m2 Flashcards
1
Q
Amphetamine was derived from
A
Ephedra sinica
2
Q
Traditional Chinese medicine herb Ma _
has been used therapeutically for _ years
A
huang
5000
3
Q
_ _ synthesized alphamethylphenethylamine (amphetamine; AMPH) in 1887 to treat _
A
Lazăr Edeleanu
asthma
4
Q
L-amphetamine (3)
A
Raises BP, opens nasal passages, causes headache
5
Q
Raises BP, opens nasal passages, causes headache
A
L-amphetamine (3)*
6
Q
D-amphetamine (3)
*
A
Same effects as L-form, * Also elevates mood, enhances energy*
7
Q
Same effects as L-form, * Also elevates mood, enhances energy*
A
D-amphetamine (3)
8
Q
meth has Increased _ solubility → increased _ and _ effects
A
lipid
potency, brain
9
Q
types of Potency for amph (least to most):
A
L-amphetamine < D-amphetamine < methamphetamin
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
11
Q
making meth: Commercial phenylacetone
commercial phenylacetone ->
A
commercial phenylacetone -> Reductive amination or Leuckart synthesis -> meth
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
13
Q
Amphetamines are recreational _
A
stimulants
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
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%
16
Q
4 ways to consume amphs:
fastest - slowest onset
A
Ingested, injected, snorted or smoked
smoking < injection < snorting < ingesting
17
Q
t/f: METH high lasts much longer than cocaine
A
t
18
Q
Liver _ metabolizes METH and AMPH
A
CYP2D6
19
Q
4-HA and norephedrine are _:
A
stimulants
20
Q
TAAR
A
trace amino associated receptor
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
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
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
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)
25
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
DAT
* Monoamine oxidase (MAO)
storage vesicles
cytoplasm
cannot, DA
DAT
DA
spike, postsynaptic
26
AMPHs cause DA surge in the _, _
NAc, basal ganglia
27
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
smaller
phosphorylation, DAT, reverses
NE, 5HT
28
Adverse effects of acute amph use
_ from contaminants
* Combining with other drugs can enhance _ effects
* E.g. MAO inhibitors due to increased release of _, _, _
Poisoning
stimulant
DA, NE, 5HT
29
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 _ - _
displacement
tyrosine hydroxylase
reduces
reduced
days or a couple weeks
30
Long-term consequences of amphetamine use (3)
Weight loss * Skin breakdown* Sores, picking
31
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
oral, tooth, jaw
corrosive, NE
α1
salivary, reduced
32
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
sensitization
aggression, anxiety
movement, memory, decision-making
DA, NE, 5HT
high
reactive species
cell death
33
amph: _ levels recover in abstinent addicts,_ may not
DAT, function
34
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
long-term
reduced
nicotinic acetylcholine receptors (nAChRs), Ca, reactive oxygen species
antagonists
schizophrenia, Parkinson’s, dementia
cingulate gyrus
word recall
75
35
ecstasy Synthesized in 1912 by _ at _ (a drug company)
Köllisch, Merck
36
_ _ published first testing in 1960 at DOW Chemicals of ecstasy
Alexander Shulgin
37
MDMA can be derived from natural or _ sources
synthetic
38
ecstasy Extracted from ( 3)
cured Ocotea pretiosa, Sassafras albidum, or Cinnamomum parthenoxylon root bark
39
Sassafras essential oil contains ~
75-85% safrole
40
_ , a.k.a. 3,4- methylenedioxymethamphetamine
* Classified as a _ , similarity to _
Ecstasy, hallucinogen, mescaline
41
_ ring shifts stimulant effects toward _ and _
Methylenedioxy, mood, perceptions
42
mdma distribution (5 organs, TI, onset)
absorption (2 ways, dosage)
metabolism (organ, amount degraded, 1/2 life, high duration)
excretion: organ, amount unchanged
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
43
how is MDMA consumed through ingestion and insufflation
ingestion: MDMA tablet/molly capsule
insufflation: molly powder
44
Acute effects of MDMA:
Empathogen, entactogen eg
* Sympathomimetic: eg
* Euphoria, emotional empathy, energy, enhanced self-esteem
