Nicotinic addiction Flashcards
Define addiction
A brain disorder characterized by compulsive engagement in rewarding stimuli, despite adverse consequences
What are the two stages of addiction?
stage 1 - impulsive
- stopping drug use has neutral effect
- however craving for pleasurable sensation
stage 2 - compulsive
- taking drug results in no pleasure but release from discomfort
- negative effect of abstinence
How is nicotine metabolised?
Mostly metabolised by cytochrome p450
- 10% concerted to other metabolites
- 10% excreted unchanged in urine
What are commono nicotine withdrawal symptoms?
- Anxiety
- Irritability
- Decreased heart rate
- Restlessness
- Depression
Which brain regions are responsible for reward systems?
Mesolimbic system
- Ventral tegmental area containing cholinergic and dopaminergic neurons
- Nucleus accumens
- Amygdala
- Prefrontal cortex
(fMRI shows enhanced activity in these areas in addiction)
Which receptors respond to
a) alcohol
b) nicotine
c) endocanabinoids
d) amphetamine
a) BAGAaR receptors (also antagonise NMDAR)
b) nAChRs
c) 1THC/CB1 cannabinoid receptors
d) DA transporters
Where are the receptors responsible for nicotine addiction located in the brain?
- nAChRs on ventral tegmental area dopamine neurons
- nAChRs on dopaminergic nucleus accumens terminals
- nAChRs in thalamus
How does the smoke from cigarettes also contribute to addiction?
- Inhibits MAO (monoamine oxidase) which breaks down dopamine in the body
- Activity supressed in smokers
What mechanisms mediate accute tolerance to nicotine?
nAChR desensitisation
Which mechanisms mediate chronic nicotine tolerance?
- upregulation of high affinity nAChRs in PFC (alpha and beta subunits, not just alpha)
- PFC-NAcc glutaminergic pathway altered, so that response inhibition and impulse control is compromised
- PFC-dorsal striatum projection stengthened, smoking becaomes automatic
- Reduced grey matter and neural activity in PFC
What are the molecular mechanisms of nicotinic addiction?
Gene upregulation of ΔFosB in NAcc and dorsal striatum
- ΔFosB is phosphorylted
- Enters nucleus to upregulate expression of CDKs (cell division kinases)
- Can then catalyse the phsophorylation of DARPP (dopamine and cAMP-regulated neuronal phosphoprotein) which is critical for dopamine dependennt synaptic plasticity
Which health risks are associated with smoking?
- Carbon monoxide
- Tar which contains carcinogens
How does bupprapin combat nicotine addiction?
Anti-depressant: DA uptake inhibitor and nAChR antagonist
Lessens cigarette craving
How does varonicline combat nicotine addiction?
Partial agonist for high affinity nAChRs in the brain
