Neuroscience of Drug Addiction Exam 2

Which routes of cocaine administration have similar absorption rates?

IV and INH

True/False: Crack cocaine is more potent than powder cocaine

False

Cocaine is a _______, and thus increases _____ signaling.

indirect sympathomimetic, NE

Which of the following is NOT a physical effect of cocaine?

- Pupillary constriction

- Increased heart rate

- Bronchodilation

- Hyperthermia

- Increased blood pressure

- All of the above are physical effects of cocaine

pupillary constriction

Cocaine's actions at which of the following targets make it a good topical anesthetic?

NET and Na+ channels

Based on discussions in class, cocaine-induced locomotor activity in mice is strongly influenced by (Select all that apply):

- D1 Receptors

- D2 Receptors

- D3 Receptors

- D4 Receptors

- DAT

- NET

- SERT

D1 Receptors and DAT

When do patients usually experience dysphoria following cocaine inhalation?

40 - 75 minutes

True/False: Stereotyped behavior is an integrated behavioral sequence that acquires a simplified character, while being performed at an increasing rate and in a repetitive manner.

True

Looking at ICSS thresholds in rats, following 40 cocaine self-injections, what is seen after 2 hours?

Dysphoria (increase in threshold)

Dr. Buczynski trains a group of rats to self-administer cocaine. Following implantation of a microdialysis probe that allows him to measure neurotransmitter release in the nucleus accumbens, he puts the rats back in the self-adminstration chamber. However, he changes the experimental conditions so that the self-administration lever is removed from the apparatus. Instead, rats receive their typical pattern of cocaine infusions without pressing a lever (non-contingent schedule). Which of the following best describes the expected changes in neurotransmitter levels in the nucleus accubens during cocaine exposure in this experiment?

Dopamine levels increase, but glutamate levels decrease

Which of the following best describes the relationship between cocaine and amphetamine?

A) Amphetamine has more efficacy than Cocaine

B) Amphetamine has less efficacy than Cocaine

C) Amphetamine has more potency than Cocaine

D) Amphetamine has less potency than Cocaine

E) Amphetamine and cocaine have similar pharmacokinetics

C) Amphetamine has more potency than Cocaine

Cocaine and amphetamines work through similar, but distinct, mechanisms of action. Which of the following are targeted by BOTH cocaine and amphetamines? (Select all that apply)

- Dopamine Transporter (DAT)

- Norepinephrine Transporter (NET)

- Sodium Channels (NaV)

- Trace Amino Acid Receptor 1 (TAAR1)

- Dopamine Transporter (DAT)

- Norepinephrine Transporter (NET)

High doses of amphetamines can cause neurotoxicity through which mechanism?

Trapping DA in the cytosol of the terminal by inhibiting transporters and oxidases

What is an example of contingency contracting?

Providing an addict with a gift voucher after successful period of abstinence

A substantial number of clinical trials have been performed to investigate all of the following as potential treatments for cocaine addiction EXCEPT:

- Acetylaldehyde DH inhibitors

- Amphetamines

- DAT partial agonists

- D2 and 5-HT2a receptor agonists

- MOR partial agonists

- KOR agonists

- KOR agonists

Which are diagnostic criteria for ADHD?

hyperactivity, impulsivity, inattention

What molecular mechanisms plays a role in ADHD?

- Higher DAT activity

- Reduced COMT activity

- Reduced MAO activity

True/False: An overexpression of the D3 receptor can be implicated in ADHD

False

Which bests describes the difference between cocaine and methylphenidate (Ritalin®)?

Pharmacokinetics: they have different half-lives

What best describes the reason mephedrone acts more like MDMA than amphetamine in vivo?

Elevates serotonin levels in vivo

Which of the following is NOT an FDA approved medical use for amphetamines?

- ADHD reduction

- Anxiolytic therapy

- Narcolepsy treatment

- Obesity reduction

- All of the above

- None of the above

Anxiolytic therapy

What is true about all drugs of abuse?

affect the DA circuit differently

Define a narcotic

drugs that blunt (rather than excite) brain activity and produce narcosis (sleepiness)

Which method of cocaine use exhibits a slow administration and elimination

PO (by mouth)

Cocaine has a half-life of _________________ and is ______________ on route of administartion

~ 60 minutes; dose-dependent

What is sympathin?

• original old-timey word for norepinephrine

• Primary mediator of the sympathetic nervous system (fight or flight)

How is cocaine considered a Direct Sympathomimetic?

Acts as an adrenergic receptor agonist (ie. NE, Phenylephrine)

What makes cocaine an indirect sympathomimetic?

