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Pmcol 305 > m2 > Flashcards

m2 Flashcards

1
Q

Amphetamine was derived from

A

Ephedra sinica

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2
Q

Traditional Chinese medicine herb Ma _
has been used therapeutically for _ years

A

huang
5000

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3
Q

_ _ synthesized alphamethylphenethylamine (amphetamine; AMPH) in 1887 to treat _

A

Lazăr Edeleanu
asthma

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4
Q

L-amphetamine (3)

A

Raises BP, opens nasal passages, causes headache

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5
Q

Raises BP, opens nasal passages, causes headache

A

L-amphetamine (3)*

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6
Q

D-amphetamine (3)
*

A

Same effects as L-form, * Also elevates mood, enhances energy*

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7
Q

Same effects as L-form, * Also elevates mood, enhances energy*

A

D-amphetamine (3)

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8
Q

meth has Increased _ solubility → increased _ and _ effects

A

lipid
potency, brain

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9
Q

types of Potency for amph (least to most):

A

L-amphetamine < D-amphetamine < methamphetamin

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10
Q

making meth: Pseudoephedrine or ephedrine from over-the-counter decongestants
- _ synthesis
- what’s the process of making meth?

A

Nagai
OTC -> hydrolic acid, red phosphorous -> meth + contaminants

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11
Q

making meth: Commercial phenylacetone
commercial phenylacetone ->

A

commercial phenylacetone -> Reductive amination or Leuckart synthesis -> meth

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12
Q

Chemical similarity to catecholamines allows
amphetamines to bind neurotransmitter _.
what are the catecholamines that are similar in shape?

A

transporters
meth, da, amph, ne

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13
Q

Amphetamines are recreational _

A

stimulants

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14
Q

METH becomes the drug of choice → extra _ group
* Slower _
*_ -intensive effects, euphoria/disphoria
* _ form, cheap/expensive

A

methyl
metabolism
CNS, euphoria
Smokeable, cheap

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15
Q

Ice is _ salt, smokeable meth → half life ~ _hours
* Ice is to METH what _ is to cocaine
(in)/Effectively absorbed from the GI tract, _ bioavailable

A

HCl, 12
crack
effectively, 70-100%

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16
Q

4 ways to consume amphs:
fastest - slowest onset

A

Ingested, injected, snorted or smoked
smoking < injection < snorting < ingesting

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17
Q

t/f: METH high lasts much longer than cocaine

A

t

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18
Q

Liver _ metabolizes METH and AMPH

A

CYP2D6

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19
Q

4-HA and norephedrine are _:

A

stimulants

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20
Q

TAAR

A

trace amino associated receptor

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21
Q
  • 4-HA activates _ , stimulates _ release and inhibits _
  • TAAR is an intracellular _
  • Monoamine oxidase (MAO) degrades monoamine NTs like _, , _
    *     reduces rate (in _% of Caucasians, _% of East and SE Asians)
A

trace amino associated receptor (TAAR), NE, MAO
GPCR
DA, NE, 5HT
CYP2D6*10
10, 75

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22
Q

Summary of AMPH/METH pharmacokinetics:
distribution (5 organs, length of onset)
absorption (4ways, bioavailability)
metabolism (enzyme, half life for meth and amph)
excretion (3 ways)

A

brain, kidney, liver, spleen, lungs, 30-120 mni
inhalation (~70%), injection, insufflation (80), ingestion (70-99)
liver CYP2D6, meth: (12+ 1/2), 10-20h duration, amph (11h 1/2), 3-12h duration
kidney, sweat, saliva

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23
Q

Acute effects of AMPHs
Euphoria, energy, aggression, grandiosity, decreased appetite
* Sympathomimetic → increased _ release
* Delusional _ (i.e. bugs under skin) and perceptual _ → increased/decreased _ release
* Locomotor activity → increased _
* _ – at high doses, repetitive meaningless behaviours; also common in _ patients
* Basal ganglia controls selection of action, too
much DA leads to more/less selectivity

A

NE
parasitosis, disturbances, increased 5HT
DA
punding, Parkinson’s
less

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24
Q

AMPHs, mechanisms of action
Elevates _, _, _, availability
* Does/Does not require DA-ergic neuron firing, unlike cocaine
* _ _ brings meth into nerve terminals
* Also enters by _
* _ pumps meth into storage vesicles

A

DA, NE, 5HT
does not
DAT transporter
diffusion
Vesicular monoamine transporter (VMAT)

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25
Q

synaptic mechanism of amph:
AMPH binds _ and enters terminal (also diffuses in)
_ degrades cytoplasmic DA, NE, 5HT
VMAT transports AMPH into _ _
* DA is displaced from vesicles into _
* MAO bound by AMPH can/cannot degrade _
AMPH-TAAR complex and cytoplasmic DA build-up reverse _
* _ leaks across terminal membrane into synapse too
* Resulting DA _ in synapse causes pre/postsynaptic cell activation

A

DAT
* Monoamine oxidase (MAO)
storage vesicles
cytoplasm
cannot, DA
DAT
DA
spike, postsynaptic

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26
Q

AMPHs cause DA surge in the _, _

A

NAc, basal ganglia

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27
Q

AMPH mechanisms differ from cocaine for 2 main reasons
Larger/smaller structure allows transporter to complete transport
* AMPH activates additional intracellular GPCR called TAAR; TAAR activates _-dependent signaling that targets _ which _ transport
* Similar effects cause increased _ and _ synaptic availability

A

smaller
phosphorylation, DAT, reverses
NE, 5HT

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28
Q

Adverse effects of acute amph use
_ from contaminants
* Combining with other drugs can enhance _ effects
* E.g. MAO inhibitors due to increased release of _, _, _

A

Poisoning
stimulant
DA, NE, 5HT

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29
Q

amph Tolerance
DA, 5HT and NE depletion via _ of these NTs from terminals
Tolerance
* Inhibition of _ _ enzyme reduces synthesis of DA and NE
*Acute dosing increases/reduces DAT function
* Causes subsequent dose to have greatly increased/reduced effects
* Lasts for _ - _

A

displacement
tyrosine hydroxylase
reduces
reduced
days or a couple weeks

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30
Q

Long-term consequences of amphetamine use (3)

A

Weight loss * Skin breakdown* Sores, picking

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31
Q

Long-term consequences of amphetamine use
Poor _ hygiene, _ decay, _ grinding tic
* Contaminants may be _ or excessive _ symptom
* Activation of _ receptors on vessels
* Activation of pre-synaptic α2 receptors on _ gland neurons → increased/reduced saliva production

