Drugs of Abuse DSA

Question 1

What is dependence?

Answer 1

compulsive use of a substance despite significant problems resulting from use

three of the following criteria must be met in a 12-month period:

1. Preoccupation with use of the chemical between periods of use
2. Using more of the chemical than had been anticipated
3. The development of tolerance to the chemical in question
4. A characteristic withdrawal syndrome from the chemical
5. Use of the chemical to avoid or control withdrawal symptoms
6. Repeated efforts to cut back or stop the drug use
7. Intoxication at inappropriate times (such as at work), or when withdrawal interferes with daily functioning (such as when hangover makes person too sick to go to work)
8. A reduction in social, occupational or recreational activities in favor of further substance use
9. Continued substance use in spite of the individual having suffered social, emotional, or physical problems related to drug use

Question 2

What is psychological dependence?

Answer 2

1. Dependency of the mind that can lead to psychological withdrawal symptoms (such as cravings, irritability, insomnia, depression, anorexia, etc)
2. Similar to the neurotic behavior patterns of the persistent coffee drinker or cigarette smoker
3. When drug use becomes compulsive, physiologic dependence and tolerance are likely to develop

Question 3

What is physiological dependence?

Answer 3

An altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome

Question 4

What is withdrawal syndrome like with hypnotics or EtOH?

Answer 4

increased anxiety, insomnia, and CNS excitability that may progress into convulsions

Question 6

What is abuse?

Answer 6

a pattern of substance use leading to significant impairment in functioning

Of dependence criteria, only 1 ssx in 9 needs to be met once in a 12 mo period

Question 7

What is addiction?

Answer 7

Analagous to psychological dependence, outdated term

compulsive, relapsing drug use despite negative consequences

• triggered by cravings that occur in response to contextual clues

Genetic component: the relative risk for addiction (addiction liability) of a drug correlates with its heritability, suggesting that the neurobiologic basis of addiction common to all drugs is what is being inherited

Question 8

What is tolerance? What happens to the dose-response curve?

Answer 8

A decrease in responsiveness to a drug following repeated exposure

The dose response curve shifts to the right

Question 9

What are the mechanisms for tolerance?

Answer 9

pharmacokinetic changes (reduction in drug concentration or shorter duration of action due to changes in drug metabolizing enzymes)

or

pharmacodynamic (changes in receptor function)

Example drug: diazepam

Question 10

What is sensitization? What happens to the dose-response curve?

Answer 10

increase in response with repetition of the same dose of the drug

(also known as reverse tolerance)

Conditioning is a form of sensitization

The dose-response curve shifts to the left

Question 11

What is a good example drug for sensitization?

Answer 11

cocaine

• repeated daily administration to rats causes an increase in motor activity that increases over several days even thought the dose remains constant

Question 12

Explain how dose-response curve shifts for tolerance and sensitization and why.

Answer 12

tolerance - shift of the curve to the right

doses higher than initial doses are required to achieve the same effects

sensitization - leftward shift of the curve

for a given dose, there is a greater effect than seen after the initial dose

Question 13

What is withdrawal? What is it evidence of?

Answer 13

adaptive changes that become fully apparent once drug exposure is terminated

The only actual evidence of physical dependence

Question 14

What causes withdrawal? How does it work with EtOH?

Answer 14

readaptation of the CNS to the absence of the drug of dependence

Example: decreased expression of GABA_A receptors and increased expression of NMDA receptors due to chronic ethanol exposure causes hyperarousal of the CNS during ethanol withdrawal

Question 15

Explain how the mesolimbic DA system works.

Answer 15

Originates in the ventral tegmental area (VTA)

projects to the nucleus accumbens, the amygdala, the hippocampus, and the prefrontal cortex

Most projections of the VTA are DA-producing neurons: large quantities of DA are released in the nucleus accumbens and the prefrontal cortex when the DA neurons of the VTA are activated

Question 16

What is the relationship between addictive drugs and the mesolimbic DA system?

Answer 16

Mesolimbic DA = Prime target of addictive drugs

As a general rule, all addictive drugs activate the mesolimbic DA system

Question 17

What is the dopamine hypothesis of addiction/DA reward pathway?

Answer 17

Dependence-producing drugs activate the mesolimbic DA system, releasing DA

The pleasure-related (hedonic) effect results from activation of this pathway

not from a subjective appreciation of the diverse other effects (such as alertness or disinhibition) that the drugs produce

Question 18

What is the evidence for the DA hypothesis of addiction?

Answer 18

Deletion of dopamine D₂ receptors in mice eliminates the reward properties of morphine without eliminating other opiate effects

D₂ receptor deletion does not prevent the occurrence of physical withdrawal symptoms in morphine-dependent animals, suggesting that the dopaminergic pathway is responsible for the positive reward but not for the negative withdrawal effects

Question 19

We know all addictive drugs activate the DA reward pathway, but do all the drugs target the same thing?

Answer 19

No,

Three classes of molecular targets have been identified:

G_io-coupled receptors

Ionotropic receptors (ion channels)

Monoamine transporters

Question 20

What drugs activate GPCRs?

Answer 20

opioids

cannabinoids

GHB

LES, mescaline, psilocybin

Question 21

What are the drugs that bind to ionotropic receptors and ion channels?

Answer 21

nicotine

alcohol

benzodiazepines

phencyclidine

ketamine

Question 22

What are the drugs that bind to transporters of biogenic amines?

Answer 22

cocaine

amphetamine

ecstasy

Question 23

Which drugs are highly addictive?

Answer 23

1-5 = relative risk of addiction, 1 being least and 5 being highest

5 = cocaine and amphetamine

4 = opioids, nicotine

3 = EtOH, benzos

2 = cannabinoids

1 = LSD, mescaline, psilocybin, phencyclidine, ketamine

Question 24

Which drugs have an unclear addiction risk?

