Neurobiology and Neurochemistry of Reward and Addictive Behaviours Flashcards
1
Q
What is Addiction / substance dependence?
A
- A persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual.
- Both physical and psychological.
2
Q
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.
A
- A persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual.
- Both physical and psychological.
3
Q
Withdrawal symptoms
- Negative … and … features that occur when the drug is not taken.
- Different for each drug of abuse, but generally … to positive experience induced by the drug.
A
- 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.
4
Q
What are Withdrawal symptoms?
A
- 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.
5
Q
What is Tolerance (drugs)?
A
- Diminished response to the effects of a given amount of drug following repeated exposures to the drug.
- This implies that increasingly larger doses of the drug are required to induce the same behavioural effect.
6
Q
Tolerance (drugs)
- … response to the effects of a given amount of drug following repeated … to the drug.
- This implies that … larger doses of the drug are required to induce the same … effect.
A
- Diminished response to the effects of a given amount of drug following repeated exposures to the drug.
- This implies that increasingly larger doses of the drug are required to induce the same behavioural effect.
7
Q
Where do drugs act in the brain?
A
- Drugs hijack the natural reward system
- Mesolimbic system and Mesocortical system - the Mesocorticolimbic pathway (reward & reinforcement, provides stimulus salience)
- Addiction also involves the:
- Pre Frontal Cortex (impulsiveness, decision making, self monitoring)
- Amygdala
- Hippocampus
8
Q
Where do drugs act in the brain?
- Drugs hijack the natural reward system
- … system and … system - the … pathway (reward & reinforcement, provides stimulus salience)
- Addiction also involves the:
- Pre … … (impulsiveness, decision making, self monitoring)
- A…
- H…
A
- Drugs hijack the natural reward system
- Mesolimbic system and Mesocortical system - the Mesocorticolimbic pathway (reward & reinforcement, provides stimulus salience)
- Addiction also involves the:
- Pre Frontal Cortex (impulsiveness, decision making, self monitoring)
- Amygdala
- Hippocampus
9
Q
Anticipation of reward recruits NAcc (stands for the … …)
A
Anticipation of reward recruits NAcc (nucleus accumbens)
10
Q
Anticipation of rewards rather than the reward itself that causes the recruitment of the … …
A
Anticipation of rewards rather than the reward itself that causes the recruitment of the Nucleus Accumbens
11
Q
What is the primary activating neurotransmitter for the reward pathway?
A
Dopamine
12
Q
DA as an “error” or “learning” signal
- Monkey hooked up with electrodes within the brain, reading activity. Completes task of hitting button in response to stimulus on the screen, electrical activity measured at tip of electrode.
- If just given a reward with no stimulus i.e. an unexpected award that cannot be predicted then when is there is a spike in activity?
- However, if presented with stimulus prior to the reward then we note a spike in activity when?
- Note that this spike is … intense than that of the one when he actually receives the reward
- If reward does not come (monkey makes an error on test) then do we still get the anticipation spike?
A
- Monkey hooked up with electrodes within the brain, reading activity. Completes task of hitting button in response to stimulus on the screen, electrical activity measured at tip of electrode.
- If just given a reward with no stimulus i.e. an unexpected award that cannot be predicted then there is a spike in activity after the reward
- However, if presented with stimulus prior to the reward then we note a spike in activity before the reward i.e. reward predicted and the response is in anticipation of the reward
- Note that this spike is more intense than that of the one when he actually receives the reward i.e. the anticipation is more ‘pleasurable’ than the reward itself
- If reward does not come (monkey makes an error on test) then still get the anticipation spike but see a fall in dopaminergic effect at time that reward would have come
13
Q
When a reward is unexpected then we see activity in the … …
- (However, once it is learnt, i.e. predictable, this response disappears from the … and the response is seen in the … … – indicating that learning has taken place)
A
- When a reward is unexpected then we see activity in the Nucleus Accumbens – think of this as a response that ‘tells’ our brain that there is something we should be learning
- (However, once it is learnt, i.e. predictable, this response disappears from the NAcc and the response is seen in the temporal lobes – indicating that learning has taken place)
14
Q
Functions of the Reinforcement System
- Detect reinforcing stimulus
- Recognise something … has just happened
- Time to …
- Strengthen … connections
- Between neurons that detect the … and the neurons that produce the … response
- Long term …
A
- 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
15
Q
The mesocorticolimbic dopamine system
- Dopamine neurons project from the … to the … and PFC
- Pathway for r… and r..
