Neurobiology and neurochemistry or reward based behaviours Flashcards
Addiction
Persistent disorder of brain function where compulsive drug use occurs despite serious negative consequences in afflicted individual
- Due to changes in synaptic plasticity
Withdrawal symptoms
Negative physiological and emotional features that occurs when a drug is not taken.
Usually opposite to positive experience induced by the drug
Tolerance
Diminished response to the effects of a given amount of drug
- Due to repeated exposure to the drug
Increasing larger dosage is required to have the same effect
Regions in the brain for the natural reward system/ addicition
Mesocorticolimbic system
Prefrontal cortex
Amygdala
Hippocampus
Dopamine error / 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 nucleus accumbens
- Tells the brain they should be something being learned
Predictable = response in temporal lobe
- 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 neurons that detect the stimulus and the neurons that produce the instrumental response
- Long term potentiation
Natural reinforcers for reward
Food
Sex
Causes extracellular dopamine release in nucleus accumbens
Psychostimulants
- Effects on dopaminergic system
Directly affects dopaminergic neurones in the nucleus accumbens
Opiates
- Effects on dopaminergic system
Indirectly – inhibit GABAergic interneurons in VTA
- Disinhibition of VTA DA neurons
Alcohol
- Effects on dopaminergic system
Disinhibition of dopamine neurones
Nicotine
- Action
Increases Nacc DA directly and indirectly
Stimulates nicotinic cholinergic receptors on mesocortiolimbic DA neurons
Dependance
Homeostatic response to repeated drug administration
Unmasked by withdrawal
Sensitisation
Repeated administrating of drug = escalating effects
Cocaine and amphetamine
- Mechanism
- Role in reinforcement
Inhibits dopamine, serotonin and noradrenaline reuptake transporters
- Cocaine inhibits
- Amphetamine reverses transporters
= Increased synaptic DA
Reinforcement
- Action on dopamine transporter on plasma membrane
Cocaine and amphetamine
- Effects
Psychosis
Long term
- Decreases dopamine transporters and terminals
- Increased cellular and molecular changes that promote dysregulation
Hypofrontality [decreased blood flow to prefrontal cortex]
Increased excitatory strength and drug abuse
Drug abuse shows significant increase in AMPA/NMDA ratio
= Increased basal excitatory synaptic strength
Dopamine receptors in addiction
Fewer D2 receptors
- Reduces sensitivity to natural rewards that develops with addicition
Molecular activity of emotional dependence
Compensatory changes in the VTA or Nucleus accumbens = lower DA transmission
At first;
- Increased D1 receptor activity in NAcc sets off Gs protein signalling
PKA and cAMP release =
VTA
- dynorphin synthesis and release is inhibited
- Acts on K opiod receptor
Nucleus accumbens
- Less DA release
Associative learning and addiction
Coincident firing in sensory and mesocorticolimbic pathways
= LTP induction = strengthened synaptic connections
Glutaminergic synapses form on reciprocal connections in: - NAcc - VTA - Cortex - Hippocampus - Amygdala = Potential sites for LTP
Information present at the time of drug induced DA release —–> associated with drug taking
Dopamine and LTP
DA acts on D1 receptor [Gs protein]
- Increase in PKA = gulatamatergic transmssion = LTP
Late phase LTP
- CREB protein mediation and protein synthesis
Synaptic remodelling - Increased spines and dendrite branches - long term molecular and cellular changes remain months after abstinence - Memories in these pathways may trigger relapse years later
Opiates
- Action
- Reward and reinforcement
Acts on endogenous opioid receptors (Gi coupled)
Morphine mainly acts on gamma receptors
Reward and reinforcement
- Disinhibition of DA neurons in VTA
- Action at opiate receptors in the NAcc - independent of DA release (μ or δ)
Alcohol
- Mechanisms
- GABA-alpha agonist
- NMDA antagonist
- In the VTA cortical inputs = disinhibits VTA DA neurones
- Increases Dopamine release in the nucleus accumbens
Rewarding effects blocked by DA receptor antagonists in NAcc
Naltrexone and alcohol
Opiate antagonist
- Reduces alcohol self administration in animals
- Used to reduce alcohol consumption, relapse and craving
Nicotine
- Mechanism
Acts on nicotinic Ach receptors
Nicotine = release of dopamine in nucleus accumbens due to:
- Activation of receptors on cell body in the VTA
- Facilitated DA release by pre-synaptic receptors in NAcc
Opiates and nicotine
Opiates block nicotine induced behaviours and self administration
- I.e Naltrexone used to add smoking cessation
Physical dependancy on opiates
Locus coeruleus
- Contains opiate receptors
- Nucleus involved in attention, arousal and vigilance [NADR]
Chronic activation of opiate receptors = homeostatic compensation = tolerance and physical dependance
Morphine and locus coeruleus
Acute morphine = inhibits LC neurones
Chronic morphine = LC neurones return to firing state
Withdrawal = Dramatic increase in LC neurones firing
- Over activation of ANS
Clonidine
Alpha-2 agonist that blocks the over activation of ANS seen in physical withdrawal of opiates
Physical dependance to alcohol
Acute effects
- GABA-alpha agonist
- NMDA antagonist
= Cell firing inhibited
Chronic
- Downregulation of GABA-alpha
- Upregulation of NMDA
- Firing rates normal in presence of alcohol
Withdrawal
- In alcohol absence= excitation
- Physical symptoms
Reward pathway in the brain
Release of dopamine in mesocorticolimbic system.
DA released from the VTA to multiple areas when a rewarding stimulus is experienced:
- Prefrontal cortex
- Nucleus Accumbens
- VTA
- Amygdala
- Hippocampus
Release of DA stimulates the desire for the stimulus again
Mechanism of emotional dependance
Due to compensatory control to decrease Dopamine release in the VTA and NAcc
- Drugs act on D1 receptors [Gs] in NAcc
- Triggers downstream events [cAMP, PKA] - Downstream events trigger release of Dynorphin from NAcc to VTA
- Dynorphin acts on Kappa receptors on VTA DA neurones. - Activation of K receptors reduces VTA DA neuronal firing= less release of DA into NAcc
As a result–> Less DA is released in the event of the drug not being there
- Naturally rewarding stimuli cannot produce enough DA
