Pharmacology-Neurobiology of Substance Abuse

Question 1

Likely reaction to 1st doses of opiates

Answer 1

Nausea and emesis

Question 2

Effects of opiates. “Side-effects”?

Answer 2

Rush in 1st few minutes, euphoria for an hour or 2, sedation and analgesia for 2-4 hours. Side-effects include respiratory depression, loss of consciousness, endocrine/immune disturbances and constipation. Note that these are decent anesthetics because they don’t depress the heart.

Question 3

Neural pathway that mediates reward and behavior reinforcement

Answer 3

VTA -> NAc by DA release

Question 4

Neural pathway that mediates the cognitive aspects of reward and learning

Answer 4

VTA -> PFC by DA release

Question 5

Neural pathway that mediates habit learning and compulsive behaviors

Answer 5

SN -> Caudate/Putamen by DA release

Question 6

Neural pathway that mediates arousal, alertness and focus of attention

Answer 6

LC -> forebrain/cerebellum by NE release

Question 7

Neural pathway that mediates mood and visual function?

Answer 7

RN -> forebrain/cerebellum by 5HT

Question 8

DA pathways in the brain

Answer 8

DA fibers project from the VTA (1) to the NAc (2), PFC (3) and extended amygdala (4).

Question 9

How do the VTA and NAc work together? What is the implication of this interaction for drug abuse?

Answer 9

VTA has dopaminergic neurons with GABA a and b receptors and GABA neurons with D2 and morphine receptors. There are regulatory enkephalin neurons that bind to the morphine receptors on the GABA neurons, inhibiting the release of GABA and increasing release of DA from the dopaminergic neurons in the VTA onto the NAc. Basically, morphine turns off GABA feedback inhibition on DA neurons.

Question 10

Why do people on opiates have difficulty focusing attention?

Answer 10

They suppress release of NE from locus ceruleus pathways to the forebrain and spinal cord.

Question 11

Physiology of opioid withdraw

Answer 11

DA pathways are less active when opiates are not suppressing the GABA inhibitory neurons -> less neural stimulation/reward. Locus ceruleus is more active than when on opiates and NE release increases -> anxiety. Some of the symptoms can be relieved by reducing NE release and potentiating DA release.

Question 12

Features of dependence to opiates

Answer 12

Cross-tolerance to other centrally acting opiates, physical dependence and withdraw syndrome after discontinuation of drug or administration of naloxone (opiate antagonist). This sometime presents as “goosebumps” after naloxone injection.

Question 13

Why do morphine and heroin have similar withdraw symptoms?

Answer 13

Heroin is diacetyl morphine, it is converted to 6 mono acetyl morphine and morphine in the liver.

Question 14

What opiate has a more rapid withdraw period? What has a slower and less intense withdraw period?

Answer 14

Rapid = meperidine. Slow and less intense = methadone.

Question 15

Psychological symptoms of opioid withdraw

Answer 15

Severe craving w/ repeated attempts to get more drugs for months to years, exaggerated claims to withdraw discomfort/dangers

Question 16

A child is born with irritability, excessive high pitched crying, tremors, violent sucking on fists, hyperactive reflexes, increased bowel activity, vomiting and fever. What drug was the child’s mom likely addicted to? How do you treat the baby?

Answer 16

This is opiate withdraw of the newborn. The baby can be treated with small amounts of opiate.

Question 17

Conditioned withdraw syndrome

Answer 17

Induced by return to an environment in which drugs have previously been used…same features of opiate withdraw

Question 18

How does opiate tolerance develop?

Answer 18

1) u opioid receptors are desensitized (accumulate in phosphorylated state and do not return to membrane as quickly) 2) Receptors are down regulated 3) Opiate-regulated neurons become less sensitive to the drugs as they compensate to chronic abuse (this is why the pathway is hyperactive in withdraw)

Question 19

How does opiate dependence develop?

Answer 19

Compensatory changes are unmasked when the opiate is removed, withdraw symptoms are opposite the acute effects of the drug and withdraw is precipitated by administration of naloxone or naltrexone.

Question 20

What parts of the brain are involved in opiate addiction?

Answer 20

1) Reinforcement from the high = VTA -> NAc. 2) Drug seeking behavior = PFC. 3) Withdraw autonomic symptoms and pain = peri-aqueductal gray, locus ceruleus. 4) Anxiety, fear, dysphoria = VTA -> NAc and amygdala.

Question 21

A 35 year old woman returns for a follow-up appointment. She has had several oxycodone refills over the past six months. She claims to feel pain all over when the oxycodone wears off and that it gives her energy. She claims to have stolen morphine from her mother. What does she have?

Answer 21

Opioid dependence

Question 22

Most common cause of deaths from drug use

Answer 22

1) Cocaine 2) Opioids 3) Methadone 4) Synthetic narcotics 5) Heroin

Question 23

Common cause of death in patients who abuse methadone

Answer 23

Arrhythmias from long QT

Question 24

Acute physiologic changes with ethanol toxicity

Answer 24

Inhibition of NMDA cation currents prevents glutamate release and decreases neuronal excitability. Potentiation of GABAa receptors activated Cl currents and facilitates hyperpolarization and reduces excitability. It may also increase adenosine levels in the NAc, causing ataxia.

Question 25

Why is decision making impaired in the drug addicted brain?

Answer 25

There is increased stimulation coming to and from the NAc and VTA, releasing inhibitions.