7

Cost and availability
Purity
Route of administration
Speed of entry into brain
Host and environment

Question 8

Host variables that influence likelihood of becoming an abuser:

Answer 8

Hereditary (40-60%)
Teenagers/young adults
Early exposure
Mental Illness

Question 9

Environment variables that influence likelihood of becoming an abuser:

Answer 9

Social setting and availability of reinforcers (peer pressure)
Community attitudes
Parental support

Question 10

What is the major neuronal reward pathway?

Answer 10

Mesolimbic Dopaminergic Pathway

Question 11

Mesolimbic Dopaminergic Pathway is constituted by

Answer 11

dopaminergic neurons linking the VTA (ventral tegmentum area) to the NA (nucleus accumbens) and the frontal cortex

Question 12

What does the Mesolimbic Dopaminergic Pathway do?

Answer 12

Mediates the psychopharmacology of reward, whether for a natural high or a drug-induced high
“Pleasure center of the brain” with dopamine as the pleasure neurotransmitter
-Modulated by many natural substances to deliver normal reinforcement to adaptive behaviors and to produce “natural highs”, such as feelings of joy or accomplishments

Question 13

Animal Model + Self-Stimulation

Answer 13

When an electrode is place in the NA, the rats press the bar repeatedly to receive the reward

Question 14

Animal Model + Self-Administration

Answer 14

Rats will press the lever to inject a dose of cocaine to the NA but not other drugs

Question 15

Addictive drugs + Reward Pathway

Answer 15

Drugs are positive reinforcers and increase the level of dopamine released in the mesolimbic dopaminergic pathway of the brain

Question 16

Drugs of Abuse MOA

Answer 16

Stimulate mesolimbic dopaminergic fibers AND increased DA release in the NA or otherwise modulate the circuit to enhance reward and reinforcements

Question 17

Brain’s Morphine/Heroin:

Answer 17

Endorphins

Question 18

Brain’s Nicotine:

Answer 18

ACh

Question 19

Drugs of Abuse in the Mesolimbic Pathway

Answer 19

Bypass the brain’s own neurotransmitters and directly stimulate the brain’s receptors in the reward system, causing dopamine release and a consequent “artificial high”
- No longer get a high from eating or drinking

Question 20

***Reactive Reward Pathway

Answer 20

“Little devil that pushes you to do something bad”

• VTA to amygdala cause it to develop adaptive changes to remember the reward of drug abuse by the release of DA/NA from VTA to amygdala
• Signals the immediate prospect of either pleasure or pain and provides motivation and behavioral drive to achieve that pleasure or to avoid that pain

Question 21

So what actually happens in the reactive reward pathway?

Answer 21

Memory of pleasure and memory of the environment cues associated with pleasurable experiences
Once reward learning occurs, connections go back to the VTA communicating whether anything relevant to a previous experienced pleasure has been detected

Question 22

***Reflective Reward Pathway

Answer 22

“Willpower to resist”
Built over time based upon neurodevelopment, genetics and experiences
Projections from orbitofrontal cortex, ventromedial PFC, dorsolateral PFC

Question 23

Projections from the orbitofrontal cortex (OFC) are involved in

Answer 23

regulating impulses

Question 24

Projections from ventromedial PFC are involved in

Answer 24

regulating emotions

Question 25

Projections from dorsolateral PFC are involved in

Answer 25

analyzing situations and regulating whether action should happen

Question 26

First Time Abuser

Answer 26

Release of DA in the NA caused by VTA → euphoria (reflective)
VTA also sends DA to amygdala and it will learn to like it and want to repeat it

Question 27

When cues are encountered, what happened?

Answer 27

the amygdala signals DA neurons in the VTA that something is good coming and this leads to DA release in the NA

Question 28

What happens after DA release in the NA?

Answer 28

Triggers GABA-ergic input to the thalamus
Thalamus input to the PFC and unless the reflective reward system is activated leads to action such as drug seeking behavior

Question 29

Will Power =

Answer 29

Reflective Reward System (PFC circuits)

- If this is low, the indiviudal may succumb to temptation

Question 30

Acute Addiction:

Answer 30

Drug causes release of DA in the NA and positive reinforcement of drug-seeking behavior

Question 31

Chronic Addiction

Answer 31

Continued drug use leads to adaptions of receptors and biochemical pathways

• Pharmacodynamics adaptions: receptor down-regulation
• Pharmacokinetics: stimulated metabolism and excretion

Question 32

Short-Term Abstinence

Answer 32

Withdrawal symptoms begin (mainly physical)

Question 33

Long-Term Abstinence

Answer 33

Physical addiction is gone, cravings still occur
Exposure to previous context of drug use can reactivate old memories
Treatment becomes life-long process to prevent relapse