increased heart rate, hyperthermia, diaphoresis
45
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
agonist, bruxism, locomotion
5HT
TAAR
NE, DA
5HT, NE
46
Blocking _ blocks MDMA-induced 5HT release in
_ and _
5HT2B, NAc, VTA
47
* Selective block of 5HT2B _ 5HT release
* Genetic deletion of 5HT2B _ 5HT release
inhibits
abrogates
48
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)
Increases
Lower
prolactin, oxytocin
Increased, blood glucose
ventral striatum, amygdala
49
how do Cephalopods exemplify pro-social effects of
MDMA
* Normally asocial octopuses interact
50
t/f: Cephalopods express an evolutionarily conserved 5HT
transporter
t
51
MDMA Additional molecular drug targets:
Adrenergic receptors →
* Histamine type 1 receptors →
* α7 nAChR →
sympathomimetic effects, hyperthermia
causes ACh release, EPSPs
partial agonist, increases NT release
52
MDMA Tolerance
* increase/decrease in 5HT transporter activity (DA and NE too)
* Due to transporter expression increases/decreases
* Also depletion of _
decrease
decreases
neurotransmitters
53
MDMA withdrawal
* Inability to _
* t/f: Can be lethal, “suicide Tuesdays”
thermoregulate
t
54
MDMA dependence
* More _ than physical, 10% once/week
* Biased agonism in _ receptor agonism may underlie low addiction risk
psychological
5HT2C
55
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. _ _
* 5HT syndrome
* Increased
SSRI
inhibitors, Prozac SSRI
56
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
temperature set point
preoptic anterior hypothalamus
reduces
increases
abrogates
57
_ is the most common cause of overdose death in MDMA
* Cumulative effects from (3)
* Hyperactivity, dysregulation of _ set points
Hyperthermia
5HT, DA, NE
temperature
58
Dangers of acute MDMA use
* Hyponatremia – low _ in blood
* Caused by _ water intake due to _
* MDMA triggers _ release
* Can result in _ edema (swelling) → (2)
Na
large, hyperthermia
anti-diuretic hormone
cerebral
vomiting, respiratory arrest (compressed brainstem)
59
t/f: Adulterants are common in street ecstasy
t
60
t/f: some street ecstasy contain no MDMA
t
61
Adulterants and metabolites cause _ _ events in users
t/f: CYP enzyme metabolism differs greatly among individuals
t/f: Certain metabolites cause cell death -> how?
‘random’ adverse
t
t; * Individuals are more or less susceptible to adverse effects, sudden death
62
_ + _ composition may explain random toxicity when consuming MDMA
Variability in _ profiles leads to particular toxic metabolite build-up
Pharmacogenomics, unknown
enzyme
63
Long-term health effects of MDMA
* _ and _ deficits
* Induction of apoptosis in _ neurons via _ pathway in rats
Memory and attention
hippocampal, caspase-3
64
Forms of inhalants:
Mixtures of several lipophilic chemicals
65
eg of inhalents (3)
solvents, aerosols, glue
66
Administration of inhalants by inhalation (3)
*Huffing *Sniffing *Bagging
67
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 = _
Rapid, wide, anesthetics
lipophilic
150-200, 100-900, fattier
exhaled
reduce, acidosis
68
Inhalant pharmacokinetics summary
distribution (speed and distribution, 2 organs, onset)
absorption
metabolism (organ, enzyme, duration)
excretion (organ, way)
distribution: rapid, wide, brain, liver, onset 10s
absorption: inhalation
metabolism: liver CYP2E1, duration 15-120m
excretion: kidneys, breath
69
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
alcohol, sedatives, hypnotics
15-45, 1-2
Euphoria, disinhibition, dizziness, light-headedness
Drowsiness, disorientation, headache
motor
high
70
Physiological mechanisms of inhalants
* Toluene → _, euphoria via _ reward pathway, elevated _ DA levels
* Motor effects, regulated in part by _ in the _ _ in mice
reward, VTA→NAc, striatal
GABA, caudate putamen
71
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, _
DA
GABA, glycine
NMDA Glu, nAChRs
VTA DA-ergic
ionotropic, Ca2+, G-proteins
72
Toluene potentiates _ and _ NT action
GABA, glycine
73
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
heterologous
NMDA, glycine, most
74
tolouene is involved in what type of drug
inhalants
75