Answer 24

GHB

ecstasy

Question 25

What are the classic presenting symptoms of someone who has abused a drug that activates Gio-coupled receptors?

Answer 25

includes opioids, cannabinoids, GHB **Classic presenting symptoms** include: depressed mental status, decreased respiratory rate, decreased tidal volume, decreased bowel sounds, miotic (constricted) pupils

Question 26

What are the classic presenting symptoms of someone who has ingested a drug that acts via ionotropic receptors?

Answer 26

includes nicotine, EtOH and benzos and barbituates

Question 27

How do nonaddictive drugs of abuse work?

Answer 27

Nonaddictive agents primarily target cortical and thalamic circuits rather than the mesolimbic dopamine system - therefore alter perception without causing sensations of reward and euphoria Animals will not self-administer hallucinogens, suggesting they are not addictive in nature Includes lysergic acid diethylamine (LSD), mescaline, psilocybin, phencyclidine, ketamine

Question 28

What are the neuropsychiatric effects of LSD, mescaline, psilocybin?

Answer 28

distortions of time perception, visual illusions, euphoria, depersonalization, and synesthesia (ie, a blending of the senses), where users report "hearing" colors or "seeing" sounds; sympathetic activation is common, but usually mild

Question 29

What are the psychedelic effects of PCP and ketamine? Are they completely nonaddictive?

Answer 29

effects last for about 1 hour; include increased blood pressure, adrenergic stimulation, impaired memory function, disorientation, nystagmus, and visual alterations animal research shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents

Question 30

What are some long-term effects of PCP and ketamine?

Answer 30

consistent use can have long-term effects PCP may lead to irreversible schizophrenia-like psychosis LSD can cause flashbacks of altered perception years after consumption

Question 31

What are the presenting symptoms of someone who has used opioids?

Answer 31

depressed mental status, decreased respiratory rate, decreased tidal volume, decreased bowel sounds, miotic (constricted) pupils

Question 32

How do opioids work within the brain?

Answer 32

activate Gio-coupled receptors: cause disinhibition of DA neurons In the VTA, µ opioids cause an inhibition of GABAergic inhibitory interneurons (via decreased adenylyl cyclase) - leads to a disinhibition of dopamine neurons µ receptors cause euphoria when activated and are implicated in the reward effects of opiates

Question 33

What are some commonly abused µ opioids?

Answer 33

morphine, heroin, codeine, oxycodone, and meperidine

Question 34

What are the withdrawal symptoms of mu opioids?

Answer 34

intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, fever

Question 35

What are the treatments for opioid overdose or addiction? How do they work?

Answer 35

**Naloxone** **MOA**: pure opioid antagonist that reverses effects of opioids within minutes **Natrexone** **MOA: long-acting** pure opioid antagonist; oral administration **Methadone** **MOA:** Long-acting opioid used for substitution therapy (half-life 25-52 hrs)

Question 36

What are the presenting symptoms of someone who has used cannabinoids?

Answer 36

tachycardia, hypertension, tachypnea, conjunctival injection (red eye), dry mouth, increased appetite, nystagmus, ataxia, slurred speech

Question 37

What does chronic use of cannabinoids result in?

Answer 37

dependence with a mild and short-lived withdrawal syndrome (includes restlessness, irritability, mild agitation, insomnia, nausea, cramping)

Question 38

Why are THC analogs used as medicine? Which ones are used?

Answer 38

THC-induced effects of increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain used as Tx **Dronabinol:** anorexia and weight loss in AIDS patients and cancer chemotherapy-induced nausea and vomiting **Nabilone:** treatment of refractory nausea and vomiting associated with cancer chemotherapy, adjunct in chronic pain management **Epidiolex:** liquid formulation of plant-derived cannabidiol (CBD), a non-psychoactive cannabinoid, experimental treatment for pediatric epilepsy syndromes

Question 39

How does GHB work?

Answer 39

GHB produced during metabolism of GABA, endogenous function is unknown GHB targets GABA_B receptors on both GABA and DA neurons, but those on GABA neurons are more sensitive to GHB and lead to disinhibition of DA neurons when activated Recreational use only inhibits GABA neurons - higher doses GHB hyperpolarizes DA neurons and inhibits DA release Activates the GABA_B receptor with low affinity

Question 40

What are the effects of GHB?

Answer 40

Activates the GABA_B receptor with low affinity and produces euphoria, enhanced sensory perceptions, feelings of social closeness, and amnesia before causing sedation and coma (originally introduced as a general anesthetic) Also known as liquid ecstasy or the date rape drug (has been used in date rapes because it is odorless, readily dissolved in beverages, reaches maximal plasma concentration 20-30 minutes after ingestion, and has an elimination half-life of 30 minutes)

Question 41

How does nicotine work?

Answer 41

selective agonist of the nicotinic acetylcholine receptor (nAChR) Neuronal nAChRs are expressed on DA neurons in the VTA; activation fulfills the DA requirement of addictive drugs

Question 42

How is nicotine addiction treated?

Answer 42

Though highly addictive, withdrawal is mild compared with opioid withdrawal and involves irritability and sleeplessness **Nicotine**: gum, lozenge, inhalers, transdermal applications **Bupropion**: likely includes direct receptor effects as well as inhibition of dopamine and norepinephrine reuptake transporters May reduce cravings by increasing dopaminergic activity in the mesolimbic pathway Used alone or in combination with nicotine-replacement therapy and/or behavioral therapy **Varenicline**: derivative of the plant-extract cytisine, partial neuronal nAChR agonist Only approved for treating smoking cessation Prevents nicotine stimulation of mesolimbic dopamine system associated with nicotine addiction May impair the capacity to drive and has been associated with suicidal ideation