L1 Neurobiology and neurochemistry of reward and addictive behaviours. Flashcards
What is addiction
A persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual.
due to changes in synaptic plasticity
What is withdrawal
Negative physiological and emotional features that occurs when the drug is not taken
generally opposite to positive experience induced by the drug.
What is Tolerance
diminishing effect of drug after repeated administration
-need more drug to get the same effect
Which regions of the brain are involved with Natural reward system?
Mesocorticolimbic system
PFC
Amygdala
Hippocampus
Evidence that Dopamine can act as error or learning signal
When given a reward with no stimulus
- There is a spike in activity after the reward
When given a stimulus prior to the reward
- Spike in activity before reward
- Anticipation of the reward is more pleasurable than receiving the reward
When reward does not come-
- Anticipation still spikes
- Fall in dopaminergic effect
Predicted vs unpredicted stimulus and learning
Unpredicted reward
increased activity in the Nucleus Accumbens – ‘tells’ our brain that there is something we should be learning
Predicted= response in temporal lobe
-indicating 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 neurons that detect the stimulus and the neurons that produce the instrumental response
- Long term potentiation
Natural Reinforces for reward
Food
Sex
Causes extracellular dopamine release in nucleus accumbens
What are the effects Pscychostimulants on dopaminergic system?
Direct action on Daergic neurons in NAcc
What are the effects Opiates on dopaminergic system?
Indirectly – inhibit GABAergic interneurons in VTA
causing disinhibition of VTA DA neurons
What are the effects Alcohol on dopaminergic system?
Disinhibition of VTA DA neurons
What are the effects Nicotine on dopaminergic system?
Increases Nacc DA directly and indirectly
stimulates nicotinic cholinergic receptors on mesocortiolimbic DA neurons
What is Dependence
- homeostatic response to repeated drug administration - unmasked by withdrawal
Sensitization
repeated administration elicits escalating effects
Cocaine and amphetamine
overview
inhibition of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) reuptake transporters
Cocaine inhibits transporters prolonging pool of DA
Amphetamine reverses transporter- increase DA
MOA- increase extracellular DA in NAcc by action on DAT
Effects of cocaine and amphetamine
Psychosis
Long term effects
- decreases DA transporters
- increased cellular and molecular changes that protmote dysregulation
Hyperfrontality [decreased blood flow to prefrontal cortex]
How does Cocaine work
inhibits transporter to prolong pool of extracellular DA
How does Amphetamine work
reverses transporter to increase extracellular DA levels
psychostimulant
How do drugs of abuse work [3]
- increase AMPA/NMDA ratio
-increases basal excitatory
synaptic strength.
-Neuronal basis of many forms of learning
Dopamine receptors in addiction
Decreased D2 receptors in cocaine addiction which normally causes inhibition and suppresses behaviour
The dopamine system central to conditioning and motivation
Changes likely responsible for reduced sensitivity to natural
rewards that develops with addiction.
Molecular activity of emotional dependence
Compensatory changes in VTA / NAcc to lower DA transmission:
Increased activity at D1 receptors (Gs coupled) in NAcc
Adenylyl cyclase - cAMP - PKA - downstream events
increased dynorphin (DYN) synthesis (endogenous opioid)
dynorphin released in VTA
acts at K opioid receptor
Inhibits VTA neuron firing
and NAcc DA release
Less DA release in NAcc
Associative learning and addiction
Coincident firing between sensory pathways and the mesocorticolimbic pathway will induce LTP and strengthen synaptic connections
Potential site for LTP
Glutamatergic synapses on reciprocal connections between
NAcc, VTA, cortex, hippocampus and amygdala
DA and LTP
DA enhances LTP
-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
