Inhalants

Question 1

Inhalants

Answer 1

aerosols, solvents, glues

gases and liquids inhaled directly or by accessory (rag, bag)
mixtures of lipophilic chemicals

Question 2

most common chemical mixtures

Answer 2

toluene
benzene
acetone

found across all forms

Question 3

use as anesthetics

Answer 3

N2O activates D2-like signaling in the nucleus accumbens → disrupts nociception

amyl nitrate releases NO in the blood → potent vasodilator = treatment of heart disease

Question 4

administration

Answer 4

inhalation:
huffing, sniffing, bagging → inhalation of vapours

Question 5

absorption

Answer 5

rapid
inhalation

Question 6

distribution

Answer 6

rapid and wide
small lipophilic molecules
distributes greatest concentration to fatty tissues = brain (myelin - lipids)
[blood] = 150-200 µM
[brain] = 100-900 µM

fast onset: ~10 seconds

Question 7

metabolism

Answer 7

toluene is metabolized in the liver by CYP2E1
toluene → 80% benzoic acid → hippuric acid

duration: 15-120 minutes

Question 8

excretion

Answer 8

kidneys
breath → gaseous nature of inhalants; volatile substances are exhaled = fast uptake and excretion

Question 9

hippuric acid

Answer 9

metabolite of toluene
can reduce blood pH at high doses = acidosis
→ can’t transport oxygen; tissues become hypoxic

Question 10

acute effects

Answer 10

biphasic effect

depressant drugs - slurred speech, inebriation

at low doses: disinhibition of motor circuits
at high doses: hallucination, anesthesia, coma, death (depression of critical structures for autonomic functions)

Question 11

biphasic effect

Answer 11

1. quick high (15-45 min) = euphoria, disinhibition, dizziness, light-headedness
2. depression (1-2 hrs) = drowsiness, disorientation, headache

Question 12

disinhibition of motor circuits

Answer 12

at low doses
depressed modulation of cerebellum
ex. can’t walk in a straight line

Question 13

physiological mechanisms of toluene

Answer 13

reward and euphoria via VTA → NAc reward pathway
elevated striatal dopamine levels

motor effects caused by effects on GABA in the caudate putamen
- basal ganglia → descending motor circuits

Question 14

cellular mechanisms of toluene

Answer 14

1. dopamine-mediated reinforcement
2. potentiates GABA and glycine (inhibitory)
3. inhibits NMDA-Glu receptors and nAChRs (excitatory)

sum of actions on ionotropic channels, Ca2+ signaling, G-proteins

Question 15

dopamine-mediated reinforcement

Answer 15

direct activation of VTA dopaminergic projections to the NAc to enhance dopamine release
stimulatory effect on DA neurons

Question 16

electrophysiology

Answer 16

stimulate neuron channels and measure current conducted through single channel

Question 17

Beckstead et al. 2000

Answer 17

use of heterologous culture: express GABA channels from humans in frog eggs

amount of current at a time through a single channel
measure deflections of current through GABA/glycine channels in presence + absence of toluene, trichloroethylene, and trichloroethane

Question 18

potentiation of GABA

Answer 18

toluene = more potently potentiating GABA channel current
>2x current passing through channel compared to only GABA

Question 19

potentiation of glycine

Answer 19

expression of channels in presence of glycine →
increase of negative current

Cl- channel
→ potentiate inhibitory current = hyperpolarization of cells → decreased electrical activity

Question 20

Cruz et al. 1998

Answer 20

recombinant NMDA receptors expressed in frog oocytes = heterologous culture
measure of current: control = NMDA + glycine (before drug); with toluene; washout recovery (after drug is gone)

Question 21

inhibition of NMDA 2B-containing receptors

Answer 21

NMDA receptors have different sub-type compositions - depending on brain region
all subunits show decreased deflection when toluene is added = less current through channels (inhibited)

2B-containing channels showed the least deflection in presence of toluene = most sensitive to toluene

dose response curve: 2B shows shift to left (steeper curve) = lower doses required to inhibit current through 2B-containing receptors

