Drugs of Abuse

Question 1

Substance Use Disorder

Answer 1

• A problematic pattern of use leading to significant impairment or distress
• Pharmacological profile of the abused agent < Psychosocial aspects driving the abuse
• Cluster of cognitive, behavioral, and physiological sx indicating that the individual continues using the substance despite significant substance related problems
• Drug seeking behavior is a critical element of substance abuse disorder

Question 2

Innate Tolerance

Answer 2

Pre-existent tolerance due to genetic variability

Individuals w/ lower innate sensitivity to ethanol are at higher risk for alcoholism

Question 3

Acquired Tolerance

Answer 3

• ↓ Effect of a substance that develops after continued use
• Dose response curve shifts right ⇒ more substance is required to achieve the same effect
• Drug toxicity curve shifts less than the psychopharmacological effect
  
  • Ex. Opiods: brain respiratory centers tolerance < psychopharmacologic effects ⇒ pt ↑ dose to achieve the same effect ⇒ ↑ risk of respiratory depression

Question 4

Pharmacokinetic Tolerance

Answer 4

Body’s ↑ capacity to metabolize or excrete the drugs

Ex. chronic ethanol consumption ⇒ induction of the mixed ethanol microsomal oxidizing system (cytochrome p450 system) ⇒ ↓ levels of ethanol in the body

Question 5

Pharmacodynamic Tolerance

Answer 5

Refers to neuronal adaptation, resulting in a reduced response to the substance

Degree of tolerance via this mechanism is much greater than pharmacokinetic tolerance

Question 6

Short-term

Pharmacodynamic Tolerance

Answer 6

Refers to neuronal adaptation, resulting in a reduced response to the substance

Short-term tolerance ⇒ ∆ in neurotransmitter release or receptors

Question 7

Long-term

Pharmacodynamic Tolerance

Answer 7

Refers to neuronal adaptation, resulting in a reduced response to the substance.

Long-term tolerance ⇒ neuroadaptive changes 2/2 ∆ gene expression responsible for the action of the drug

May explain the cravings that occur after the drug has been discontinued

ETOH example:

• ETOH acutely ⊕ GABA receptors and ⊗ NMDA receptors
  
  • Leads to dec. excitability
• Long-term exposure
  
  • ∆ in subunit structure of GABA receptors ⇒ dec. sensitivity
  • Phosphorylation of NMDA receptors ⇒ enhanced conduction Ca²⁺
• Changes are in the opposite direction of the acute effect

Question 8

Learned Tolerance

Answer 8

There are two types:

• Behavioral Tolerance
  
  • Changes in behavior to accommodate to the drug’s effects
• Conditioned Tolerance
  
  • Environmental cues associated w/ the drug, which elicit reflexive compensatory changes
  • Ex. drug paraphernalia may elicit pre-emptory compensatory changes to counteract the drug
  • A drug taken in a familiar environment may have a lethal effect if taken in an unfamiliar environment

Question 9

Physical Dependence

Answer 9

Related to tolerance and neuroadaptation

• Substance use disorders ⇒ need the drug to be present to maintain “near” normal functioning
• Removal of drug ⇒ an acute w/d syndrome
  
  • Lasts days while the system is re-equilibrating to the absence of drug
  • Acute phase is mediated by signal transduction systems at the cellular level
• After the acute phase, a protracted w/d syndrome occurs which may continue indefinitely
  
  • Manifested as craving for the drug
  • Likely due to dysregulation of learning and reward systems in the brain

Question 10

Psychological Dependence

Answer 10

• This type of dependence is mediated by a common neuronal pathway that leads to reinforcement
• All drugs of abuse ↑ dopamine release from ventral tegmental area → nucleus accumbens
• Peak of dopamine release in the nucleus accumbens corresponds w/ peak drug effect on CNS
• Important in the brain reward pathway, ⊕ of nucleus accumbens reinforces motivated behavior and learning/memory via links to other parts of the brain
• Long-term dependence after w/d is over due to an
• *interaction between the reward and memory circuitry**
• Cues in the environment can generate intense cravings and relapse

Question 11

Substance Use Disorders

Factors

Answer 11

Variables affecting development:

• Pharmacokinetics
  
  • The more rapid the rise of drugs in the brain, the
• *greater activation of reward pathways**
  
  • Heroin rapidly enters the brain ⇒ more addictive than morphine
  • Cocaine:
    
    • Chewing on coca leaves has a relatively low potential for addiction
    • Inhaling extracted cocaine through the nasal mucosa is more reinforcing
    • The most reinforcing and therefore, most addictive are intravenous injections or inhalation of smoked freebase
    • This leads to the most rapid rise in cocaine concentration
• Genetics
  