in presence of toluene, β2 receptors shift _ indicating they're more sensitive to inhibitory effects
β4 shift _ indicating they're less sensitive
left
right
76
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 →
hippocampal, insensitive
77
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
epinephrine
voltage-gated Na+ & Ca2+ channels
480
Lighters
78
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
chilling
hypoxia
vagal
ACh
Bradycardia, cardiac
79
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%
asphyxiation
vomit
glue sniffing
1/5
80
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
NMDA/AChR
GABA/Glycine
neuroadaptation
ACh
excitotoxicity
81
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
4
spiny
40 200
hippocampal CA1, CA3, memory
82
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
Memory, cognitive, behavioural
basal ganglia, cerebellum, thalamus, pons
Myelin
83
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 _
myelinated
accumulate
2,5-hexanedione, cross, cytoskeletal
Long peripheral, motoneurons
hands and feet
atrophie
84
what functional group makes up alcohols
OH
85
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
Fast
long
t
86
Fermentation
* Multiple additional molecules are produced E.g. _
* 15% _ is toxic to yeast
* Distillation concentrates [alcohol] to 40%+
* Proof, alcohol-by-volume
phenols,
ethanol
87
Calculating ABV → proof
88
Wine, beer and scotch chemistry – common molecules
Complex plant chemistry + yeast metabolism [+ conditioning] = chemical profile in finished products
*know what the molecules look like
89
Alcohol use is split into 4 categories
AMBH
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
* How much ethanol (EtOH) in a standardized drink?
23.3g EtOH/oz. x 0.6 oz. = 13.98 g
91
Ethanol is absorbed in the _ _
* Food increases retention time in the stomach → speeds up/slows absorption
* Low pH does/does not alter ethanol
small intestine
slows
does not
92
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
aqueous
BAC
* Higher
93
how to estimate BAC
94
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 _
freely
lower
lower
large
smaller, lean
95
acute effects of EtOH
What causes phases?
* Increased/decreased sociability, increased/decreased anxiety especially in adolescent animals
metabolism
Increased, decreased
96
know acute effects of etoh consumption slide (OH 1)
97
physl effects of etoh
Vasodilation/vasoconstriction → autonomic brainstem nuclei
* decreased/Increased gastric/salivary secretions
* Loss of stomach mucosal lining → _
Vasodilation
Increased
ulcers
98
etoh increases or slows neuronal activity
slows
99
NT affected by ETOH
4
gaba, glutamate, da and endogenous opioids, other nts
100
Anxiolytic effects likely due to _
Increased/Decreased activity when threatened
amygdala
decreased
101
etoh metabolized in _
_ % metabolized in liver
_ % excreted untouched: breath, urine, skin
_ % metabolized in stomach, _% other
liver
90, 2, 3, 5
102
_ background influences _ levels, effects, vulnerability to addiction
* E.g. Asian populations have slower/faster ALDH variant
Genetic, acetaldehyde, slower
103
* 0 order vs. 1st order kinetics → _ vs. _ elimination curve
linear, exponential
104
_ BAC elimination per hour in avg person
* Gender difference, BAC after one drink is
higher in females/males
0.015
females
105
Amount of alcohol exhaled is _ the concentration in the blood
* Basis of roadside _ tests (BrAC)
_ - _% is lethal
1/2100th, breathalyzer; 0.4-0.5
106
The _ are also a common side-effect of excessive drinking EtOH, BAC ~ _
spins, 0.04
107
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 _
endolymph, cupula
cupula, endolymph
Cupula, endolymph
Sensory, motion
108
Depressed/stimulated hippocampal activity underlies memory
loss with etoh
depressed
109
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
ACh
suppressed, anterograde
Hippocampal dentate gyrus
thiamine
pro-inflammatory
110
Antifreeze (ethylene glycol) → _ acid and _ acid which causes stupor/ _, _/arrhythmia/lung edema
glycolic, oxalic, coma, hyperventilation
111