A

oral, tooth, jaw
corrosive, NE
α1
salivary, reduced

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32
Q

Long-term consequences of amphetamine use
* Psychological effects are exaggerated → _
* Unprovoked _, starts to include homicidal/suicidal thoughts, extreme _ over time
* DA depletion is significant in _, _, _ - _ brain regions
* Damage to _, _, _ terminals
* As cells recover from MAO inhibition (which occurs at high/low AMPH conc.), elevated DA metabolism results in _ _ formation → damages cell membrane, proteins, mitochondria
* Excitotoxicity stresses neurons and induces _ → brain damage

A

sensitization
aggression, anxiety
movement, memory, decision-making
DA, NE, 5HT
high
reactive species
cell death

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33
Q

amph: _ levels recover in abstinent addicts,_ may not

A

DAT, function

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34
Q

amph: Neuron loss in the limbic system underlies
short/long-term symptoms
* Damage measured by reduced volume = increased/reduced number of neurons
* AMPH may trigger _ , allowing _ influx leading to _ production and cellular stress
* Blocked by nAChR _
* Seen in several conditions like (3)
* Most significant losses in _ _
* Hippocampal losses correlate with _ issues in long-term METH users
* DA-ergic neurons die and METH addicts are ~_% more likely to develop Parkinsonism

A

long-term
reduced
nicotinic acetylcholine receptors (nAChRs), Ca, reactive oxygen species
antagonists
schizophrenia, Parkinson’s, dementia
cingulate gyrus
word recall
75

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35
Q

ecstasy Synthesized in 1912 by _ at _ (a drug company)

A

Köllisch, Merck

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36
Q

_ _ published first testing in 1960 at DOW Chemicals of ecstasy

A

Alexander Shulgin

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37
Q

MDMA can be derived from natural or _ sources

A

synthetic

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38
Q

ecstasy Extracted from ( 3)

A

cured Ocotea pretiosa, Sassafras albidum, or Cinnamomum parthenoxylon root bark

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39
Q

Sassafras essential oil contains ~

A

75-85% safrole

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40
Q

_ , a.k.a. 3,4- methylenedioxymethamphetamine
* Classified as a _ , similarity to _

A

Ecstasy, hallucinogen, mescaline

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41
Q

_ ring shifts stimulant effects toward _ and _

A

Methylenedioxy, mood, perceptions

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42
Q

mdma distribution (5 organs, TI, onset)
absorption (2 ways, dosage)
metabolism (organ, amount degraded, 1/2 life, high duration)
excretion: organ, amount unchanged

A

distribution: brain, lungs, liver, kidney, spleen; onset 30-45 m
TI 14-16
absorption: ingestion, insufflation, 75-100mg dose
metabolism: liver, 80% degreaded by CYP2D6, 6 1/2, 2-3h high
excretion: kidney, 20% unchanged

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43
Q

how is MDMA consumed through ingestion and insufflation

A

ingestion: MDMA tablet/molly capsule
insufflation: molly powder

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44
Q

Acute effects of MDMA:
Empathogen, entactogen eg
* Sympathomimetic: eg

A
  • Euphoria, emotional empathy, energy, enhanced self-esteem
    increased heart rate, hyperthermia, diaphoresis
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45
Q

Physiological mechanisms of MDMA
* 5HT1B/2 agonist/antagonist → causes _ (jaw grinding), increased _
* Reverses _ transporter → involves _ mediated phosphorylation of transporter
* Also blocks _ and _ transporters
* 10x higher affinity for _ vs _ transporters

A

agonist, bruxism, locomotion
5HT
TAAR
NE, DA
5HT, NE

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46
Q

Blocking _ blocks MDMA-induced 5HT release in
_ and _

A

5HT2B, NAc, VTA

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47
Q
  • Selective block of 5HT2B _ 5HT release
  • Genetic deletion of 5HT2B _ 5HT release
A

inhibits
abrogates

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48
Q

MDMA physl mechanisms
* Increases/decreases dopamine → not very reinforcing, limited self-administration
* higher/lower breaking points, i.e. number of times animals respond to obtain drug
* Increases _ / _→ due to 5HT, involved in bonding, empathy
* Increased/decreased cortisol → 800% rise, correlates with feelings of excitement and happiness, increases _
* Shifts activation towards _ _ (thoughtfulness), decreases _ activity (fear, rage)

A

Increases
Lower
prolactin, oxytocin
Increased, blood glucose
ventral striatum, amygdala

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49
Q

how do Cephalopods exemplify pro-social effects of
MDMA

A
  • Normally asocial octopuses interact
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50
Q

t/f: Cephalopods express an evolutionarily conserved 5HT
transporter

A

t

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51
Q

MDMA Additional molecular drug targets:
Adrenergic receptors →
* Histamine type 1 receptors →
* α7 nAChR →

A

sympathomimetic effects, hyperthermia
causes ACh release, EPSPs
partial agonist, increases NT release

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52
Q

MDMA Tolerance
* increase/decrease in 5HT transporter activity (DA and NE too)
* Due to transporter expression increases/decreases
* Also depletion of _

A

decrease
decreases
neurotransmitters

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53
Q

MDMA withdrawal
* Inability to _
* t/f: Can be lethal, “suicide Tuesdays”

A

thermoregulate
t

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54
Q

MDMA dependence
* More _ than physical, 10% once/week
* Biased agonism in _ receptor agonism may underlie low addiction risk

A

psychological
5HT2C

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55
Q

Dangers of acute MDMA use :
Bad trips involve depression, anxiety, hallucinations,
paranoia -> what NT snydrome is this?
* Increased/decreased heart rate, BP
* Muscle rigidity, hyper-diaphoresis, delirium, diarrhea,
rhabdomyolysis → kidney failure, convulsion, death
* Combining with _ reduces effects of MDMA due to
competition for 5HT transporters
* Combining with MAO _ can potentiate effects of MDMA due to increased NT availability, e.g. _ _

A
  • 5HT syndrome
  • Increased
    SSRI
    inhibitors, Prozac SSRI
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56
Q

D1 receptor in preoptic anterior hypothalamus augments _ in vivo
* MDMA increases DA release in _ _ _
* D1 receptor antagonist increases/reduces DA release
* MDMA increases/decreases temperature set point
* D1 receptor antagonist _ increases in temperature

A

temperature set point
preoptic anterior hypothalamus
reduces
increases
abrogates

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57
Q

_ is the most common cause of overdose death in MDMA
* Cumulative effects from (3)
* Hyperactivity, dysregulation of _ set points

A

Hyperthermia
5HT, DA, NE
temperature

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58
Q

Dangers of acute MDMA use
* Hyponatremia – low _ in blood
* Caused by _ water intake due to _
* MDMA triggers _ release
* Can result in _ edema (swelling) → (2)

A

Na
large, hyperthermia
anti-diuretic hormone
cerebral
vomiting, respiratory arrest (compressed brainstem)

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59
Q

t/f: Adulterants are common in street ecstasy

A

t

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60
Q

t/f: some street ecstasy contain no MDMA

A

t

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61
Q

Adulterants and metabolites cause _ _ events in users
t/f: CYP enzyme metabolism differs greatly among individuals
t/f: Certain metabolites cause cell death -> how?