- … … activate this system
A
- Dopamine neurons project from the VTA to the Nacc and PFC
- Pathway for reward and reinforcement
- Addictive drugs activate this system
16
Q
Mesocorticolimbic dopamine system
- Behaviours activating system are …
- More likely to be …
- … drugs causes more powerful and reliable activation than … rewards
- they hijack the system
- … of … in this region
- attenuates most measurable reinforcing and rewarding effects of addictive drugs
A
- Behaviours activating system are reinforced
- More likely to be repeated
-
Addictive drugs causes more powerful and reliable activation than natural rewards
- they hijack the system
-
Blockade of DA in this region
- attenuates most measurable reinforcing and rewarding effects of addictive drugs
17
Q
Common drug effects on DA system
- All drugs have effect on DAergic system
- Though through different mechanisms – e.g:
- … - Direct action on Daergic neurons in NAcc
- … - Indirectly – inhibit GABAergic interneurons in VTA = disinhibition of VTA DA neurons
- … - Disinhibition of VTA DA neurons
- … - Increases Nacc DA directly and indirectly, stimulates nicotinic cholinergic receptors on mesocortiolimbic DA neurons
A
- All drugs have effect on DAergic system
- Though through different mechanisms – e.g:
- Psychostimulants - Direct action on Daergic neurons in NAcc
- Opiates - Indirectly – inhibit GABAergic interneurons in VTA = disinhibition of VTA DA neurons
- Alcohol - Disinhibition of VTA DA neurons
- Nicotine - Increases Nacc DA directly and indirectly, stimulates nicotinic cholinergic receptors on mesocortiolimbic DA neurons
18
Q
Common drug effects on DA system
- All drugs have effect on DAergic system
- Though through different mechanisms – e.g:
- Psychostimulants - … action on Daergic neurons in NAcc
- Opiates - Indirectly – inhibit … interneurons in VTA = disinhibition of VTA DA neurons
- Alcohol - … of VTA DA neurons
- Nicotine - … Nacc DA directly and indirectly, stimulates nicotinic cholinergic receptors on mesocortiolimbic DA neurons
A
- All drugs have effect on DAergic system
- Though through different mechanisms – e.g:
- Psychostimulants - Direct action on Daergic neurons in NAcc
- Opiates - Indirectly – inhibit GABAergic interneurons in VTA = disinhibition of VTA DA neurons
- Alcohol - Disinhibition of VTA DA neurons
- Nicotine - Increases Nacc DA directly and indirectly, stimulates nicotinic cholinergic receptors on mesocortiolimbic DA neurons
19
Q
This dopaminergic response is a normal reaction
- The … system will be activated in response to many stimuli – central to …
A
The mesolimbic system will be activated in response to many stimuli – central to motivation
20
Q
Drugs increase DA release in the NAcc -> Drug taking is reinforced -> But how do we get addicted?
- HOMEOSTATIC CHANGES – NEURONAL ADAPTATIONS lead to …:
- diminishing effect of drug after repeated administration
- need more drug to get the same effect
- …:
- physical or emotional - adaptive state
- homeostatic response to repeated drug administration
- unmasked by withdrawal
- ASSOCIATIVE LEARNING PROCESSES – SYNAPTIC PLASTICITY lead to
- …:
- repeated administration elicits escalating effects
- effect of psychostimulants (used in animal models)
- …:
- compulsive taking
- craving and relapse
- persistent for many years
A
- HOMEOSTATIC CHANGES – NEURONAL ADAPTATIONS lead to Tolerance:
- diminishing effect of drug after repeated administration
- need more drug to get the same effect
-
Dependence:
- physical or emotional - adaptive state
- homeostatic response to repeated drug administration
- unmasked by withdrawal
- ASSOCIATIVE LEARNING PROCESSES – SYNAPTIC PLASTICITY lead to
-
Sensitization:
- repeated administration elicits escalating effects
- effect of psychostimulants (used in animal models)
-
Addiction:
- compulsive taking
- craving and relapse
- persistent for many years
21
Q
Drugs increase DA release in the NAcc -> Drug taking is reinforced -> But how do we get addicted?
