3 - Addiction Flashcards
reward circuit
- descending glutamatergic pathway from anterior bed nuclei to VTA
- ascending dopaminergic VTA to NAc
- GABA-ergic NAc pathway to ventral palllidum
neurotransmitters in addiction
- dopamine
- glutamate
- GABA
- norepinephrine
- acetylcholine
- serotonin
dopamine (DA)
- catecholamine
- primary driver of reward circuit
- 2nd step in reward circuit
glutamate (Glu)
- amino acid
- major role in relapse (cue-triggering)
- LTP/LTD plasticity (adapting)
GABA
- inhibitory
- major role in disinhibitory mechanisms of reward (no self-control)
- norepinephrine (NE)
- catecholamine (NTs released in stress)
- comes from locus coeruleus in brain
acetylcholine (ACh)
- receptors found in VTA DA-ergic neurons
- major role in learning/memory
serotonin (5-HT)
- monoamine indole (hallucinogens)
- comes from raphe nuclei
- low source of 5-HT results in violence and impulse actions
dopamine receptors (DRs)
- 5 genes
- all GPCRs
- D1-like type
- D2-like type
D1-like type receptors
- D1 and D5
- Gs coupled
- increase cAMP via adenylyl cyclase
D2-like type receptors
- D2, D3, and D4
- Gi coupled
- decrease cAMP via adenylyl cyclase
role of dopamine in addiction from animal tests
- effort exerted in self-administration is directly proportional to the degree of reward
- conditioned place preference
- nicotine injections produced CPP and voluntary self-administration
conditioned place preference (CPP)
- the link of an environment with VTA DA-ergic projections
- results in animal’s preference in drug related chamber
- time spent in the drug-paired chamber = drug-seeking behaviour
neurotransmitter levels
- measured in nuclei with microdialysis
- inputs made to the reward circuit control hedonic tone
dopamine antagonists
- negative reinforcers
- enhance behaviours in attempts to decrease administration of a drug
- causes aversive effects (punish stimulus behaviour), therefore drug-taking behaviour is ceased
microdialysis in NAc
- first dose increases tonic extracellular level by 200%
- fluctuates between 100-200%
- low points predict next self-administered dose
tolerance in addicts
- leads to lowered hedonic tone, therefore more drug is required to mimic euphoric effect from 1st dose
- depressed activity in the reward circuit post-use (withdrawl stages) causes dysphoria
sensitization
reverse tolerance (moves further away from baseline)
AMPA receptors (AMPARs)
- 4 genes, 4 protein subunits
- fast, excitatory transmission
- ionotropic (membrane-bound receptor proteins)
- forms tetramers
- C-terminus forms intracellular scaffolds
- major role in LTD
N-methyl-D-aspartate receptors (NMDARs)
- 7 genes, 7 protein subunits
- ionotropic (membrane-bound receptor proteins)
- coactivated by Glu AND Ser/Gly
- calcium dependent
- subunits are heterotetramer (2 GluN1 + 2GluN2)
- major role in LTP/LTD
glutamate receptors (mGlu-R)
- 8 genes
- metabotropic (metabolic steps for activity)
- group C GPCRs
- each encodes a receptor
- involved in synaptic plasticity (change in synapses)
- Group 1
- Group 2/3
Group 1 mGlu-R
- Gq-linked
- increase excitotoxicity risk
- explains lower volume of addicts’ brains as cells are dying
Group 2 mGlu-R
- Gi/o-linked
- decrease excitotoxicity risk
long-term potentiation (LTP)
- strengthening of synaptic transmission between two neurons downstream of glutamate receptors