A

‘random’ adverse
t
t; * Individuals are more or less susceptible to adverse effects, sudden death

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62
Q

_ + _ composition may explain random toxicity when consuming MDMA
Variability in _ profiles leads to particular toxic metabolite build-up

A

Pharmacogenomics, unknown
enzyme

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63
Q

Long-term health effects of MDMA
* _ and _ deficits
* Induction of apoptosis in _ neurons via _ pathway in rats

A

Memory and attention
hippocampal, caspase-3

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64
Q

Forms of inhalants:

A

Mixtures of several lipophilic chemicals

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65
Q

eg of inhalents (3)

A

solvents, aerosols, glue

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66
Q

Administration of inhalants by inhalation (3)

A

*Huffing *Sniffing *Bagging

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67
Q

ADME of inhalants
* _ and _ distribution, similar to _
* Small _ molecules,
* [blood] = _ - _ μM, [brain] = _ - _ μM, sometimes 10x higher in _ tissue
* More volatile substances (i.e. gases under standard conditions) are mostly _ (e.g. propane, butane)
* Can increase/reduce blood pH at higher doses = _

A

Rapid, wide, anesthetics
lipophilic
150-200, 100-900, fattier
exhaled
reduce, acidosis

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68
Q

Inhalant pharmacokinetics summary
distribution (speed and distribution, 2 organs, onset)
absorption
metabolism (organ, enzyme, duration)
excretion (organ, way)

A

distribution: rapid, wide, brain, liver, onset 10s
absorption: inhalation
metabolism: liver CYP2E1, duration 15-120m
excretion: kidneys, breath

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69
Q

Acute effects of inhalants:
* Similar to ASH (3)
* Biphasic _ - _ min; then _ - _ hours
* 1. ELDD
* 2. DDH
* Disinhibition of _ circuits at low doses
* Slurred speech, inebriation
* Hallucinations, anesthesia, coma and death at high/low doses

A

alcohol, sedatives, hypnotics
15-45, 1-2
Euphoria, disinhibition, dizziness, light-headedness
Drowsiness, disorientation, headache
motor
high

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70
Q

Physiological mechanisms of inhalants
* Toluene → _, euphoria via _ reward pathway, elevated _ DA levels
* Motor effects, regulated in part by _ in the _ _ in mice

A

reward, VTA→NAc, striatal
GABA, caudate putamen

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71
Q

Cellular mechanisms of toluene action:
* _ -mediated reinforcement
* Potentiates _ and _ neurotransmitters
* Inhibits _ _ receptors and _
* Direct activation of _ projections to the NAc → reinforcement
* Sum of actions on several _ channels, _ signaling, _

A

DA
GABA, glycine
NMDA Glu, nAChRs
VTA DA-ergic
ionotropic, Ca2+, G-proteins

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72
Q

Toluene potentiates _ and _ NT action

A

GABA, glycine

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73
Q

Dose- and subunit-dependent inhibition of NMDA 2B containing receptors by toluene:
* Recombinant NMDARs expressed in frog oocytes = _ culture
* _ + _, then with toluene, then after washout showed that 2B -containing channels are most/least sensitive

A

heterologous
NMDA, glycine, most

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74
Q

tolouene is involved in what type of drug

A

inhalants

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75
Q

in presence of toluene, β2 receptors shift _ indicating they’re more sensitive to inhibitory effects
β4 shift _ indicating they’re less sensitive

A

left
right

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76
Q

Dose- and subunit-dependent inhibition of nAChR β2-
containing receptors by toluene:
● Dose-dependent inhibition of β2- containing nAChRs
● Cultured _ neurons are _ to ACh in presence of toluene →

A

hippocampal, insensitive

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77
Q

Acute adverse effects of intoxication of inhalants
* Sensitize the heart to _
* Cardiac dysrhythmias → inhibited inactivation of _ and _, QTc > _ ms is prolonged
* _ (i.e. propane/butane) are common causes of ER visits

A

epinephrine
voltage-gated Na+ & Ca2+ channels
480
Lighters

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78
Q

Acute adverse effects of intoxication from inhalants
* Aerosol-evoked cardiac arrest:
Rapid heating/chilling of the larynx (liquid-to-gas phase change of inhalants)
Mucosal oedema and laryngospasm cause _
Irritate descending _ nerve
Elevated _ release onto heart
_ and _ arrest

A

chilling
hypoxia
vagal
ACh
Bradycardia, cardiac

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79
Q

Acute adverse effects of intoxication from inhalants
* Mechanical _
* Aspiration of _
* Trauma especially prevalent with _ _
* Unconsciousness, respiratory suppression, coma
* Sudden sniffing death syndrome reported in 1977:
* _ new users, 20%

A

asphyxiation
vomit
glue sniffing
1/5

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80
Q

How do mechanisms relate to long-term inhalant abuse?
Physiology is heavily inhibitory →
* _ / _ (activate EPSPs) are inhibited
* _ / _ (activate IPSPs) are potentiated
* Subunit composition may change, _ → altered sensitivity of channels to drug binding
* _ attenuation initially, but _ occurs after each withdrawal period

A

NMDA/AChR
GABA/Glycine
neuroadaptation
ACh
excitotoxicity

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81
Q

Maladaptive hippocampal adaptations:
* Structural changes in hippocampus as quickly as _ days
* NMDA receptor subunit composition changes
after 4 days, receptor staining on medium _ neuron membranes increases
* _ -day _ ppm (2.2 mM) toluene cycle causes
neuronal death in _ _ and _ regions → correlates with _ loss

A

4
spiny
40 200
hippocampal CA1, CA3, memory

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82
Q

Long-term health risks and damage of inhalants:
_, _, _ impairment → greater risk of drug abuse in adult life
* Damaged brain regions: (4)
* _ loss → cognitive decline, slower processing, cerebellar ataxia

A

Memory, cognitive, behavioural
basal ganglia, cerebellum, thalamus, pons
Myelin

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83
Q

Long-term damage of inhalants:
targets _ neurons
* Myelin is a fatty substance (70% lipid) → inhalants _
* _ is a metabolite of hexane that _ -links neuron _ components
* _ _ neurons, like _, contain more of these components
* Symptoms of damage include tingling _ and _
* If muscle is denervated it _

A

myelinated
accumulate
2,5-hexanedione, cross, cytoskeletal
Long peripheral, motoneurons
hands and feet
atrophie

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84
Q

what functional group makes up alcohols

A

OH

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85
Q

Yeast
* Fast/slow generation time
* Dried for short/long-term storage
* Rehydrated for use
* Genomes fully sequenced
* Model organism → aging, DNA repair, brewing
* t/f: Multiple unique strains available → optimized for an application: beer vs. wine
* Ale vs lager yeast
* E.g. WY3724 Belgian Saison yeast

