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
activity-dependent changes effects
changes in neurotransmitter release can also change structure as well
specificity of LTP
confined to specific contact sites
associativity of LTP
strong stimulation in one pathway will induce LTP for weak pathways (pathways pushed to overdrive)
cooperativity of LTP
many weak stimuli induces LTP through constructive interference
persistance of LTP
- potentiation can last min, wks, … etc.
- unique to LTP (this is not what happens in other plasticity)
long-term depression (LTD)
weakening of synaptic transmission between two neurons
dopamine prediction error hypothesis
- an unexpected reward in phasic firing of VTA DA-ergic neurons resulted in learning
- learning stops when reward is predictable, therefore DA-ergic neurons are not triggered
- learning signal leads to drug adaptive behaviours, therefore there is a compulsive drug intake at the expense of all other behaviours
- ex: lab animals prefer drugs over food, water, toys, sex, even if it causes pain
NE in addiction
- innervation activates sympathetic responses
- major role in stress-induced relapse
5-HT in addiction
- binds several 5-HT receptors that are triggered by hallucinogens and entactogenic drugs
- drugs binding the receptors are less addicting
- bi-synaptic 5-HT inputs to the VTA and NAc from RN
ACh in addiction
- activates parasympathetic responses
- major role in learning and memory circuits
- nicotinic ACh receptors display several isoforms with brain region-specific expression including on VTA DA-ergic neurons
pleiotropic
- all drugs are pleiotropic
- psychoactive effects do not occur in isolation
- long periods of addiction causes tissues to become dysfunctional
cocaine pleiotropy
- damages heart cell sarcolemmal membranes
- releases lactate dehydrogenase
smoking pleiotropy
- sustained stress
- inflammation in oral/lung tissue
alcohol pleiotropy
liver disease (epicentre of dysfunction)