Increases NE signaling (ie. cocaine, Amphetamine)

How does cocaine interact with NE?

is a NE reuptake inhibitor; blocks reuptake via NET (trapped in synapse)

Describe cocaine's use as an anesthetic

- NET inhibitor: vasoconstriction

- Na+ channel blocker: block AP's, vasodilation; local anesthetic

What can occur when cocaine blocks Na+ channels?

heart arrhythmia

Describe cocaine as a Monoamine Reuptake inhibitor

- block DA reuptake => highly elevated synaptic levels of DA

- block 5HT reuptake via SERT +> increased 5HT in synapse to bind to pre/post receptors

Rank the potent effects of cocaine on the three neurotransmitter transporters in acts on

DAT (230 nM) > NET (480 nM) > SERT (740 nM)

There is a _______________ fold increase in DA levels with cocaine

300-400

What are behavioral effects of cocaine use?

1) Simple Tasks:

Performance Typically Improves

(Example: Locomotor Activity)

2) Complex Tasks:

Performance Typically Declines

(Example: DMS Task)

Cocaine has no affect on _________________ knockout, but affects knockout of ____________________

DAT; NET and SERT

What is seen in NET and SERT KO Mice that isn't seen in DAT KO in regards to cocaine injections?

They have increased levels of LA

Why doesn't cocaine affect DAT KO?

- Animals are genetically "permanently on cocaine"; whenever DA is released into synapse, it stays there because there is nothing to reuptake it

- More DA = more locomotor activity

What is the theory behind stereotyped behavior?

increasing rate of behavior in a decreasing number of response categories (doing less things more often)

_____________ is goal directed but meaningless actions and can bee seen in Parkinson's patients given _______________________

Punding; D1 agonist stimulants (act on on D1Rs)

In the cocaine binge cycle (smoked), when is the peak euphoria?

20 min

Even in the presence of very large plasma cocaine concentration, there is a ________________ effect from ________________

temporal effect; E => D

What occurs as cocaine dose increases (ie 80 injections) in regards to binge cycle?

can go from general dysphoria to paranoia and psychosis

Compare paranoia and hallucinations

Paranoia:

inability to recognize reality from false perceptions

Hallucinations:

false perceptions of sensory experiences

Describe cocaine's effects on the different neurotransmitters as it is a monoamine reuptake inhibitor blocker.

1) SERT: increased 5HT in synapse

2) DAT: D1Rs/D2Rs activated lead to increased DA in synapse

3) NET: elevated NE levels to bind to alpha + beta receptors

What can occur during a cocaine binge?

- Euphoria

- Alleviate fatigue

- Sexual motivation

- Appetite suppressant

- Performance "enhancement"

The deletion of _____________ is responsible for changes in LA + other reward like behaviors during cocaine binge cycle

D1R

True/False: As dysphoria occurs, cocaine plasma levels are below baseline

False (can still be high)

Why can both euphoria and dysphoria be occurring during ICSS?

threshold is changing

Describe the "crash" stage of cocaine

- 9 hrs to 4 days

- Dysphoria, lethargy, insomnia, irritability, anxiety, depression

Describe the withdrawal phase of cocaine use

- 7 to 10 days

- anxiety, depression, fatigue, anhedonia, limited interest, cravings (situational)

- Can lead to relapse into cocaine binge to relieve effects

Describe the craving stage

- weeks to months

- mild dysphoria, high cravings (brief episodic or cue-induced)

- Can lead to relapse

Compare the effects of cocaine injections has on DA between naïve rodents and users?

Naïve rodents shows a robust increase (6-fold) of DA release into NAc while users is only ~50%

True/False: The dose-response curve shows a rightward shift with chronic cocaine exposure

False

The left shift of cis-Fluoenthixol doses with chronic cocaine shows a ________________ change

within-systems

Compare findings between ShA and LgA rats in regards to cocaine withdrawal

- ShA not seeing changes in reward thresholds after sessions of SA compared to LgA who show dysphoria before/after administration

In ICSS rats, immediately after withdrawal there is no changes in __________________, but a significant increase from _________________ after (anti-reward compensation)

threshold; 1-24 hrs

What was found in regards to the amygdala during micordialysis in cocaine SA rats?

- Seen that had a stable baseline of CRF that is released into extracellular space (via in-vivo micro-dialysis)

- During self-administration, don't see change in CRF during 12-hour session

- During withdrawal session, [about 3-6 hrs.in session] see a statistically significant increase in the release of CRF in the amygdala (from 3-6 through 24 hrs. into withdrawal)

Use despite negative consequences (cocaine) can be seen in animal models by ...

Rats with long-access continue to push lever despite receiving foot shock

How is disruption of normal life measured in animal models?

looking at use throughout day (pushing of lever even during normal sleeping hours)

What is true about Glutamate in self-administration?

act of pressing lever robustly increases Glu. release (even with saline) due to being a measurement of drug seeking

What occurs in regards to DA and Glu. with non-contingent cocaine administration/why?

Will have similar DA release patterns to SA (pharmokinetics the same), but a decrease in Glu. as the act of pressing lever is important

Glutamate and dopamine act on the ____________ to signal for ___________________

NAc; basal locomotor activity

With acute cocaine use, glutamate and _____________ DA act on the NAc to produce increased LA and ________________

increased; reward

What underlies cravings that lead to relapse in cocaine?

