Neurobiology Of Drug Addiction Exam 2 Part 2

Front 1

What is characteristic of fixed schedules? What is characteristic of variable schedules?

Back 1

Fixed: results in pauses in responding

Variable: results in steady responding

Front 2

What is the difference in response rate between ratio versus interval schedules of reinforcement?

Back 2

Ratio: result in high rates of responding

Interval: result in low rates of responding

Front 3

What is the best kind of schedule of reinforcement to use during the acquisition of a behavior?

Back 3

Continuous fixed schedule

Front 4

What is the best kind of schedule of reinforcement to use to maintain an established behavior?

Back 4

An intermittent schedule

Front 5

What kind of schedule of reinforcement results in the quickest rate of extinction of a behavior?

Back 5

Continuous ratio schedule

Front 6

How do opiates work?

Back 6

They increase dopamine release from VTa by inhibiting (-) GABA interneurons (-) They also inhibit the Nucleus accumbens directly.

Front 7

How does neuroadaptation with opiates happen? (Acute tolerance? Chronic use/tolerance?)

Back 7

Acute: mu receptors are rapidly desensitized --> acute tolerance.

Chronic use: NMDA (glutamate) receptors become upregulated in the Nucleus accumbens to counterbalance inhibitory effects of opioids. This leads to a tolerance to the rewarding effects of opioids. Over time, there's a downregulation of mu and delta receptors and finally, an upregulation of kappa (dynorphin) receptors.

Front 8

What are the 3 steps/long term effects of opiate use that lead to the rapid development of opiate tolerance?

Back 8

1) acute desensitization of mu (endorphin) receptor

2) Downregulation of mu receptor (within 1-2 hours): mu receptor is internalized/hidden/deactivated in the cell.

3) upregulation of dynorphin receptors.

Front 9

What is the exact sequence of events that leads to dynorphin receptors being upregulated from chronic opiate (heroin) use?

Back 9

1) Increased glutamate action in NaCC drives increases in cAMP activity.

2) Increased cAMP activity leads to increases in CREB.

3) increases in CREB leads to increases in dynorphins.

Front 10

What are the 2 cannibanoid receptors, where are they found in the body and what aspects of cannabis are they involved in?

Are they metabotropic or ionotripic?

Back 10

both inhibitory and metabotropic

1) CB1: in presynaptic axon terminal HIGHLY localized in GABA interneurons and the reward areas. Involved in the high effects (appetite stimulation, pain suppression, feeling "high", etc.)

2) CB2: mostly in immune cells in periphery. Can lead to immunosuppression (useful for inflammatory drugs).

Front 11

In what 2 ways does cannabis act on the reward system in the body? (acute level)

Back 11

1) Cannabis binds to localized CB1 receptors, which inhibit GABA release from interneurons, leading to disinhibition of VTA and more dopamine.

2) Activation of CB1 receptor leads to increases in endogenous opioid (endorphin/enkephalin) levels which further inhibit GABA interneurons, driving increased dopamine from the VTA.

Front 12

How can you get addicted/tolerant to cannabis?

Back 12

Over a couple of weeks of chronic cannabis use, CB1 receptors lower in number.

Front 13

true or false: cannabinoid receptors are the most widely expressed receptors in the brain.

Back 13

TRUE, so cannabis has a lot of effects

Front 14

What are the 2 main things that endogenous cannabinoids are involved with in the brain?

Back 14

1) regulating adaptation to stress/stress response.

2) regulation of D2 receptors in brain (reduces drug seeking behavior)

Front 15

True or false: endocannabinoids are retrograde messengers?

Back 15

TRUE; they go from the postsynaptic terminal to the presynaptic terminal to bind to presynaptic receptors (CB1) (inhibiting voltage-gated Ca2+ channels and letting K+ flow out of cell --> hyperpolarization).

Front 16

What does FAAH do?

Back 16

metabolizes endocannabinoids once they're taken up by POSTsynaptic transporter proteins. (note: endocannabinoids are not stored in vesicles)

(remember: endocannabinoids are retrograde messengers)

Front 17

What are the 2 (3) ways by which cannabis lowers pain?

Back 17

1) In brain, it inhibits GABA --> drives serotonin release --> lowers pain perception

2) In the spinal cord, it enhances inhibitory effects of glycine, preventing pain-sensing fibers from delivering pain signal to brain.