Question 22

inhibition of nAChR B2-containing receptors

Answer 22

dose dependent inhibition of β2 containing nAChRs
α4β2 subunit exhibits highest sensitivity to toluene-mediated inhibition

Question 23

nACh receptors in hippocampus

Answer 23

cultured hippocampal neurons are insensitive to acetylcholine in presence of toluene
still some firing seen but drastically reduced by toluene

Question 24

acute adverse effects

Answer 24

sensitize heart to epinephrine = sympathetic responses
cardiac dysrhythmias
mechanical asphyxiation
aspiration of vomit
trauma
unconsciousness, respiratory suppression, coma

Question 25

cardiac dysrhythmias

Answer 25

inhibited inactivation of voltage-gated Na+ and Ca2+ channels
QT interval (ventricular depolarization to complete repolarization) is prolonged = >480 ms
causes symptoms: tightness in chest, shortness of breath, palpitations

chemicals in nerve membrane alter kinetics of channel activation → don’t inactivate (can’t be turned off)
→ disregulation of action potentials

Question 26

aerosol-evoked cardiac arrest

Answer 26

chemicals at high pressure are cold → rapid chilling of epithelium in the larynx → mucosal edema and laryngospasm cause hypoxia (low O2 levels in throat and tissues) → irritate descending vagal (C10) nerve (controls heart tone)
→ elevated ACh release onto heart → bradycardia (slowed heart rate) and cardiac arrest

(blood is no longer being pumped because the heart is out of regulation)

Question 27

sudden sniffing death syndrome

Answer 27

encapsulates acute adverse effects into one syndrome
1/5 new users = 20% at risk of sudden death

Question 28

tolerance

Answer 28

may occur to euphoric effects of some inhalants

potentiation of receptor = cell decreases expression (restore normal)
increased NMDA receptor responses + decreased GABA receptor responses = hyperexcitable state in withdrawal

Question 29

withdrawal

Answer 29

mild symptoms; depends on frequency, dose (how much receptor levels change)
slow to develop
nausea, tremors, irritability, anxiety, sleep disturbances

Question 30

dependence

Answer 30

no psychological/physical
mild (usually only used for 1-2 years)
long term use → excitotoxicity/demyelination
increased NMDAR levels = too much Ca2+ release → cellular signaling

seen in rats: conditioned place preference by self-administration of toluene

Question 31

mechanisms → long term abuse

Answer 31

inhibitory:
NMDA/AChR inhibition
GABA/glycine potentiation

neuroadaptation - altered sensitivity of channels to drug binding (less prevalence of NMDA 2B and nAChR B2 subunits = shift away from sensitivity)

ACh attenuation initially → excitotoxicity (long term consequence = brain damage)

Question 32

hippocampal adaptations

Answer 32

Acetylcholine

structural changes as quickly as 4 days
- NMDA receptor subunit composition changes = increased 2B proteins (receptor subunits) seen in Western blot
- on medium spiny neuron membranes, receptor staining increases

Question 33

neuronal death in hippocampus

Answer 33

CA1 and CA3 regions after 40 day 200ppm toluene cycle
= memory loss

Question 34

long term risks

Answer 34

memory, cognitive, behavioural impairment
in youth, affects development of critical circuits → greater risk of drug abuse in adult life
damaged brain regions: basal ganglia, cerebellum, thalamus, pons, hippocampus
myelin loss → cognitive decline, slower processing, cerebellar ataxia (slowed neuronal transmission)

Question 35

targeting myelinated neurons

Answer 35

myelin is made of lipids = accumulation of inhalants

chronic toluene abuser → decreased brain volume and exaggerated sulci

Question 36

2,5-hexanedione

Answer 36

metabolite of hexane
penetrates neuronal axons and cross-links neuron cytoskeletal components
more components (targets) found in long peripheral neurons (ex. motoneurons) → more susceptible to damaging effects