* Methanol → _ and _ acid, causes blindness by damaging optic nerve _; eventually respiratory _ or sudden respiratory arrest is common
formaldehyde, formic acid
mitochondria, failure
112
* Hand sanitizer epidemic
* Iso[propanol] → metabolized to _
t/f: alcohol metabolites are toxic
acetone
t
113
2 ways to treat methanol/wood alcohol poisoning
EtOH, fomepizole
114
etoh treat methanol poisoning
out-competes methanol for _ enzymes reducing _ production; methanol is excreted changed/unchanged via _
metabolic, formaldehyde, unchanged, kidneys
115
Fomepizole treat methanol poisoning:
_ inhibitor of alcohol _, prevents build-up of toxic metabolites, more/less expensive than ethanol used in antifreeze/methanol cases
competitive, dehydrogenase, more
116
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 _?
‘lipid theory’
soluble
VTA
increases
VTA
soma
117
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
reduced
extra
higher
lower
sedative
δ
118
WHY DO VTA DA-ergic NEURONS INCREASE ACTIVITY
receive input from multiple areas
119
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
EtOH,
PFC, RN
NAc, VTA interneurons
Glutamate, GABA
120
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
Cys
Heteropentameric
19
low, striatum
hyperpolarizing, mini inhibitory post-synaptic currents (mIPSCs)
potentiates
121
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
Ionotropic Glu
Heterotetrameric
1, 4, 2
directly
less, NR1/2A, NR1/2B
8
high
depressed
122
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 _ _
opioid, arcuate
more, alcohol abuse
123
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
GABA
Glu, GABA
less
phasic
124
Rising BAC → triggers _ DA release, disinhibition
VTA-to-NAc
125
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
GABAA, NMDA, Ca, depressed,
126
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
decrease, up-regulated, up-regulated, emotional, GABA
127
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
down-regulated, up-regulated, do change, up-regulated, higher excitability, up-regulation
128
etoh tolerance CYP2E1 levels increase/decrease
increase
129
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
prevents
more
0.017
130
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
0, do
131
minor chemical constituent,
especially one that gives a distinctive
character to a wine or liquor or is responsible
for some of its toxic effects
congener
132
acetone, methanol, acetaldehyde, furfural are eg of
congener
133
substances with increased complexity of colour and flavour have more _ and result in more/less severe hangover
congener, more
134
t/f: Alcohol withdrawal is more severe than
most other drugs, e.g. heroin, meth
t
135
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
136
want to treat aws to reduce over/under excitation
over excitation
137
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
3, 4
acamprosate
α2
β
acetaldehyde dehydrogenase
DA-ergic
138
neuroadaptations that underlie long term dependence for etoh - 6
* Changes in reinforcement, enhanced anxiety, increased sensitivity to stress
Glu, GABA
* Dopamine, 5HT, opioids, corticotrophin-releasing factor (CRF)
139
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
Glu-ergic
140
2 regions of NAc
core, shell
141
morphological changes of neuronsn in nac:
_ = immature
* Scaffolding proteins support synapses – (2) _ = mature
stubby, homer2, PSD-90, mushroom
142
Most pronounced changes observed in nac during _
see largest changes among _ thing neurons
withdrawal
long thin
143
Increased GABA release in CeA and basolateral amygdala indicated by measuring _
mini inhibitory post-synaptic currents
144
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
GI tract is irritated and can’t absorb it from food;
Neurons die off; ROS/acetaldehyde
Glu;
145
Nutritional deficiencies from OH→
(2) W, K
to cover memory loss,
disorientation, loss of
coordination
Wernicke’s encephalopathy,
Korsakoff’s confabulation
146
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
brainstem
more
147
EtOH contains more _ than carbs, protein
* Accompanied by metabolic changes in energy usage →
causes the brain to metabolize _, not glucose