A

Fast
long
t

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86
Q

Fermentation
* Multiple additional molecules are produced E.g. _
* 15% _ is toxic to yeast
* Distillation concentrates [alcohol] to 40%+
* Proof, alcohol-by-volume

A

phenols,
ethanol

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87
Q

Calculating ABV → proof

A
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88
Q

Wine, beer and scotch chemistry – common molecules
Complex plant chemistry + yeast metabolism [+ conditioning] = chemical profile in finished products
*know what the molecules look like

A
89
Q

Alcohol use is split into 4 categories
AMBH

A
  1. Abstinent
  2. Moderate
  3. Bingeing → 5 or 4 drinks on one
    occasion in the last 30 days for men
    or women
  4. Heavy (alcoholic
90
Q
  • How much ethanol (EtOH) in a standardized drink?
    23.3g EtOH/oz. x 0.6 oz. = 13.98 g
A
91
Q

Ethanol is absorbed in the _ _
* Food increases retention time in the stomach → speeds up/slows absorption
* Low pH does/does not alter ethanol

A

small intestine
slows
does not

92
Q

Alcohol distributes through _ tissues
* Volume available for distribution determines _
* g ethanol / 100 mL blood
* Higher/lower proportion of body fat = higher BAC after
1 drink

A

aqueous
BAC
* Higher

93
Q

how to estimate BAC

A
94
Q

BAC overtime, EtOH distribution
Ethanol is _ distributed throughout tissues
* Larger people have higher/lower BAC → greater body volume
* Leaner people have higher/lower BAC → greater water volume within body volume
* Small/large size allows easy passage into brain
* Gender differences: Females tend to be _ and less _

A

freely
lower
lower
large
smaller, lean

95
Q

acute effects of EtOH
What causes phases?
* Increased/decreased sociability, increased/decreased anxiety especially in adolescent animals

A

metabolism
Increased, decreased

96
Q

know acute effects of etoh consumption slide (OH 1)

A
97
Q

physl effects of etoh
Vasodilation/vasoconstriction → autonomic brainstem nuclei
* decreased/Increased gastric/salivary secretions
* Loss of stomach mucosal lining → _

A

Vasodilation
Increased
ulcers

98
Q

etoh increases or slows neuronal activity

A

slows

99
Q

NT affected by ETOH
4

A

gaba, glutamate, da and endogenous opioids, other nts

100
Q

Anxiolytic effects likely due to _
Increased/Decreased activity when threatened

A

amygdala
decreased

101
Q

etoh metabolized in _
_ % metabolized in liver
_ % excreted untouched: breath, urine, skin
_ % metabolized in stomach, _% other

A

liver
90, 2, 3, 5

102
Q

_ background influences _ levels, effects, vulnerability to addiction
* E.g. Asian populations have slower/faster ALDH variant

A

Genetic, acetaldehyde, slower

103
Q
  • 0 order vs. 1st order kinetics → _ vs. _ elimination curve
A

linear, exponential

104
Q

_ BAC elimination per hour in avg person
* Gender difference, BAC after one drink is
higher in females/males

A

0.015
females

105
Q

Amount of alcohol exhaled is _ the concentration in the blood
* Basis of roadside _ tests (BrAC)
_ - _% is lethal

A

1/2100th, breathalyzer; 0.4-0.5

106
Q

The _ are also a common side-effect of excessive drinking EtOH, BAC ~ _

A

spins, 0.04

107
Q

how spins work:
* EtOH permeates _ and _
* EtOH diffuses out of _ before _
* _ is now more dense than _ and does not stabilize when
lying down
* _ fibres are activated -> Brain interprets activity as _

A

endolymph, cupula
cupula, endolymph
Cupula, endolymph
Sensory, motion

108
Q

Depressed/stimulated hippocampal activity underlies memory
loss with etoh

A

depressed

109
Q

etoh depressed hippocampus
* Septohippocampal pathway is driven by _ activity
* Over- _ activity by high dose ethanol lead to transient retro/anterograde amnesia
* _ _ _ neurons are susceptible to ethanol damage
* Chronic alcoholism can coincide with nutritional deficiencies (e.g. _)
* Alcohol-related brain damage (ARBD) is driven by _ - _ signaling that induces cellular damage and death

A

ACh
suppressed, anterograde
Hippocampal dentate gyrus
thiamine
pro-inflammatory

110
Q

Antifreeze (ethylene glycol) → _ acid and _ acid which causes stupor/ _, _/arrhythmia/lung edema

A

glycolic, oxalic, coma, hyperventilation

111
Q
  • Methanol → _ and _ acid, causes blindness by damaging optic nerve _; eventually respiratory _ or sudden respiratory arrest is common
A

formaldehyde, formic acid
mitochondria, failure

112
Q
  • Hand sanitizer epidemic
  • Iso[propanol] → metabolized to _
    t/f: alcohol metabolites are toxic
A

acetone
t

113
Q

2 ways to treat methanol/wood alcohol poisoning

A

EtOH, fomepizole

114
Q

etoh treat methanol poisoning
out-competes methanol for _ enzymes reducing _ production; methanol is excreted changed/unchanged via _

A

metabolic, formaldehyde, unchanged, kidneys

115
Q

Fomepizole treat methanol poisoning:
_ inhibitor of alcohol _, prevents build-up of toxic metabolites, more/less expensive than ethanol used in antifreeze/methanol cases

A

competitive, dehydrogenase, more

116
Q

OH early studies
Early 19th century: Meyer-Overton proposed
* 1980s: EtOH inhibits _ enzyme (luciferase)
* i.v. EtOH increases _ DA-ergic firing frequency
* 10-200 mM EtOH increases/decreases spontaneous VTA firing frequency in vitro
* EtOH must be applied directly in _, not in NAc
Direct effects on _?