High Glutamate/low Dopamine imbalance

In cocaine abusers there is less ability of _________________of DA system due to diminished __________________ in basal ganglia

activation; D2R expression

Describe cognitive dysfunction seen in cocaine users

- Preoccupation/anticipation stage: drug seeking

- Increased Glutamate release w/DA staying the same leads to craving

_______________ is a model of relapse and shows that during abstinence there is an increase in ______________ due to withdrawal making it ____________ induced

Reinstatement; CRF; stress

In reinstatement models, what is true in regards to stress?

Increase in lever pressing despite still saline due to foot shock

Describe drug induced reinstatement

There is an increase in NE levels/adrenergic signaling

What is D-Phe

a CRF antagonist

______________ facilitate cue-induced reinstatement

Opioids

In regards to reinstatement, what is true about DOR KO?

decreased reinstatement (enkephalin is important)

MOR is a ______________ and when KO, there is a ________________ in reinstatement

Beta-endorphin; 50% reduction (drives behavior)

How is extinction made in animal models of reinstatement?

unpairing of CS and Drug

With KOR KO, there is a 2-fold ____________ in cue-induced reinstatement due to ________________

increase; dysphoria

Which of the following SUD criteria has been captured by LgA Cocaine Model?

• Tolerance

• Withdrawal

• Larger Intake

• Disruption of normal life

• Drug Seeking

• Use despite consequences

• Loss of control

• Compulsivity

• Tolerance

• Withdrawal

• Larger Intake

• Disruption of normal life

• Drug Seeking

• Use despite consequences

Compare brain imaging biomarker studies between controls and cocaine abusers

- Control: striatum with strongly expressed D1/D2 neurons

- Abuser: downregulation of D2 receptor availability (within systems plasticity)

Describe efficacy in regards to therapeutics for addiction

be able to treat addiction + reduce relapse risk

Is there currently any drug approved to treat cocaine addiction?

No, but have been six attempts

List the six attempts to treat addiction via drugs and their targets

1) Modafinil => DAT (partial inhibitor)

2) Risperidone (atypical antipsychotic) => D2 and 5HT2A receptor (antagonist)

3) Buprenorphine => MOR partial agonist, KOR+DOR antagonist

4) Naltrexone => MOR+KOR antagonist

5) Disulfiram => Acetylcholine DH (inhibitor)

6) Amphetamines (own addiction potenital)

What is true about the PK between methamphetamine and cocaine?

- Both block DAT to increase DA

- Meth is more potent

- Meth has a longer half life (60 min vs 12 hrs)

- Equally effective

Describe the PD of amphetamines

- Indirect Sympathomimetic (NET blocker)

- Elevate synaptic dopamine (DAT inhibitor)

What are the mechanisms of action of amphetamines?

1. Dopamine Transporter (DAT) Inhibitor

2. TAAR1 Agonist

3. Monoamine Oxidase (MAO) Inhibitor

4. Vesicular Monoamine Transporter (VMAT) Inhibitor

What is responsible neurotoxicity when high does of amphetamines are taken?

it being a VMAT inhibitor

Describe neuropeptide CART

• Psychostimulant increases in Nac

• Decreased in hypothalamus during fasting

• CART peptide blocks feeding in rats

• Mechanism of action unknown

__________________ changes are similar between amphetamine and cocaine use

Neuropetide

Describe binge/intoxication of amphetamines

- changes in sensory perception (i.e. skin picking due to "bugs")

- more punding like behavior as dose increases

What is true about ICSS thresholds of amphetamines in regards to withdrawal/negative affect?

increased from a day to 5-7 (similar affects to cocaine, but with longer duration until return to baseline)

What is the preoccupation stage of amphetamine abuse like?

similar to cocaine

What are treatment options for amphetamine addiction?

- Contingency contracting

- Relapse Prevention

- Behavioral therapy

- Like cocaine, no FDA approved drug

Unlike cocaine, amphetamines can have __________________

lots of therapeutic uses

ADHD can be due to having what?

too much or too little dopamine

What can be a helpful treatment to those with ADHD?

amphetamines

Describe the ADHD paradox

ADHD is marked by hyperactivity and those with it are often give stimulants which create their own hyperactivity

Those with ADHD have ______________ DAT binding; which means it is ____________________ (DA back to neuron)

more; highly expressed

As we age, where does DA go to?

the synapse

As seen in those with ADHD and young adults do increased levels of DAT indicate?

more DA release to activate D1 neurons to produce euphoria and reward

The Dopamine _____________ receptor ________________ is associated with ADHD

D4; gene polymophism

Why is there less addiction in drugs for ADHD like Adderall than other amphetamines?

is targeting the D4 receptor to heighten attention without affecting reward by hitting D1/D2