Neurobiology and neurochemistry of reward and addictive behaviours Flashcards
Addiction/ substance dependence
A persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual
Both physical and psychological
Withdrawal symptoms
Negative physiological and emotional features that occur when the drug is not taken
Different for each drug of abuse, but generally opposite to positive experience induced by the drug
Tolerance
Diminished response to the effects of a given amount of drug following repeated exposures to the drug
Implies increasingly larger doses of the drug are required to induce the same behavioural effect
Where do drugs act in the brain?
Drugs hijack reward system
- mesolimbic system
- mesocortical system
Also involves
- PFC
- amygdala
- hippocampus
Dopamine
- error or learning signal
Primary activating neurotransmitter for the reward pathway
Animal has to change behaviour in order to get reward
Reinforcement system is activated by unexpected reinforcing stimuli, and by presence of reward relative to its prediction
Unexpected reward
Activity in the nucleus accumbens
Response that tells our brain there is something we should be learning
Pretictable response
Disappears from NAcc ad response is seen in temporal lobes
Indicates learning has taken place
Functions of the reinforcement system
Detect reinforcing stimulus
Recognise something good has just happened
Time to learn
Strengthen neural connections
Between neurones that detect the stimulus and neurones that produce instrumental response
Long term potentiation
The mesocorticolimbic dopamine system
Drug induced synaptic plasticity in the
- NAcc
- dorsal striatum
Contribute to addiction by consolidating
- drug wanting
- drug seeking
- drug taking
Mesocorticolimbic dopamine system
Behaviours activating system are reinforced
- more likely to be repeated
Addictive drugs cause more powerful and reliable activation than natural
- they hijack the system
Blockade of DA in the region
- attenuates most measurable reinforcing and rewarding effects of addictive drugs
Action of psychostimulants
Direct action on DAergic neurones in NAcc
Action of opitates
Indirectly inhibit GABAergic interneurones in VTA
Disinhibition of VTA DA nruones
Action of alcohol
Disinhibition of VTA DA neurone
Action of nicotine
Increases NAcc DA directly and indirectly
Stimulates nicotinic cholinergic receptors on mesocorticolimbic DA neurones
Cocaine and amphetamine
DA agonists
Potentiate monoaminergic transmission by inhibition of dopamine, serotonin and norepinephrine reuptake transporters
Action at dopamine transporter most directly related to reinforcing effects
Feelings of euphoria
Cocaine action
Blocks and inhibits transporter to prolong pool of extracellular DA
Amphetamine action
Reverses transporter to increase extracellular DA
Effects of cocaine and amphetamine
Psychotic behaviour
Adverse long term effects on the brain
- reduced DA transporters/ terminals
Cellular and molecular changes the promote dysregulation
- increased activity of VTA tyrosine hydroxylase
Hypofrontality
Increased excitatory strength
All drugs of abuse - significant increase in AMPA/ NMDA ratio
Increase in basal excitatory synaptic strength
Fewer D2 receptors in addiction
Decreased D2 receptors in cocaine addict
Dopamine system central to conditioning and motivation
Changes likely responsible for reduced sensitivity to natural rewards that develops with addiction
Emotional dependence
Compensatory changes in VTA/ NAcc to lower A transmission
Increased activity at D1 receptors in NAcc
Adenylyl cyclase- cAMP- PKA - downstream eventes increased DYN synthesis
DYN released in VTA acts as K opioid receptor
Inhibits VTA neurone firing and NAcc DA release
Less DA release in NAcc
Associative learning
Potential sites for LTP
- glutamatergic synpases on reciprocal connections between NAcc, VTA, cortex, hippocampus and amygdala
Sensory information, people, places, emotions etc at time of drug taking associated with taking the drug
Dopamine enhances long term potentiation
Dopamine at D1 receptors
Adenylyl cyclase- cAMP- PKA
Modifies glutamatergic transmission allowing LTP
CREB mediated gene transcription and new protein synthesis
Synaptic remodelling- increased spines and dendritic branches
Long term molecular and cellular changes remain months after abstinence
Memories in these pathways may trigger relapse years later
Opiates action
e.g. morphine and heroin
Endogenous opioid receptors
Inhibitory
- decrease adenylyl cyclase activity
- lead to open K+ channels, close Ca2+ channels
Different receptor subtypes
- on different cells in different brain regions
Opiates reward and reinforcement
Disinhibition of DA neurones in VTA
Action at opiate receptors in NAcc- independent of DA release
Alcohol
GABA agonist (inhibitory)
NDMA antagonist (blocks excitation)
Large doses inhibit funcitoning of most voltage gate channels
EtOH leads to increased DA release in NAcc
Nicotine
Acts at nicotinic acetylcholine receptors
- ligand gated ion channels
- presynaptic receptors- influx of Ca2+- transmitter release
Nicotine treatment increases DA release in NAcc
Activation of receptors on cell body in VTA
Facilitation of DA release by pre-synaptic receptors in NAcc