A

‘lipid theory’
soluble
VTA
increases
VTA
soma

117
Q

Mechanism of EtOH action → increased/reduced electrical activity
* δ subunit GABAA receptors may be _ -synaptic
* Inhibition of iGlu-NMDA receptors and voltage-gated Ca channels at lower/higher [EtOH]
* Strong potentiation of GABAA receptors at lower/higher [EtOH]
* Overall effect → neuronal inhibition, _ -like effects
* Especially _ subunit-containing
* Asphyxiation at lethal doses via depressed activity in autonomic centres

A

reduced
extra
higher
lower
sedative
δ

118
Q

WHY DO VTA DA-ergic NEURONS INCREASE ACTIVITY

A

receive input from multiple areas

119
Q

VTA DA-ergic neurons receive inputs from multiple regions
* Most important for _ reinforcement
* Glu-ergic inputs to VTA from _, _
* GABA-ergic inputs to VTA include _, _ _
* _ and _ are the most common NTs in the brain, balance activation/inhibition

A

EtOH,
PFC, RN
NAc, VTA interneurons
Glutamate, GABA

120
Q

GABAA receptors
* _ -loop ligand-gated channel superfamily
* _ receptors:
* 19 genes give rise to _ subunits:
* α4δ-containing GABAA receptor responds to _ EtOH and is expressed in _, part of reward circuit
* Causes depolarizing/hyperpolarizing currents, threshold _
* EtOH _ channels after activation

A

Cys
Heteropentameric
19
low, striatum
hyperpolarizing, mini inhibitory post-synaptic currents (mIPSCs)
potentiates

121
Q

NMDA receptors
* _ _ receptor superfamily
* _ receptors:
* Subunits arise from _ NR1 gene (grin1), _ NR2 genes
(grin2; A-D) and _ NR3 genes (grin3; A and B)
* Subunit composition in/directly affects function
NR1/2C is more/less sensitive to EtOH than _ and _
_ NR1 splice variants in humans
Inhibited by EtOH at low/high doses → additive effect
with GABA potentiation towards overall _ electrical activity

A

Ionotropic Glu
Heterotetrameric
1, 4, 2
directly
less, NR1/2A, NR1/2B
8
high
depressed

122
Q

VTA DA-ergic neurons receive inputs from multiple regions
Also receives _ -ergic input from _ nucleus of hypothalamus
* Individuals with low baseline levels of endorphin release
more/less when given alcohol → predisposed to _ _

A

opioid, arcuate
more, alcohol abuse

123
Q

Control of VTA DA-ergic firing to NAc
* _ -ergic inputs are the main control
What controls GABA-ergic input to VTA DA-ergic neurons?
_ -ergic inputs balanced by opioid-ergic inputs = baseline _-ergic activity = tonic firing of VTA → NAc
* Decreased Glu-ergic inputs + increased opioid-ergic inputs = more/less active
GABA-ergic interneurons = phasic/tonic firing of VTA → NAc

A

GABA
Glu, GABA
less
phasic

124
Q

Rising BAC → triggers _ DA release, disinhibition

A

VTA-to-NAc

125
Q

Dropping BAC:
Potentiates _ receptor IPSPs
* Blocks _ (GluN) receptor EPSPs
* Blocks select _ channels
* Overall, stimulated/depressed electrical activity
* Highly dependent on BAC rising or falling, toxic metabolites

A

GABAA, NMDA, Ca, depressed,

126
Q

Tolerance of etoh:
* GABAA receptor functions increase/decrease
* NMDA (GluN) receptors down/up-regulated
* Ca channel receptors down/up-regulated
* = over-active brain, hyperexcitable → _ volatility
* Cross-tolerance to other drugs that affect GABA/Glu receptors, e.g. benzos and barbees

A

decrease, up-regulated, up-regulated, emotional, GABA

127
Q

etoh tolerance:
GABAA receptors are up/down-regulated
* NMDA receptors are down/up-regulated
* Subunit compositions and receptor localizations in membrane dont/do change
* Ca channels are down/up-regulated
* Altogether → lower/higher excitability
* Behavioural → masking of inebriation
* Metabolic → down/up-regulation of liver enzymes, especially in heavy drinkers

A

down-regulated, up-regulated, do change, up-regulated, higher excitability, up-regulation

128
Q

etoh tolerance CYP2E1 levels increase/decrease

A

increase

129
Q

CYP2E1 knockout prevents/induces EtOH-induced liver damage
* Over-active CYP2E1 induces more/less EtOH damage
Can increase to _ BAC / hour in every day/other day drinkers

A

prevents
more
0.017

130
Q

AWS - hangover
Symptoms are physical and psychological
* Physical → headache, diarrhea, fatigue, restlessness, nausea
* Psychological → haziness, slower thought/cognition, impaired reaction times, poor reasoning
* Symptoms peak as BAC reaches _, metabolites do/don’t continue to cloud brain function

A

0, do

131
Q

minor chemical constituent,
especially one that gives a distinctive
character to a wine or liquor or is responsible
for some of its toxic effects

A

congener

132
Q

acetone, methanol, acetaldehyde, furfural are eg of

A

congener

133
Q

substances with increased complexity of colour and flavour have more _ and result in more/less severe hangover

A

congener, more

134
Q

t/f: Alcohol withdrawal is more severe than
most other drugs, e.g. heroin, meth

A

t

135
Q

stages of etoh withdrawal:
1. STAGE 1
a. Elevated heart rate/bp b. Diaphoresis, c. Tremors d. No appetite, insomnia
2. STAGE 2
a. Hallucinations
3. STAGE 3
a. Delusions, delirium, amnesia
b. Tremens peak 3-4 days after last drink
4. STAGE 4
a. Seizure

A
136
Q

want to treat aws to reduce over/under excitation

A

over excitation

137
Q

treating aws
Goal is to prevent withdrawal stages _ and _
* Glutamate antagonists, e.g. _ → reduce hyperexcitability
* Benzodiazepines or ketamine for reducing AWS severity
* Clonidine → pre-synaptic _ adrenergic agonist prevents excessive neurotransmitter release
* Propranolol → _ adrenergic antagonist reduces sympathetic effects and tremor
* Disulfiram → inhibits _ _, build-up of acetaldehyde, aim is to prevent alcohol use but does not decrease craving
* Naltrexone and nalmefene opioid antagonists → prevent _ reward

A

3, 4
acamprosate
α2
β
acetaldehyde dehydrogenase
DA-ergic

138
Q

neuroadaptations that underlie long term dependence for etoh - 6
* Changes in reinforcement, enhanced anxiety, increased sensitivity to stress

A

Glu, GABA
* Dopamine, 5HT, opioids, corticotrophin-releasing factor (CRF)

139
Q

Structural neuroadaptations represent alterations in the space available for synaptic connections and are among the major neurobiological adaptations by which experience alters the brain in the service of future behavior
* _ synapses located almost entirely on ‘head’
of spines

A

Glu-ergic

140
Q

2 regions of NAc

A

core, shell

141
Q

morphological changes of neuronsn in nac:
_ = immature
* Scaffolding proteins support synapses – (2) _ = mature

A

stubby, homer2, PSD-90, mushroom

142
Q

Most pronounced changes observed in nac during _
see largest changes among _ thing neurons

A

withdrawal
long thin

143
Q

Increased GABA release in CeA and basolateral amygdala indicated by measuring _

A

mini inhibitory post-synaptic currents

144
Q

oh in brain:
Nutritional deficiency → thiamine (vitamin B1) deficiency because _ ->
* Reduced volume in alcoholics compared to healthy controls; why? -> Induced by _ production in the brain
* Hyperactive _ systems cause excitotoxicity via excessive Ca influx leading to cell death
* Affects glucose metabolism, protein synthesis, myelin formation all of which damage neurons and cause cell death