(3) Cannabis is a TRPV1 agonist, BUt it causes the receptors to be taken into the cell and deactivated (lowered pain)

Front 18

What is the difference between precipitated withdrawal and spontaneous/protracted withdrawal?

Back 18

1) precipitated withdrawal: giving a drug antagonist

2) spontaneous withdrawal: stopping drug administration

Front 19

Why do animals addicted to cannabis show precipitated withdrawal but not spontaneous/protracted withdrawal?

Back 19

THC is stored in the fat

Front 20

What is FAAH's role in the potential of cannabis as a "gateway" drug?

Back 20

People with a single-nucleotide polymorphism (SNP) of FAAH are more likely to use other drugs.

-suggests that the breakdown of cannabinoids (which happens in the POSTSYNAPTIC neuron) has some effect on drug taking in general.

Front 21

What role may cannabis CB2 receptors have in the rewarding effects of drugs?

Back 21

CB2 activation may reduce rewarding effects of drugs.

Front 22

What was the general take home message of the cannabis paper

Back 22

In general, cannabinoid receptors inhibit neurotransmission. Cannabis might play an epigenetic role in making offspring of cannabis users more subsceptible to drug use in general (heroin especially)

Front 23

Cocaine works by blocking the auto-receptors that reuptake 3 NTs.

-What are these NTs? Which has the highest affinity?

-Cocaine's effects on which receptor drive addictive effects of cocaine?

Back 23

Blocks reuptake of:

1) Norepinephrine (lowest affinity)

2) Dopamine (medium)

3) Serotonin (highest)

Dopamine is the most important one for mediating reinforcing/addictive properties of cocaine.

Front 24

Why is cocaine unique (hint: RBCs)

Back 24

it's the only drug that's autometabolized by Red blood cells (in addition to the liver, that is)

Front 25

What is the triple-whammy effect meth has on dopamine that leads it to releasing the most dopamine out of any drug?

Back 25

1) Enters presynaptic terminal and mobilizes DA vesicles to dump DA.

2) Straight-up reverses DA autoreceptors/transporter proteins so that any remaining DA in the presynaptic terminal is also spit out.

3) Because the transporter proteins are reversed, they can't do their normal function of reuptaking DA and so DA is in the synapse way longer than normal.

Front 26

How many receptors are there for Dopamine? What categories are there for these receptors?

Back 26

5 receptors that fall into 2 categories: D1 and D2-type receptors.

Front 27

What 2 responses to cocaine can you observe in D1 knockout mice?

What 2 responses to cocaine can you observe in D2 knockout mice?

What do these results suggest?

Back 27

1) D1:

-lowered motor responses to stimulants

-lowered rewarding response to stimulants (but reward responses from food/opiates remained normal)

2) D2:

-lowered motor response to stimulants

-increased addiction vulnerability to stimulants.

Conclusion: D1 receptors may play a bigger role in the rewarding effects of cocaine than D2 receptors.

Front 28

What role do glucocorticoids play in the dopaminergic response to cocaine?

Back 28

If you take out adrenal glands that release glucocorticoids, self-administration behavior decreases.

Front 29

What is the role of PSD-95 in stimulant sensitization?

Back 29

PSD-95 knockout mice do not experience sensitization, so the PSD-95 protein might be associated with sensitization.

Front 30

What causes the neurotoxicity of stimulants?

Back 30

Dopamine oxidation which leads to free radicals that damage tissues.

Front 31

What is alcohol's role in messing with the SCN/natural body clock's rhythms?

give example

Back 31

Glutamate mediates the phase-shifting effects on light and alcohol has direct effects on the NMDA/glutamate receptors located on the SCN.

-example: If you give a glutamate pulse (usually happens after light exposure) to someone AND pair it with the alcohol equivalent of 1 cocktail, the phase-shifting effects of light/glutamate are blunted.

Front 32

True or false: cocaine has permanent effects on the SCN?

Back 32

TRUE

Front 33

How do we know that cocaine acts to reset the SCN clock via a serotonin pathway?

Back 33

If you give an SCN cocaine, you see a 3-hour advance in the clock but if you pair cocaine with serotonin administration at the same time, the phase shifting effect of cocaine is blocked.

Front 34

What did Dr. Glass's study on the male offspring of father mice who took cocaine show?

Back 34

Male (not female) offspring show blunted phase shifting effects from light pulses.

Front 35

What does the COMT enzyme do?