  • Most studied in alcoholism
    
    • Inheritance may account for 50-60% of variability in this disorder
  • Polymorphisms in alcohol dehydrogenase and acetaldehyde dehydrogenase ⇒ ↑ levels of acetaldehyde ⇒ flushing and other sx which are aversive
  • Individuals w/ this polymorphism would be less likely to develop alcoholism
• Psychiatric Disorders
  
  • Association between psychiatric disorders and substance abuse disorders
  • Individuals w/ major depressive disorders are 2-3x more likely to have a substance abuse disorder
  • A large proportion of addicts self-medicate to reduce distress associated w/ co-occurring psychiatric and medical disorders
  • These conditions are then further exacerbated by the continued substance abuse

Question 12

Opioids

Answer 12

• CNS Depressant
• Multiple inputs into the reward circuits of the brain
• Opioids are co-abused w/ other drugs w/ different pharmacological actions
  
  • Heroin + cocaine = “speedball”
• Shows significant tolerance
• Drug should be tapered when discontinued to avoid severe w/d sx

Question 13

Barbiturates and Benzodiazepines

Answer 13

• CNS Depressant
• Euphoric feelings occur early in intoxication and may contribute to the abuse potential
• Anxiolytic properties may also contribute to their abuse liability
• Often co-abused w/ other drugs, e.g. ethanol
  
  • Combo w/ ethanol can cause respiratory depression and death

Question 14

Alcohol

Answer 14

• CNS Depressant
• Alcoholism is the most prevalent drug problem in the US, because it is readily available, affordable and legal
• It has complex mechanism of action, involving GABA, NMDA, and cannabinoid receptors

Question 15

Nicotine

Overview

Answer 15

CNS stimulant

• Mechanism of Action:
  
  • Activates nicotinic receptors in the body, CNS, periphery, and NMJ
  • ⊕ of nicotinic receptors in VTA ⇒ dopamine release in the nucleus accumbens ⇒ activates reward pathway
  • Inhaled and has a short half-life
  • High addiction potential
• CNS Effects:
  
  • Nicotine is rapidly distributed into the brain
  • ⊕ of nicotinic receptors in the CNS has anxiolytic effects, ↑ arousal, and suppresses appetite

Question 16

Nicotine

Metabolism

Answer 16

• Parent compound w/ short half-life
• Metabolized to the active metabolite cotinine ⇒ half-life of 2 hours
• Tars in cigarette smoke cause an induction of cytochrome p450 ⇒ ↑ metabolism of nicotine + drugs (ex. B-blockers)
  
  • Smokers may require higher doses of these agents

Question 17

Nicotine

Withdrawal

Answer 17

• Leads to irritability, anxiety, autonomic arousal, and intense craving
• Treatment:
  
  • Nicotine replacement therapy
    
    • Chewing gum, lozenges, or transdermal patches
  • Varenicline
    
    • Partial agonist @ α4β2 nicotinic receptor
  • Bupropion (antidepressant)
    
    • Enhances dopamine release in the nucleus accumbens

Question 18

Nicotine

Long-term Effects

Answer 18

Cancer, heart disease, and COPD

Question 19

Amphetamine/Cocaine

Mechanism of Action

Answer 19

CNS stimulant

• Cocaine
  
  • ⊗ Reuptake monoamines in the presynaptic terminal
  • Most effective at blocking reuptake of dopamine
  • Can also block NE and 5-HT transporters @ higher concentrations
• Amphetamine
  
  • Substrate for the monoamines transporter
  • Enters the synaptic terminal ⇒ displaces primarily NE from the vesicles
  • NE then exits the synaptic terminal through the reversal of the transporter
  • Amphetamine causes the release of norepinephrine
  • Other neurotransmitter systems are affected but less so

Question 20

Amphetamine/Cocaine

CNS Effects

Answer 20

• Locus ceruleus contains noradrenergic cell bodies
  
  • Diffuse projections throughout the brain
  • Descending projections to the medulla and the spinal cord
  • Cocaine and amphetamine enhance the actions of norepinephrine released from these projections ⇒ ↑ arousal and vigilance
• Also enhance the release of dopamine within the nucleus accumbens ⇒ activates the reward pathway
  
  • Initial effects: profound sense of well-being, energy, and optimism
    
    • Contributes to abuse potential
  • Initial effects can progress to psychomotor agitation, paranoia and psychosis
  • Cocaine has more euphoric effects initially d/t release of dopamine ⇒ effect is relatively short lived
  • Cocaine can alter tactile sensation, causing the user to feel insects crawling below the skin ⇒ “cocaine bugs”
  • Effects of amphetamine are more prolonged

Question 21

Amphetamine/Cocaine

Withdrawal

Answer 21

• Characterized by listlessness, drowsiness, and depressed mood, dysphoria and anhedonia
• Sx occur upon w/d of the drug but is not classic w/d because re-administration of drug does not alleviate sx
• W/d sx may occur in the presence of the drug, because of a phenomenon called tachyphylaxis
  