A

GI tract is irritated and can’t absorb it from food;
Neurons die off; ROS/acetaldehyde
Glu;

145
Q

Nutritional deficiencies from OH→
(2) W, K
to cover memory loss,
disorientation, loss of
coordination

A

Wernicke’s encephalopathy,
Korsakoff’s confabulation

146
Q

Reward circuit in the NAc elevates DA levels → _
nuclei raise heart rate
* People with low baseline beta-endorphin levels are prone to drinking more/less alcohol

A

brainstem
more

147
Q

EtOH contains more _ than carbs, protein
* Accompanied by metabolic changes in energy usage →
causes the brain to metabolize _, not glucose

A

energy
acetate

148
Q

2E1 produces _ and _
* ROS react with _ systems under controlled
conditions
* At elevated levels, anti-oxidant systems are _
* ROS react with proteins, lipids, DNA which the cell
must deal with
* If the cell cannot detoxify, it becomes stressed
* Stress leads to _, _, _

A

acetaldehyde, ROS; anti-oxidant; overwhelmed; membrane & DNA damage, cancer,
cell death

149
Q

metabolic switch in liver leads to fatty liver disease
Metabolism produces high levels of _ relative to NAD+
* High NADH:NAD+ reduces _ oxidation
* Excess fat is stored in _
* Cells start to lyse and induce inflammation → _
* irreversible/Reversible at early stages before vast cell death

A

NADH, fatty acid; droplets; hepatitis; Reversible

150
Q

A lethal mix:
OPIOIDS +
_

A

sedatives

151
Q

Naloxone – opioid receptor (OR) _
* Methadone – _ agonist

A

antagonist; μ

152
Q

Natural
* _ – alkaloid-laden latex; MC =
Semi-synthetic
* _, hydro-codone/-morphone,, oxycodone, krokodil
* Buprenorphine, etorphine
Synthetic
* Methadone, meperidine
* Tramadol
* Fentanyl

A

Opium; Morphine, codeine; Heroin;

153
Q

Narcotic and non-narcotic alkaloids
* Major narcotics are morphine (~ _ %), codeine (_ %)
* Morphine is 10x more potent than _
* CYP2D6 converts _ to morphine in _ + _
* 10% of Caucasians have _ 2D6 → codeine has no effect
* 2% of population has _ 2D6 → morphine intoxication

A

10; 0.5; opium; codeine; brain and liver; deficient; overactive

154
Q

Fatty liver disease progresses to

A

cirrhosis

155
Q
  • Cirrhosis is characterized by a chronic _ state and cell death
  • TGF-beta cytokine production by infiltrating immune cells
    triggers _ changes
  • Cells begin producing _ that is dumped into the
    extracellular space
  • Functional _ cells are replaced by fibrous, collagenous
    matrix
  • Liver irreversibly loses _ capacity
A

inflammatory; transcriptional; collagen; liver; detoxifying

156
Q

Cell death and reactive species-induced changes to
macromolecules facilitate immune infiltration → _ _ _
* Immune cells become activated within the liver
* Start targeting immune cells deemed to be _
* Progression to cancer requires massive dysfunction
* Reactive lipids are highly _
* Retinoic acid receptor increases/reduces cell proliferation, anti-cancer -> increased/reduced expression in stressed cells

A

chronic inflammatory state; foreign; mutagenic; reduces; reduced

157
Q

50% of cancers linked to _ consumption
* Upper/lower GI tract susceptible because _ contribute to EtOH metabolism
* _ can reach 10-100x higher concentrations than in the blood
* Poor hygiene increases _ count
* Smoking increases _ production

A

alcohol; Upper; microflora; Acetaldehyde; microbe; acetaldehyde

158
Q

_ is an alcohol
dehydrogenase
(ADH) inhibitor

A

4MP

159
Q

_ interferes with DNA synthesis and repair
* Binds and inactivates DNA _ proteins
* DNA synthesis stops when complexes
encounter modified bases
* 2 acetaldehyde + guanine = propanodeoxyguanosine
* Acetaldehyde + DNA = N2-ethylidene-dG
If open, _ links with DNA or proteins
form
* Causes mutations and chromosomal
abnormalities

A

Acetaldehyde; repair; covalent

160
Q

fetal oh:
Face and brain development vulnerable in _ week
Brain development vulnerable in _ trimester * Poor impulse control, planning
In mice, _ receptor 1 and _ deacetylase modify long-term gene expression → cognitive decline

A

3rd; 3rd; cannabinoid; histone

161
Q

Cardioprotective effects of OH:
* low doses, 1 drink per 1-2 days
* wine several beneficial _, increases _ which prevents lipid
deposition in arteries (anti-atherosclerotic), decreases/increases platelet aggregation

A

antioxidants; HDL; decreases

162
Q

Cardiotoxic effects of OH:
* _ at high EtOH doses
* direct modulator of Ca release → inhibits SR Ca release, negative _ effect
* _ inhibits _ synthesis, heart has high protein turnover due to muscle fibre and beating function; also damages _ (powerhouse of cell)

A

cardiomyopathies; inotropic; acetaldehyde; protein; mitochondria

163
Q

opioids used for:
Pain (e.g. post-op) → pro/anti-nociceptive
* Block afferent transmission in the _ / _, _
* Safe and effective when used appropriately

A

anti; spinal cord/brainstem* Periaqueductal gray (PAG);

164
Q

naloxone = _ antagonist
methadone = _ agonist

A

OR, mu

165
Q

“semi-synthetic” = produced by
modifying a _ -derived
chemical
* Two acetyl groups make molecule
10x more _

A

naturally; lipophilic

166
Q

Early 1960s, synthesis of naloxone → reversal of _ effects
_ + _ discover opioid receptors in the brain
4 classes of pre- and post-synaptic opioid receptors →
Pre-synaptic receptors modulate
* Post-synaptic receptors alter

A

morphine; Candace Pert & Sol Snyder; μ, δ, κ, ORL-1; NT release (e.g. DA, NE, GABA); membrane
potential

167
Q

discovered opioid r by _ _ in brain tissue slices

A

Radioligand binding

168
Q

endogenous opioids -> _ different peptide ligands,

A

18

169
Q

μ (MOR; after Morpheus):
* Expressed in:
* VTA, NAc * PAG * Hypothalamus * LC * Brainstem * Pupils * GI tract
t/f: most opioids bind mu; involved in reward, breathing, constriction

A

t

170
Q

δ (DOR; after vas
deferens):
* Expressed in:
* Neocortex * Striatum, NAc * Substantia nigra * Olfactory bulb
bound by _

