Inhalants Flashcards
Inhalants
aerosols, solvents, glues
gases and liquids inhaled directly or by accessory (rag, bag)
mixtures of lipophilic chemicals
most common chemical mixtures
toluene
benzene
acetone
found across all forms
use as anesthetics
N2O activates D2-like signaling in the nucleus accumbens → disrupts nociception
amyl nitrate releases NO in the blood → potent vasodilator = treatment of heart disease
administration
inhalation:
huffing, sniffing, bagging → inhalation of vapours
absorption
rapid
inhalation
distribution
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
metabolism
toluene is metabolized in the liver by CYP2E1
toluene → 80% benzoic acid → hippuric acid
duration: 15-120 minutes
excretion
kidneys
breath → gaseous nature of inhalants; volatile substances are exhaled = fast uptake and excretion
hippuric acid
metabolite of toluene
can reduce blood pH at high doses = acidosis
→ can’t transport oxygen; tissues become hypoxic
acute effects
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)
biphasic effect
- quick high (15-45 min) = euphoria, disinhibition, dizziness, light-headedness
- depression (1-2 hrs) = drowsiness, disorientation, headache
disinhibition of motor circuits
at low doses
depressed modulation of cerebellum
ex. can’t walk in a straight line
physiological mechanisms of toluene
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
cellular mechanisms of toluene
- dopamine-mediated reinforcement
- potentiates GABA and glycine (inhibitory)
- inhibits NMDA-Glu receptors and nAChRs (excitatory)
sum of actions on ionotropic channels, Ca2+ signaling, G-proteins
dopamine-mediated reinforcement
direct activation of VTA dopaminergic projections to the NAc to enhance dopamine release
stimulatory effect on DA neurons
electrophysiology
stimulate neuron channels and measure current conducted through single channel
Beckstead et al. 2000
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
potentiation of GABA
toluene = more potently potentiating GABA channel current
>2x current passing through channel compared to only GABA
potentiation of glycine
expression of channels in presence of glycine →
increase of negative current
Cl- channel
→ potentiate inhibitory current = hyperpolarization of cells → decreased electrical activity
Cruz et al. 1998
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)
inhibition of NMDA 2B-containing receptors
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
inhibition of nAChR B2-containing receptors
dose dependent inhibition of β2 containing nAChRs
α4β2 subunit exhibits highest sensitivity to toluene-mediated inhibition
nACh receptors in hippocampus
cultured hippocampal neurons are insensitive to acetylcholine in presence of toluene
still some firing seen but drastically reduced by toluene
acute adverse effects
sensitize heart to epinephrine = sympathetic responses
cardiac dysrhythmias
mechanical asphyxiation
aspiration of vomit
trauma
unconsciousness, respiratory suppression, coma
cardiac dysrhythmias
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
aerosol-evoked cardiac arrest
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)
sudden sniffing death syndrome
encapsulates acute adverse effects into one syndrome
1/5 new users = 20% at risk of sudden death
tolerance
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
withdrawal
mild symptoms; depends on frequency, dose (how much receptor levels change)
slow to develop
nausea, tremors, irritability, anxiety, sleep disturbances
dependence
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
mechanisms → long term abuse
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)
hippocampal adaptations
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
neuronal death in hippocampus
CA1 and CA3 regions after 40 day 200ppm toluene cycle
= memory loss
long term risks
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)
targeting myelinated neurons
myelin is made of lipids = accumulation of inhalants
chronic toluene abuser → decreased brain volume and exaggerated sulci
2,5-hexanedione
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
