Alcohol Flashcards
Mechanism of Action of alcohol
- positive modulation of GABAA
receptor function - negative modulation of AMPA and
NMDA receptor function - general CNS depression
Mechanism of Action of alcohol ?
- positive modulation of GABAA
receptor function - negative modulation of AMPA and
NMDA receptor function - general CNS depression
what is the effect of chronic alcohol exposure on the receptor function
Downregulation of GABA A receptor function
what is the mechanism of alcohol tolerance
- subunit switch (e.g. π°4)
(cross-tolerance to other
positive modulators) - increased internalization
- altered phosphorylation
- uncoupling of the GABA /
ethanol sites
what are the ethanol receptors
Glycine receptor
BK channel
what are the alcohol withdrawal symptoms
minor withdrawal symptoms
seizures
delirium tremens
hallucination
what are the Pharmacological therapy for alcohol use disorder
Diazepam
Acamprosate
Naltrexone
how does Diazepam work
- benzodiazepine that is used to treat anxiety and convulsions
- approved for acute alcoholic withdrawal: symptomatic relief of acute
agitation, tremor, and impending acute delerium tremens
how does Acamprosate work
- dissociates into acetylhomotaurine and calcium
- homologue of GABA
- action not fully understood; restores the excitatory / inhibitory balance
in the brain - indicated for maintenance of abstinence from alcohol
how does Naltrexone work
- long-acting opioid receptor antagonist (π»,πΉ,π³)
- action not fully understood; endogenous opioid system may be involved
how does
As an antagonist at the π» opioid receptor,
naltrexone may reduce the urge to consume
alcohol through two mechanisms:
* Suppression of alcohol-mediated
π±-endorphin stimulation of dopamine
neurons in the nucleus accumbens
* Reduction of π±-endorphin disinhibition of
the tonic inhibition of dopamine cells by
GABAergic neurons in the ventral
tegmental area
How does Naltrexone reduce the urge to consume alcohol
As an antagonist at the π» opioid receptor,
naltrexone may reduce the urge to consume
alcohol through two mechanisms:
* Suppression of alcohol-mediated
π±-endorphin stimulation of dopamine
neurons in the nucleus accumbens
* Reduction of π±-endorphin disinhibition of
the tonic inhibition of dopamine cells by
GABAergic neurons in the ventral
tegmental area
what is cannabis
delta9-tetrahydrocannabinol
(Ξ9-THC)
how is the Ξ9-THC concentrations in declining order:
flowering tops -> bracts -> leaves -> stems -> roots -> seeds
which cannabinoid is Psychoactive, Less Psychoactive, Not Really Psychoactive
Psychoactive (i.e., activation of CB1 receptors)
* Ξ9-THC
Less Psychoactive
* Cannabichromene
Not Really Psychoactive (not active at CB1 or CB2 receptors)
* Cannabinol
* Cannibidiol
compare Pharmacokinetics of the cannabinoid
inhalation: Fast acting and early onset
- In blood within seconds
- 10-35% of THC in blood
ingestion;
- Slow acting and late onset
- Passes through the liver
what are the behavioral effects of the cannabinoid
Subjects may have a form of disinhibition in that there is an inclination
to increase motor activity, and behavior is impulsive. However,
paradoxically, even the simplest tasks appear to require enormous
effort»_space;»» Motor activity & impulsivity is up. Effort & coordination is down.
what are the Problematic effects of Cannabinoid
- Forgetfulness (working memory tasks)
- Poor concentration
- Motor coordination impairment
- Poor sense of time
- Reaction time slower
- Some anxiety or paranoia
what are the common withdrawal symptoms of cannabinoids
Common Symptoms
Decreased Appetite
Irritability
Nervousness/Anxiety
Anger
Restlessness
Sleep Difficulty/Strange Dreams
how is the dopamine level after the THC withdrawal
Dopamine levels
are down during
withdrawal from
chronic THC
what are the The βendocannabinoidsβ
- Anandamide
- 2-arachidonyl glycerol (2-AG)
How do Endocannabinoids work
Agonists at CB1 and CB2
how does CB1 work
- Expressed in the CNS (cerebral cortex, hippocampus, caudate putamen,
basal ganglia, cerebellum) - Located on presynaptic terminals (thus, modulate neurotransmitter release)
where does CB2 work
- Very low expression
in the CNS - Predominantly located
in the periphery
what is Endocannabinoids: Mechanism of Action
Retrograde second messenger signalling to provide negative feedback
What are CB1 and CB2 receptors coupled with
Both CB1 and CB2 receptors are GPCRs that are coupled with Gi/o (inhibitory)
what is the signalling consequences of receptor activation
decreased function
of adenylate cyclase
- increased function
of GIRK K + channels
- decreased function
of voltage-gated
Ca2+ channels
This all acts to
hyperpolarize the local
membrane potential
and decrease
neurotransmitter release
how annabinoids contribute to the reward pathway
Cannabinoids can activate the inhibitory CB1 receptor on GABAergic neurons
to disinhibit the VTA dopaminergic neurons β> increased DA release
what is the Acute THC reward pathway
- increased DA neuron firing in the VTA
- increased DA release in the nucleus accumbens and prefrontal cortex
(mesolimbic and mesocortical dopamine pathways) - increased content for tyrosine hydroxylase (DA synthesizing enzyme)
- increased DA synthesis
(CB1 receptor)
what is the Chronic THC reward pathway
- altered GLU and GABA signalling onto VTA DA neurons (below)
- decreased DA synthesis and release in response to a rewarding stimulus
- increased D2 receptor availability in postsynaptic neurons
- morphological alterations to dendrites