A

enkephalins

171
Q

κ (KOR; after
ketocyclazocine):
* Expressed in: * Pituitary * Hypothalamus * PAG * Spinal cord * Others
t/f: bound by EDPK

A

endorphins, dynorphins, PCP and ketamin

172
Q

(ORL) 1:
* Expressed in:
* Limbic system
* Spinal cord
bound by B

A

buprenorphine

173
Q

Illegal fentanyl comes mostly from _ to Canada
* Looks like 80mg _
* Sold as _
* dec/Increasing detection in heroin samples
* Can be found in cocaine, ecstasy

A

asia; oxycontin; heroin; Increasing;

174
Q

fentanyl med use:
100x more potent than _
* 40-50x more potent than _
* Highly _

A

morphine; heroin; lipophilic

175
Q

t/f: Fentanyl derivatives are even more potent
* Increased affinity for _ receptors + enhanced entry into the brain = higher/lower potency

A

t; mu; higher

176
Q

t/f: Higher purity, safer for administration
t/f: * Street opioids are often contaminated

A

t, t

177
Q

methods to absorb opioids - 6

A

inhale, ingest, inject, snort, subling, rectal

178
Q

__ metab reduce bioavailability of opioids

A

first pass

179
Q

chasing dragon:
Heat up on tin foil, inhale fumes; * More commonly smoked in a pipe
* Linked to _
* Brain tissue looks spongy with holes – _
* Progresses to ataxia, apathy, akathisia to complete inability to _ or _
* Seems like _ toxicity
* consistent/Inconsistent outcomes

A

leukoencephalopathy; spongiform; speak or move; metal; inconsistent

180
Q

injecting heroin:
Mixed with some water in a spoon; _ or _ may help dissolve,
* Drawn up through a cotton ball to remove _
* Leaves track marks eventually; Damage to vessels by the
needle, the drug, injection rate, infection or ‘flushing’
* Uneven blood flow, _ and clots form
* Vessel collapses, need to find a new one
* Crushed tablets contain _ that are dangerous to
inject

A

Acid or heat; particulates; thrombosis; fillers

181
Q

t/f: opioids Most not lipophilic, does not readily cross BBB
* _ % reaches CNS sites
* Heroin → _ in the brain
* Metabolized in the _, excreted by _

A

t; 0.1; morphine; liver; kidneys

182
Q

opioid adme:
distribution: 5 (LLSGB)
abs: 6
metab: 2
exc: 2

A

Liver * Lungs * Spleen * GI tract * Brain
inhale, ingest, inject, snort, subling, rectal
liver, brain
kidney, feces

183
Q

heroin pharmk
Faster/slower distribution to the brain, higher potency
* Metabolized to _ in the brain
* Two monoacetylmorphine (MAM) intermediates are _, _
* 6-MAM binds _; 3-MAM does /does not
* 6-MAM is/ is not naturally occurring, used in legal cases to establish heroin use

A

Faster; morphine; 3-MAM and 6-MAM; MOR; does not; is not

184
Q

opioid acute effects
Brainstem CTZ in the area _ of the medulla triggers _, _
* Generally, users acquire tolerance to _ effects
μ/κ receptors in _ nucleus cause constricted/dilated pupils* similar/opposite to other drugs

A

postrema; nausea, vomiting; CTZ
oculomotor; constricted; opposite

185
Q

physl effects of opioids:
GnRH, LH, FSH levels are increased/reduced → decrease libido, impotence, amenorrhea
* _ → babies are irritable, vomit, diarrhea, seizures, respiratory distress
* Require close attention, NICU → _ contact reduces hospital time

A

reduced; Neonatal abstinence syndrome (NAS); physical

186
Q

physl opioid effects: GI
Isometric muscle contractions increase/reduce bowel movements, secretions → _
* Constrict ureter and
sphincters of bladder,
stimulate _ hormone release → _ urination

A

reduce; constipation; anti-diuretic; decrease

187
Q

t/f: evidence in mice contradicts runners high from pfc and limbic endorphin’s increased release

A

t

188
Q

Mu, delta and kappa opioid receptors (ORs) come from same/separate Opr genes
* Expressed in multiple brain regions (PAG, pons, VTA, NAc, raphe nuclei, etc.), spine, GI tract, upper airways, immune cells, etc.
* ORL orphan displays structural _
* Most effects are due to _ signaling
Sub-types likely due to _ variation which indirectly/directly impacts function

A

separate; homology; mu; allelic; directly

189
Q

all endogenous opioids contain an

A

N-terminal tyrosine residue

190
Q

Morphine structure mimics

A

tyrosine

191
Q

All ORs are GPCRs, linked via _
* Ligand binding triggers α-GTP loading; _ and βγ subunits dissociate
* α-GTP inhibits _, reduces [cAMP], inhibits protein kinase _
* α-GTP activates _ and _ pathways
* βγ subunits:
* Activate _ (G-protein gated inward rectifying _ channel) causing hyperpolarization
* Block _ channels (mainly N-type) causing reduced
intracellular Ca and increasing/suppressing neurotransmitter release
* Chronic exposure to morphine results in G-protein coupled receptor kinase (GRK)-mediated phosphorylation of opioid receptors and binding of β-arrestin → _

A

Gi/o; α; adenylate cyclase; A; PLCβ, MAPK;
GIRK3; potassium; Ca; suppressing; desensitization

192
Q

t/f: Differential activation of signaling pathways by OR ligands
t/f: Not all signaling is G-protein-mediated

A

t; t

193
Q

Classic opioid signaling is due to biased _ effects
* E.g. morphine keeps receptor phosphorylation high/low
* Other opioids produce high receptor phosphorylation leading to receptor _, decreased/increased tolerance and
dependence
* E.g. _ produces high receptor phosphorylation

A

Gprotein; low; internalization; increased; fentanyl

194
Q

Altered patterns in
_ and _
mutants affect signaling and fx

A

L85I and R181C

195
Q

opioid mediated analgesia
μOR primarily involved → expressed in TPRDh

A

thalamus, PAG, rostroventral medulla and dorsal horn of spine

196
Q
  • Descending pain pathway: C(t)PRD
  • Activation of _ on GABA-ergic _ interneurons
  • phasic/Tonic firing from RVM to _ horn sets pain afferent threshold
  • Activation of μOR on GABA-ergic RVM interneurons increases/reduces inhibition of
    RVM “ON/OFF” projecting cells to the spinal cord, leading to elevated/decreased signaling out of the RVM to the spinal cord and decreased/increased afferent pain transmission into the
    spine
A
  • Cortex → [thalamus →] PAG → RVM → DHs
    μOR, RVM; Tonic, dorsal;
    reduces, OFF, elevated, decreased
197
Q
  • Activation of μOR on RVM “ON” projecting cells to the spinal cord decreases/increases outputs to the dorsal horn of spine, adding to the analgesic effect
  • Indirect role for _ in modifying pain transmission
  • In dorsal spine horns:
  • Pre-synaptic μOR activation on afferent pain neurons (that also release GSpC _, _, _) reduces NT release and pain transmission
A

decreases,
amygdala
Glu, subP, calcitonin gene-related peptide [CGRP]