- … CHANGES – … ADAPTATIONS lead to Tolerance:
- diminishing effect of drug after repeated administration
- need more drug to get the same effect
- Dependence:
- physical or emotional - adaptive state
- homeostatic response to repeated drug administration
- unmasked by withdrawal
- … … PROCESSES – SYNAPTIC … lead to
- Sensitization:
- repeated administration elicits escalating effects
- effect of psychostimulants (used in animal models)
- Addiction:
- compulsive taking
- craving and relapse
- persistent for many years
A
-
HOMEOSTATIC CHANGES – NEURONAL ADAPTATIONS lead to Tolerance:
- diminishing effect of drug after repeated administration
- need more drug to get the same effect
- Dependence:
- physical or emotional - adaptive state
- homeostatic response to repeated drug administration
- unmasked by withdrawal
- ASSOCIATIVE LEARNING PROCESSES – SYNAPTIC PLASTICITY lead to
- Sensitization:
- repeated administration elicits escalating effects
- effect of psychostimulants (used in animal models)
- Addiction:
- compulsive taking
- craving and relapse
- persistent for many years
24
Q
Cocaine and amphetamine have different actions - Though similar net effect
-> … synaptic DA
A
Cocaine and amphetamine have different actions - Though similar net effect
-> Increased synaptic DA
25
Q
Binding sites of cocaine following acute administration
A
- These studies show a similarity between the time-course of cocaine receptor (dopamine transporter) occupancy and the timecourse of the psychological effects of cocaine in humans, suggesting a direct relationship. Also, prolonged use or high doses of cocaine causes paranoia and psychosis - symptoms often associated with schizophrenia, a syndrome thought to involve the dopaminergic limbic pathway.
27
Q
Increased excitatory strength - 24 hours after injection (addictive drugs)
- All drugs of abuse - significant … in the AMPA/NMDA ratio
- An … in basal excitatory synaptic strength.
- Neuronal basis of many forms of …
- One injection – changes persist for … days
- Animal receives injections for … weeks – changes persist in VTA
A
- All drugs of abuse - significant increase in the AMPA/NMDA ratio
- An increase in basal excitatory synaptic strength.
- Neuronal basis of many forms of learning
- One injection – changes persist for 5 days
- Animal receives injections for 2 weeks – changes persist in VTA
30
Q
more or less D2 receptors in addiction?
A
- Fewer - D2 receptors cause inhibition and suppress behaviour
- Decreased dopamine (D2) receptors in cocaine addict
- The dopamine system central to conditioning and motivation
- Changes above likely responsible for reduced sensitivity to natural rewards that develops with addiction.
31
Q
Fewer D2 receptors in addiction - why?
A
- D2 receptors cause inhibition and suppress behaviour
- Decreased dopamine (D2) receptors in cocaine addict
- The dopamine system central to conditioning and motivation
- Changes above likely responsible for reduced sensitivity to natural rewards that develops with addiction.
32
Q
Emotional Dependence (e.g. psychomotor stimulants) - (dysphoria, anhedonia, anxiety on withdrawal)
- Compensatory changes in VTA / NAcc to lower DA transmission:
- Increased activity at … receptors (Gs coupled) in NAcc
- Adenylyl cyclase - cAMP - PKA - downstream events
- increased dynorphin (DYN) synthesis (endogenous opioid)
- dynorphin released in VTA acts at K … receptor
- Inhibits VTA neuron firing and NAcc DA release
- therefore … DA release in NAcc
- In absence of drugs boosting DA function, not enough DA for natural rewarding stimuli - anhedonia, dysphoria etc.