  • Occurs when the target becomes less responsive to the drug
  • Most likely due to depletion of neurotransmitters
• Very difficult to treat because of the tachyphylaxis and other neuroadaptive factors

Question 22

Methamphetaminea

Answer 22

CNS stimulant

• _Related to amphetamin_e, however, by comparison, it causes more dopamine release
• Crystal form of methamphetamine can be smoked, resulting, very rapid rate of dopamine release in the nucleus accumbens
  
  • Enhances the abuse potential of the drug
• Cheap cost and wide availability have led to widespread abuse of this agent

Question 23

3,4-methylenedioxymethamphetamine

(MDMA)

Answer 23

CNS stimulant

• Also known as “ecstasy”
• Similar effects to methamphetamine on dopamine
• Primary effect is ↑ serotonin release and ⊗ synthesis and reuptake of serotonin
• Actions ↑ serotonin release but ultimately lead to the depletion of serotonin
• May be neurotoxic to a subpopulation of serotonergic neurons
• This agent has stimulant as well as hallucinogenic properties

Question 24

Caffeine

Answer 24

CNS stimulant

• A methylxanthine
  
  • Found in many beverages and chocolate
• ⊗ presynaptic adenosine receptors ⇒ normally ⊗ release of dopamine and norepinephrine
  
  • Results in enhanced dopamine/norepinephrine release ⇒ stimulatory effect
• Adenosine is thought to promote sleep, so caffeine works to counteract this effect
• W/d sx are mild, but may include lethargy, irritability and headache

Question 25

Cannabis Mechanism of Action

Answer 25

_Psychoactive Drug_ * Active component is **tetrahydrocannabinol (THC)** * **Partial agonist at the cannabinoid receptor (CB1)** * THC mimics **anandamide** ⇒ endogenous ligand derived from arachidonic acid * Made in **activated dopaminergic neurons of VTA** by ***diacylglycerol lipase*** * Acts as a **retrograde neurotransmitter** on **presynaptic GABAergic neuron** ⇒ ⊗ their inhibitory action * Disinhibition of these interneurons ⇒ **release of dopamine within the nucleus accumbens**

Question 26

Cannabis CNS Effects

Answer 26

* Rapidly causes **euphoria, laughter, giddiness, and a feeling of detachment** * After 1-2 hours, **cognitive functions are compromised** and individual has **trouble concentrating** * Known as the “**mellowing phase**” * _High doses_ cause **panic reactions, perceptual distortions, and changes in perception of reality** * This drug or its synthetic derivative, **dronabinol** is used to **treat nausea and stimulate appetite**

Question 27

Cannabis Tolerance & Withdrawal

Answer 27

* **Tolerance** can occur via the **down regulation of CB1 receptors** * W/d sx are mild because of the **large volume of distribution** and **long half-life** * Sx can include **insomnia, loss of appetite, irritability and anxiety** * Treatment: CB1 antagonist was taken off the market because of adverse effects

Question 28

Synthetic Cannabinoids

Answer 28

* Sometimes called K2 or Spice products * Normally marketed as herbal material laced w/ synthetic cannabinoid (not a natural product) * Synthetic derivatives are **full agonists at the CB1 receptor** ⇒ more potent than THC * These are not safe or legal alternatives to marijuana * **Significant CNS and cardiovascular toxicity**

Question 29

Lysergic Acid (LSD)

Answer 29

**Synthetic ergot derivative** * **⊕** **serotonin-2 receptors** in _cortical layers_ ⇒ **↑** **glutamate release** * Mesolimbic dopamine system is not targeted * Usually causes **visual hallucinations** but may also cause other types * Some report **synesthesia** ⇒ condition where one sensory modality assumes the characteristics of another * Ex. colors may be heard * **Little effect on cognitive function or arousal** * **Mood changes** are usually pleasant but can be terrifying and cause a panic attack ⇒ “bad trip”

Question 30

Mescaline

Answer 30

Found in the Peyote cactus Similar mechanism of action to LSD

Question 31

Psilocybin

Answer 31

From the species of mushroom **Psilocybin coprophilia** that grows on cow dung Similar mechanism of action to LSD

Question 32

Phencyclidine | (PCP)

Answer 32

* Originally developed as a **dissociative anesthetic**, similar to ketamine * Taken off the market due to **post-anesthetic hallucinations and delirium** * It sometimes called “**angel dust**” because it may be sprinkled on other products * **⊗** **NMDA glutamate receptors** on _GABA interneurons_ ⇒ **disinhibition of pyramidal neurons** ⇒ **↑ glutamate in the cortex** * It can cause **euphoria, hallucinations, and psychotic behavior** * Sometimes accompanied **hostility and violent behavior** * Thought to provide a model for psychotic behavior