energy
acetate
148
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 _, _, _
acetaldehyde, ROS; anti-oxidant; overwhelmed; membrane & DNA damage, cancer,
cell death
149
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
NADH, fatty acid; droplets; hepatitis; Reversible
150
A lethal mix:
OPIOIDS +
_
sedatives
151
Naloxone – opioid receptor (OR) _
* Methadone – _ agonist
antagonist; μ
152
Natural
* _ – alkaloid-laden latex; MC =
Semi-synthetic
* _, hydro-codone/-morphone,, oxycodone, krokodil
* Buprenorphine, etorphine
Synthetic
* Methadone, meperidine
* Tramadol
* Fentanyl
Opium; Morphine, codeine; Heroin;
153
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
10; 0.5; opium; codeine; brain and liver; deficient; overactive
154
Fatty liver disease progresses to
cirrhosis
155
* 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
inflammatory; transcriptional; collagen; liver; detoxifying
156
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
chronic inflammatory state; foreign; mutagenic; reduces; reduced
157
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
alcohol; Upper; microflora; Acetaldehyde; microbe; acetaldehyde
158
_ is an alcohol
dehydrogenase
(ADH) inhibitor
4MP
159
_ 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
Acetaldehyde; repair; covalent
160
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
3rd; 3rd; cannabinoid; histone
161
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
antioxidants; HDL; decreases
162
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)
cardiomyopathies; inotropic; acetaldehyde; protein; mitochondria
163
opioids used for:
Pain (e.g. post-op) → pro/anti-nociceptive
* Block afferent transmission in the _ / _, _
* Safe and effective when used appropriately
anti; spinal cord/brainstem* Periaqueductal gray (PAG);
164
naloxone = _ antagonist
methadone = _ agonist
OR, mu
165
“semi-synthetic” = produced by
modifying a _ -derived
chemical
* Two acetyl groups make molecule
10x more _
naturally; lipophilic
166
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
morphine; Candace Pert & Sol Snyder; μ, δ, κ, ORL-1; NT release (e.g. DA, NE, GABA); membrane
potential
167
discovered opioid r by _ _ in brain tissue slices
Radioligand binding
168
endogenous opioids -> _ different peptide ligands,
18
169
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
t
170
δ (DOR; after vas
deferens):
* Expressed in:
* Neocortex * Striatum, NAc * Substantia nigra * Olfactory bulb
bound by _
enkephalins
171
κ (KOR; after
ketocyclazocine):
* Expressed in: * Pituitary * Hypothalamus * PAG * Spinal cord * Others
t/f: bound by EDPK
endorphins, dynorphins, PCP and ketamin
172
(ORL) 1:
* Expressed in:
* Limbic system
* Spinal cord
bound by B
buprenorphine
173
Illegal fentanyl comes mostly from _ to Canada
* Looks like 80mg _
* Sold as _
* dec/Increasing detection in heroin samples
* Can be found in cocaine, ecstasy
asia; oxycontin; heroin; Increasing;
174
fentanyl med use:
100x more potent than _
* 40-50x more potent than _
* Highly _
morphine; heroin; lipophilic
175
t/f: Fentanyl derivatives are even more potent
* Increased affinity for _ receptors + enhanced entry into the brain = higher/lower potency
t; mu; higher
176
t/f: Higher purity, safer for administration
t/f: * Street opioids are often contaminated
t, t
177
methods to absorb opioids - 6
inhale, ingest, inject, snort, subling, rectal
178
__ metab reduce bioavailability of opioids
first pass
179
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
leukoencephalopathy; spongiform; speak or move; metal; inconsistent
180
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
Acid or heat; particulates; thrombosis; fillers
181
t/f: opioids Most not lipophilic, does not readily cross BBB
* _ % reaches CNS sites
* Heroin → _ in the brain
* Metabolized in the _, excreted by _
t; 0.1; morphine; liver; kidneys
182
opioid adme:
distribution: 5 (LLSGB)
abs: 6
metab: 2
exc: 2
Liver * Lungs * Spleen * GI tract * Brain
inhale, ingest, inject, snort, subling, rectal
liver, brain
kidney, feces
183
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