A
- 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
- therefore Less DA release in NAcc
- In absence of drugs boosting DA function, not enough DA for natural rewarding stimuli - anhedonia, dysphoria etc.
33
Q
Associative learning - what makes drugs addictive?
- Coincident firing between sensory pathways and the mesocorticolimbic pathway will induce LTP and strengthen synaptic connections
- Reminder – LTP = … … …
- A persistent strengthening of synapses based on recent patterns of activity
- Used to explain …
- Potential sites for LTP:
- … synapses on reciprocal connections between NAcc, VTA, cortex, hippocampus and amygdala
- Thus sensory information, people, places, emotions etc. present at the time when drug induced DA release occurs will become … with taking the drug
A
- Coincident firing between sensory pathways and the mesocorticolimbic pathway will induce LTP and strengthen synaptic connections
- Reminder – LTP = Long Term Potentiation
- A persistent strengthening of synapses based on recent patterns of activity
- Used to explain memory
- Potential sites for LTP:
- Glutamatergic synapses on reciprocal connections between NAcc, VTA, cortex, hippocampus and amygdala
- Thus sensory information, people, places, emotions etc. present at the time when drug induced DA release occurs will become associated with taking the drug
34
Q
Associative learning - what makes drugs addictive?
- Coincident firing between sensory pathways and the … pathway will induce LTP and strengthen synaptic connections
- Reminder – LTP = Long Term Potentiation
- A persistent … of … based on recent patterns of …
- Used to explain memory
- Potential sites for LTP:
- Glutamatergic synapses on reciprocal connections between NAcc, VTA, cortex, hippocampus and amygdala
- Thus sensory information, people, places, emotions etc. present at the time when … induced … release occurs will become associated with…
A
- Coincident firing between sensory pathways and the mesocorticolimbic pathway will induce LTP and strengthen synaptic connections
- Reminder – LTP = Long Term Potentiation
- A persistent strengthening of synapses based on recent patterns of activity
- Used to explain memory
- Potential sites for LTP:
- Glutamatergic synapses on reciprocal connections between NAcc, VTA, cortex, hippocampus and amygdala
- Thus sensory information, people, places, emotions etc. present at the time when drug induced DA release occurs will become associated with taking the drug
35
Q
Associative learning - sensory information, people, places, emotions etc. present at the time when drug induced DA release occurs will become associated with …
A
sensory information, people, places, emotions etc. present at the time when drug induced DA release occurs will become associated with taking the drug
37
Q
Dopamine enhances Long Term Potentiation
- Dopamine at D1 receptor (Gs coupled)
- adenylyl cyclase - cAMP - PKA
- modifies glutamatergic transmission allowing …
- CREB mediated gene transcription and new protein synthesis (steps in late phase LTP)
- synaptic … - increased spines and dendritic branches
- long term molecular and cellular changes remain months after …
- … in these pathways may trigger relapse years later
A
- Dopamine at D1 receptor (Gs coupled)
- adenylyl cyclase - cAMP - PKA
- modifies glutamatergic transmission allowing LTP
- CREB mediated gene transcription and new protein synthesis (steps in late phase LTP)
- 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
38
Q
Dopamine enhances Long Term Potentiation
- Dopamine at … receptor (Gs coupled)
- … cyclase - cAMP - …
- modifies glutamatergic transmission allowing LTP
- CREB mediated gene transcription and new protein synthesis (steps in late phase LTP)
- synaptic remodelling - increased spines and dendritic branches
- long term … and … changes remain months after abstinence
- memories in these pathways may trigger … years later
A
- Dopamine at D1 receptor (Gs coupled)
-
adenylyl cyclase - cAMP - PKA
- modifies glutamatergic transmission allowing LTP
- CREB mediated gene transcription and new protein synthesis (steps in late phase LTP)
- 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
47
Q
Overview - firing in VTA and nucleus accumbens
A
52
Q
Physical dependence to opiates
A