198
Q
  • Glu, DA and GABA play important roles
  • NMDARs and AMPARs appear involved; _ maybe a bit more important
  • Role of hippocampal mu receptors:
  • Disinhibition of _ and _ gyrus cells via GABA-ergic
    interneurons
  • Astrocytes also express MORs, activation causes _ release onto _ neurons
  • Both facilitate _ memory → associative conditioning
  • NAc MSNs either express _ -like receptors (D1 and D5) or _ -like receptors (D2, D3, D4) which subdivides their functions
  • D1 receptors usually co-express _, D2 usually co-express _
  • _ receptors are usually co-expressed on dynorphin/D1 receptor-expressing cells
A

AMPARs; CA1, dentate gyrus;
Glu, CA1
contextual; D1, D2; dynorphin, enkephalin, mu

199
Q

tolerance: Opioid receptors are up/down-regulated, need higher/lower dose for same effects
* Molecular uncoupling may disrupt OR signals
* Learned (behavioural) – behaving _ when intoxicated
* Altogether: analgesia, vomiting, euphoria and respiratory
depression fade; _ and pupil dilation/constriction do not → big implications for relapse

A

down; higher; sober;
constipation, constriction

200
Q

t/f: Tolerance is influenced by environment
* Rats were given high dose (15mg/kg) that would kill a naïve rat in the same (ST) or different (DT) environment
implies: _ tolerance in different/strange locations

A

t; lower

201
Q

_ et al. (1978) used ‘rat park’ vs. bare cage environments
* Isolated rats in bare cages administered much more/less morphine

A

Alexander; more

202
Q

techniques to measure opioid tolerance (2)

A
  • Tail immersion test
  • Hot plate test
203
Q

_ _ Used to gauge psychological addiction → escalating
behavioural responses to a stimulus like a drug of abuse after a drug-free period

A

Behavioural sensitization

204
Q

Factors that contribute to sensitization include receptor _, _ levels, cell signaling _

A

density, NT; deregulation

205
Q

Behavioural sensitization is driven by _ inputs
Driven by DA-ergic and Glu-ergic projections from
the VTA and PFC, respectively, to the NAc
* Blocking _ in NAc impairs sensitization in rats
Morphine sensitization coincides with reduced/elevated D1 expression in NAc shell plus elevated _ / _ activity
* AMPAR/NMDAR _ block the induction of
sensitization, but not the expression of sensitization

A

NAc; D1; elevated; ERK1/2 MAPK; antagonists

206
Q

Tolerance is due, in part, to _
t/f: these terms refer to mechanisms over different timelines affecting different aspects of signaling
* Desensitization is slow/rapid (on and off),
* Direct consequence of drug-receptor activation
* Depends on _ and _ activities
* Seen in in vitro studies
* Sustained desensitization reduces _ effects
but enhances _ signaling
G-protein uncoupling, α-GTP binding is reduced in _ treated animals
* GRK phosphorylation of μOR causes _ binding and
reduced euphoria/analgesia
* Causes addicts to use higher doses for same/diminished effects

A

desensitization; t; rapid; Ca, K
acute, intracellular; morphine, β-arrestin

207
Q

Desensitization leads to _ in pain circuits
Heroin tolerance results in hyperalgesia, decreased latency in pain sensing → barbadin is _ inhibitor

A

hyperalgesia
β-arrestin

208
Q

Naloxone injection to NAc causes _ (CPA)
* _ -like, but not D1-like, receptor agonist injection into NAc
attenuates _ withdrawal signs
* DA in NAc is inc/decreased during withdrawal
Affective/cognitive symptoms include dysphoria,
anxiety, irritability, cravings
Affective symptoms are most important targets for
therapy, to prevent relapses
* Anxiety persists for up to 80 days
* Conditioned place aversion only 20 days

A

conditioned place aversion; D2; somatic; decreased

209
Q

LC Expresses _OR and _OR mostly
* Chronic opioid use inc/suppresses LC activity → less
noradrenaline released
* Tolerance allows LC to normalize activity in the
presence of opioids
* Upon removal of opioids, LC becomes overactive → _ surge
* Produces sweating, chills, stomach cramps, emesis,
diarrhea, muscle pain, runny nose/eyes

A

μ, K, suppresses;
noradrenaline

210
Q

Lateral paragigantocellularis (LPGi)
in the _ medulla
* Stimulates LC via _ -ergic inputs
* Modulates opioid withdrawal
symptoms
* Adolescent/elderly opioid exposure alters
long-term activity, increases severity
of adult withdrawal symptoms and
dependence in rats

A

rostroventral,
glu
Adolescent

211
Q

Clonidine or Lofexidine
* α2
-adrenoceptor agonists
* Prevents noradrenaline release via pre-synaptic α2
autoreceptors
* Targets LC and LC projections
*

A
212
Q

Buprenorphine – for maintenance
* Semi-synthetic partial agonist
* Out-competes morphine, blocks heroin with mild effects
* Taken orally, 37 hour half-life, safer
* Suboxone = 4:1 buprenorphine-to-naloxone sublingual
* Effects are blocked if injected → naloxone does not cross mucosal membrane

A
213
Q
  • Methadone – for maintenance
  • Long half-life, also an NMDAR antagonist
  • No adulterants, sometimes free
  • Mild euphoria, still causes constipation
  • Ingested
A
214
Q

opioid adulterants: increase _ or modulate _
Talcum powder, powdered milk → inert, increase mass, decrease purity
Quinidine/ _→ bitter taste mimics heroin,
hypotensive effect feels like heroin ‘rush’

A

bulk, rushes
quinine

215
Q

Fentanyl → in >50% of street opioids, 100x more potent than morphine
* Carfentanil → 10000x more potent than _

A

morphine

216
Q

increased/Reduced pre-Bötzinger complex output is the main
mechanism of depressed respiration in opioid overdose
* Multiple factors contribute: unresponsiveness
* upper airway obstruction due to reduced upper airway muscle
tone → _
* central respiratory depression → Pre/post -BötC effects
* Main brainstem network: Pre-Bötzinger complex + retrotrapezoid nucleus/parafacial respiratory group
(RTN/pFRG) = coupled oscillator that influences _ (MN) that produce breathing

A

Reduced; genioglossus; pre
motoneurons

217
Q

_ delivery prevents depression in preo-botzingner complex

A

naloxone

218
Q

opioid triad: CDrP

A

coma (unresponsiveness), depressed respiration,
pinpoint pupils

Pmcol 305 (2 decks)

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