Faster; morphine; 3-MAM and 6-MAM; MOR; does not; is not
184
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
postrema; nausea, vomiting; CTZ
oculomotor; constricted; opposite
185
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
reduced; Neonatal abstinence syndrome (NAS); physical
186
physl opioid effects: GI
Isometric muscle contractions increase/reduce bowel movements, secretions → _
* Constrict ureter and
sphincters of bladder,
stimulate _ hormone release → _ urination
reduce; constipation; anti-diuretic; decrease
187
t/f: evidence in mice contradicts runners high from pfc and limbic endorphin's increased release
t
188
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
separate; homology; mu; allelic; directly
189
all endogenous opioids contain an
N-terminal tyrosine residue
190
Morphine structure mimics
tyrosine
191
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 → _
Gi/o; α; adenylate cyclase; A; PLCβ, MAPK;
GIRK3; potassium; Ca; suppressing; desensitization
192
t/f: Differential activation of signaling pathways by OR ligands
t/f: Not all signaling is G-protein-mediated
t; t
193
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
Gprotein; low; internalization; increased; fentanyl
194
Altered patterns in
_ and _
mutants affect signaling and fx
L85I and R181C
195
opioid mediated analgesia
μOR primarily involved → expressed in TPRDh
thalamus, PAG, rostroventral medulla and dorsal horn of spine
196
* 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
* Cortex → [thalamus →] PAG → RVM → DHs
μOR, RVM; Tonic, dorsal;
reduces, OFF, elevated, decreased
197
* 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
decreases,
amygdala
Glu, subP, calcitonin gene-related peptide [CGRP]
198
* 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
AMPARs; CA1, dentate gyrus;
Glu, CA1
contextual; D1, D2; dynorphin, enkephalin, mu
199
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
down; higher; sober;
constipation, constriction
200
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
t; lower
201
_ et al. (1978) used ‘rat park’ vs. bare cage environments
* Isolated rats in bare cages administered much more/less morphine
Alexander; more
202
techniques to measure opioid tolerance (2)
* Tail immersion test
* Hot plate test
203
_ _ Used to gauge psychological addiction → escalating
behavioural responses to a stimulus like a drug of abuse after a drug-free period
Behavioural sensitization
204
Factors that contribute to sensitization include receptor _, _ levels, cell signaling _
density, NT; deregulation
205
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
NAc; D1; elevated; ERK1/2 MAPK; antagonists
206
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
desensitization; t; rapid; Ca, K
acute, intracellular; morphine, β-arrestin
207
Desensitization leads to _ in pain circuits
Heroin tolerance results in hyperalgesia, decreased latency in pain sensing → barbadin is _ inhibitor
hyperalgesia
β-arrestin
208
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
conditioned place aversion; D2; somatic; decreased
209
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
μ, K, suppresses;
noradrenaline
210
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
rostroventral,
glu
Adolescent
211
Clonidine or Lofexidine
* α2
-adrenoceptor agonists
* Prevents noradrenaline release via pre-synaptic α2
autoreceptors
* Targets LC and LC projections
*
212
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
213
* Methadone – for maintenance
* Long half-life, also an NMDAR antagonist
* No adulterants, sometimes free
* Mild euphoria, still causes constipation
* Ingested
214
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’
bulk, rushes
quinine
215
Fentanyl → in >50% of street opioids, 100x more potent than morphine
* Carfentanil → 10000x more potent than _
morphine
216
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
Reduced; genioglossus; pre
motoneurons
217
_ delivery prevents depression in preo-botzingner complex
naloxone
218
opioid triad: CDrP
coma (unresponsiveness), depressed respiration,
pinpoint pupils