What is it's potential role in linking cannabis use to schizophrenia risk?

Back 35

It breaks down dopamine (and other catecholamines).

People with a polymorphism where one (or both) of the Valines in COMT are replaced with met (methionine) have LOWER COMT function.

People who are homozygous (val/val) for the valine version of COMT gene have highest functioning of COMT enzyme and are HIGHEST risk for developing schizophrenia (maybe because of lower dopamine availability?)

Front 36

1) How can methadone be used to mitigate the effects of opiates?

2) how can Buprenorphine be used to mitigate the effects of opiates?

3) How can Nalaxone be used to mitigate the effects of opiates?

Are these drugs for opioid treatments opioid receptor agonists, partial agonist/antagonists, or full antagonists?

Back 36

1) Methadone: agonist.

-Has a much longer half-life than opiates, which can give milder feelings of pleasure to wean someone off opiates.

2) Buprenorphine: partial agonist/antagonist

-Partially activates the receptors, but also competitively blocks the receptors so that opiates can't bind.

3) Naloxone: full antagonist

-Completely blocks opiate receptors (especially Mu). It has a short half life and is used for short-term, rapid detox.

Front 37

What are 4 (5ish) main long term neuroadaptations/long term effects of cocaine use?

Back 37

1) In the NaCC, CREB gets upregulated which means dynorphin production goes up.

2) Some cells in the prefrontal cortex die (not as much as in meth, though)

3) Permanent alterations in circadian rhythm (blunted photic phase shift effects) due to cocaine's effects on the serotonin pathway.

4) epigenetic effects on circadian rhythm of male offspring of cocaine-using fathers:

-blunted phase-shifting effects from light pulses

-male offspring actually prefer cocaine less.

Front 38

What are the main (4ish) long term effects of methamphetamine use?

Back 38

Basically, huge downregulation of ALL dopamine activity and response.

1) Loss of DA axons and terminals

2) Reduced DA levels

3) Reduced #s of DA transporters and Tyrosine hydroxylase (makes DA) in NaCC

4) Cell death in prefrontal cortex

Front 39

What is the main behavior associated with cocaine? What's the main withdrawal symptom?

Back 39

Behavior: Repetitive behaviors

Withdrawal: Exhaustion

Front 40

What's the main behavior and withdrawal symptom associated with Heroin?

Back 40

Behavior: Feelings of intense well-being

withdrawal: Increased pain sensitivity

Front 41

What's the main behavior and withdrawal symptom associated with alcohol?

Back 41

Behavior: reduced anxiety

Withdrawal: seizures

Front 42

What's the main behavior and withdrawal symptom associated with marijuana?

Back 42

behavior: slowed perception of time

Withdrawal symptom: mild irritability

Front 43

What was the main implication/conclusion of the research paper on opioids?

Back 43

GLT-1 transporter protein could be critical in heroin relapse (potentially all drug)

-GLT-1 normally prevents glutamate spillover in the synapse; in other words, it clears excess glutamate.

Excess glutamate is positively correlated with heroin relapse.

Front 44

1) What is the main hypothesis tested from the paper on Cannabis?

2) What was the main mechanism discussed?

3) What was the main conclusion/result of the paper?

Back 44

1) hypothesis: "Epigenetic exposure of marijuana to offspring of parents who smoked could contribute to the development of neuropsychiatric disorders (addiction) in future generations"

2) Main mechanism: gave offspring of pot-using parents heroin and watched how much they lever pressed for heroin to determine addiction vulnerability. Tested glutamate, dopamine and CB1 receptors in the striatum.

3) Result: THC-exposed heroin rats showed more severe acute withdrawal and altered expression of NT receptors in the striatum (area associated with reward)

Front 45

Regarding the research paper on Alcohol:

1) What was the main hypothesis tested?

2) What was the main mechanism discussed?

3) What was the main conclusion/result of the paper?

Back 45

1) Hypothesis: Upregulated dynorphin/KOR (kappa) receptor system contributes to excessive alcohol consumption in alcoholic rats via negative reinforcement.

2) Mechanism: dynorphins and KOR (Kappa receptors) in the amygdala, which plays a big role in craving and relapse. Vapor-exposed (alcoholic) and air-exposed (non-alcoholic) mice were compared.

3) Results: During withdrawal, alcoholic rats lever press a lot more for alcohol. The alcoholic rats also had much more Dynorphin/KOR signaling. so, hypothesis supported.