Neurobiology and Neurochemistry of Addiction

Question 1

Where do drugs act in the brain?

Answer 1

• 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

Question 2

What is instrumental conditioning and which neurotransmitter pathway is involved?

Answer 2

• 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

Question 3

Explain DA as an ‘error’ or ‘learning’ signal

Answer 3

• 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

Question 4

What happens in the brain to cause learning?

Answer 4

• 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

Question 5

What is the function of the Reinforcement System?

Answer 5

• 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

Question 6

How does the mesocorticolimbic dopamine system contribute to addiction?

Answer 6

• 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
• Contribute to addiction by consolidating:
  
  • Drug wanting
  • Drug seeking
  • Drug taking

Question 7

Which common drugs have an effect on the DA system?

Answer 7

• 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

Question 8

What is the effect of drug abuse on the DA system?

Answer 8

• 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

Question 9

What is the biochemical effect of Dopamine receptors?

Answer 9

• 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.

Question 10

What are the stages of reaching Addiction?

Answer 10

• 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

Question 11

Cocaine and amphetamine as DA agonists

Answer 11

• 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

Question 12

Explain how Associative learning makes drugs addictive

Answer 12

• 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

Question 13

How do Opiates (Morphine and Heroine) act in the body to cause addiction

Answer 13

• 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)

Question 14

What is Naloxone?

Answer 14

• opiate receptor blocker
• very effective in saving those with an overdose

Question 15

What is Naltrexone?

Answer 15

• an opiate agonist
• reduces EtOH self-administration in animals
• used as a treatment to reduce; alcohol consumption, relapse and craving in alcoholics

Question 16

Explain the action of Alcohol and how it causes addiction?

Answer 16

• GABA_A 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

Question 17

How do Opiates and Alcohol cause an increase in DA release

Answer 17

• 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

Question 18

What is the action of Nicotine and how does it cause addiction?

Answer 18

• Acts at nicotinic acetylcholine receptors (nAChRs)
  
  • Ligand gated ion channels located pre or post-synaptically (present throughout the brain, excitatory or modulatory)
  • Presynaptic receptors –> influx of Ca2+ –> transmitter release
• Nicotine treatment increases DA release in the NAcc
• Release of DA likely due to:
  
  • activation of receptors on cell body in the VTA (increasing cell firing)
  • facilitation of DA release by pre-synaptic receptors in NAcc

Question 19

How can nicotines action be blocked?

Answer 19

• Opiate and DA antagonists can block nicotine-induced behaviours and self-administration
• Naltrexone

Question 20

Explain physical dependence to Opiates

Answer 20

• Opiate receptors present in mesocorticolimbic circuits but also other systems such as
  
  • Spinal cord and pain pathways
  • Locus coeruleus (LC) - Noradrenergic nuclei controlling attention, arousal and vigilance (responsible for eliciting “fight or flight” autonomic responses)
• Chronic activation of opiate receptors leads to a homeostatic mechanism that compensates for the functional changes leading to tolerance and physical dependence
• Acute morphine - acutely inhibits the firing of LC neurons
• Chronic treatment - LC neurons return to their normal firing rates
• Withdrawal - a dramatic increase in LC firing
  
  • correlates with the physical withdrawal symptoms
  • trigger overactivation of the autonomic nervous system
  • can be blocked by clonidine (a2 adrenergic receptor agonist)
• Intracellular mechanism in LC neurons leads to the compensation (same events will result in tolerance to analgesic effects)

Question 21

Explain physical dependence to alcohol

Answer 21

• Acute effects of alcohol: Cells inhibited from firing
  
  • agonist at GABAA receptor
  • antagonist at NMDA receptor
• Chronic alcohol: In presence of alcohol firing rates return to normal
  
  • Downregulation of GABAA receptors
  • Upregulation of NMDA receptors
• Withdrawal: in absence of alcohol balance shifts to excitation
  
  • physical symptoms: agitation, tremors, hypertension, seizures