Neurobiology and Neurochemistry of Addiction Flashcards
1
Q
Where do drugs act in the brain?
A
- addiction begins in the mesolimbic dopaminergic system
- the mesocorticolimbic pathway controls reward and reinforcement provides stimulus salience
- this then produces long-term changes in other brain regions that receive input from these neurons
- Prefrontal cortex: impulsiveness, decisions making, self-monitoring
- Amygdala
- Hippocampus
2
Q
What is instrumental conditioning and which neurotransmitter pathway is involved?
A
- a learning process in which behaviour is modified by the reinforcing or inhibiting effect of its consequence.the behaviour is instrumental or necessary for the conditioning process to occur
- DA is the primary activation neurotransmitter for the reward patway
3
Q
Explain DA as an ‘error’ or ‘learning’ signal
A
- anticipation effect is seen even before the reward is given
- if the reward isn’t given there is a depression of the DA neuron when the reward would have been given
4
Q
What happens in the brain to cause learning?
A
- when a reward is unexpected then there is activity in the Nucleus Accumbens
- indicates to the brain that the circumstances of the reward should be learned
5
Q
What is the function of the Reinforcement System?
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
6
Q
How does the mesocorticolimbic dopamine system contribute to addiction?
A
- Drug-induced synaptic plasticity in the:
-
NAcc and ventral striatum,
- motivational significance of stimuli early reinforcement
-
Dorsal striatum, including caudate, putamen
- learning and execution of behavioural sequences for efficient responses- instrumental conditioning,
- changes that make behaviours habitual
-
NAcc and ventral striatum,
- Contribute to addiction by consolidating:
- Drug wanting
- Drug seeking
- Drug taking
7
Q
Which common drugs have an effect on the DA system?
A
- 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
8
Q
What is the effect of drug abuse on the DA system?
A
- After repeated exposure to most drugs of abuse, VTA neurons decrease in size.
- Repeated psychostimulant or nicotine exposure induces dendritic outgrowth in NAcc neurons
- Decreased basal DA levels in the NAcc and
- Enhanced DA release induced by a stimulus (e.g., drug exposure or stressor).
- Fewer D2 Receptors in addiction- D2 cause inhibition and suppress behaviour
- Increase in basal excitatory synaptic strength- additional AMPA receptors in postsynaptic DA neurons
9
Q
What is the biochemical effect of Dopamine receptors?
A
- Dopamine receptors differentially regulate cAMP intracellular signalling and cellular activity
- D1-like receptors (D1R) are associated with stimulatory G-proteins (Gs and Golf)
- when activated, increase the activity of the membrane-bound enzyme adenylyl cyclase (AC).
- Active AC catalyzes the conversion of ATP to cAMP, leads to the activation of protein kinase A (PKA) and subsequent increases in gene expression
- D2-like receptors (D2R), are coupled to inhibitory G-proteins (Gi and Go)
- when activated, the alpha subunit of these G-proteins inhibits the activity of AC,
- leading to decreased cAMP production, PKA activity, gene expression, and cellular activity.
10
Q
What are the stages of reaching Addiction?
A
- 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
- Sensitization: repeated administration elicits escalating effects, the effect of psychostimulants (used in animal models)
- Addiction: compulsive taking, craving and relapse, persistent for many years
11
Q
Cocaine and amphetamine as DA agonists
A
- They inhibit DA, 5-HT and NE reuptake transporters
- this potentiates monoaminergic transmission
- Cocaine blocks and inhibits transporter –> prolongs extracellular DA levels in NAcc
- Amphetamine reveres transporter –> increase extracellular DA levels in NAcc
- this action primarily occurs at the Dopamine transporter (DAT) involved in the reinforcing effects
- feelings of euphoria through activation of this pathway
12
Q
Explain how Associative learning makes drugs addictive
A
- Coincident firing between sensory pathways and the mesocorticolimbic pathway will induce LTP (long-term potentiation) and strengthen synaptic connections
- A persistent strengthening of synapses based on recent patterns of activity used to explain memory
- Sites of LTP include glutamatergic synapses on reciprocal connections between
- NAcc, VTA, Cortex, Hippocampus and Amygdala
- sensory info, ppl, places, emotions etc. present at the time of high will become associated with taking the drug
13
Q
How do Opiates (Morphine and Heroine) act in the body to cause addiction
A
- endogenous opioid receptors (Gi coupled) with inhibitory action
- decrease adenylyl cyclase activity
- lead to open K+ channels, close Ca2+ channels
- most morphine’s analgesic and rewarding properties are through actions at mu receptors
- Reward and reinforcement by:
- Disinhibition of DA neurons in VTA
- DA neurons fire tonically but are inhibited by GABA interneurons
- mu receptor activation on GABA neurons inhibits them from firing
- inhibition on DA neurons is prevented
- Action at opiate receptors in the NAcc - independent of DA release (mu or delta)
- Disinhibition of DA neurons in VTA
14
Q
What is Naloxone?
A
- opiate receptor blocker
- very effective in saving those with an overdose
15
Q
What is Naltrexone?
A
- an opiate agonist
- reduces EtOH self-administration in animals
- used as a treatment to reduce; alcohol consumption, relapse and craving in alcoholics
16
Q
Explain the action of Alcohol and how it causes addiction?
A
- GABAA agonist (inhibitory)
- NMDA antagonist (blocks excitation)
- Large doses inhibit the functioning of most voltage-gated channels
- EtOH leads to increased DA release in NAcc
- NMDA antagonism of cortical inputs to VTA disinhibits VTA DA neurons
- results in an increase of DA released in NAcc.
- Ethanol rewarding effects blocked by DA receptor antagonists in NAcc
17
Q
How do Opiates and Alcohol cause an increase in DA release
A
-
Opiates: act in the Ventral Tegmental Area (VTA)
- cause disinhibition of DA neurons in the VTA through inhibition of GABA interneuron
- Morphine acts at the mu-opioid receptor to complete action
-
Alcohol: act in the Cortex as an NMDA antagonist
- causes suppression of cortical output –> no activation of GABA interneuron
- DA neuron disinhibited in VTA and able to fire
