Dopamine & addiction

Question 1

Introduce the topic of addiction

Answer 1

• Drug misuse and dependence is a significant healthcare issue facing the UK, which has significant individual consequences across social, economic, and legal domains.
• Newer biological research provides insight into the neurological underpinnings of dependence, that hopefully will aid solutions affects thousands of lives.
• Therefore, this essay will provide an overview of dependence syndrome, the different views on its biological, basis, the relevance of the mesolimbic system, and evidence supporting the role of dopamine within a unified neural circuit.

Question 2

List the commonly addictive drugs

Answer 2

• There are several groups of drugs known to be addictive.
• Examples and their mechanisms of action (Carlson, 2010) are as follows:
  
  • ​Ethanol (glutamate antagonist and GABA agonist)
  • Benzodiazepines (GABA agonist)
  • Cannabis (cannabinoid agonist)
  • Nicotine (acetylcholice agonist)
  • Opiates (opiate agonist)
  • Phencyclidine/Ketamine (glutamate antagonist)
  • Cocaine/Amphetamine (dopamine agonist)

Question 3

Discuss the general role of dopamine in the mesolimibic system

Answer 3

• Animal models have shown dopamine (DA) release into the nucleus accumbens (NAc) increases during naturally rewarding/reinforcing behaviours such as feeding, drinking, and sex (White, 1996), and aversive stimuli (Salamone, 1992).
• The NAc, ventral tegmental area (VTA), and dopaminergic neurones between the two, form the mesolimbic system.

Question 4

Discuss the evidence support dopamine role in reward

Answer 4

• Behavioural studies support the role of dopamine in reward.
• Self-stimulation uses lever-presses to provide electrical stimulation to pre-determined areas of the brain.
• This is most effective when stimulating the mesolimbic system.
• Frequnecy of lever-pressing correlated with increased stimulation strength.
• Continuous increasingly frequent lever-induced self-stimulation increases total dopamine release into the NAc, whilst dopamine antagonists reduce lever-pressing (Young, 2019).
• This demonstrates a drive to receive dopamine release.

Question 5

Discuss behavioural studies of self-administration

Answer 5

• Self-administration involves lever-pressing to receive drug doses to the brain. Once again, this is more evident when administered to the NAc.
• Here, low doses of dopamine antagonists increase lever-pressing, so the administered drug outcompetes the antagonists, leading to dopamine release into the NAc (Young, 2019).
• Conversely, NAc lesions abolish self-stimulation behaviour, again highlighting the drive to obtain dopamine into the NAc.

Question 6

Relate dopamine function to dependence syndrome

Answer 6

• One key aspect of dependence syndrome is the “progressive neglect of alternative pleasures or interests” (WHO, 1992).
• Taking the central role of DA, if an animal has a NAc dopamine threshold that is met by administration of addictive drugs, then there is less/no motivation to seek other sources of natural DA from feeding, drinking, or sex behaviours.
• With this focus on DA, dependence syndrome can be simplified down to dopamine-seeking behaviours and cognitions.
• Indeed, polysubstance dependence is suggested to account for 15-39% of adolescent dependence syndrome (Conway et al., 2013).

Question 7

Outline how dopamine is suggested to result in dependence

Answer 7

• Key to understanding this argument is how all these different drugs relate to dopamine release into the NAc (Mechanisms of action are referenced from Carlson, 2010).
• A leading hypothesis regarding addictive drugs, is that mesolimbic dopamine surges trigger synaptic adaptations and circuit reorganisations that evenutally cause behavioural changes of dependence (Brown et al., 2010).

Question 8

Discuss how amphetamine and cocaine are addictive

Answer 8

• Schizophrenia models of unfied neurocircuitry containing glutamate and DA (Carlson, 2010) provides framework by which these drugs alter DA release.
• Amphetamine and cocain directly increase synaptic dopamine by enhancing its release and reversing reuptake respectively.

Question 9

Discuss how NMDA antagonists are addictive

Answer 9

• Ethanol (in part), phencyclidine, and ketamine are NMDA glutamate antagonists.
• Glutamate is the predominant excitatory neurotransmitter.
• Glutaminergic neurones profect from the prefrontal cortex to the VTA where they synapse with GABAergic neurones.
• GABA is the major inhibitory neurotransmitter.
• These then synapse with and inhibit dopaminergic neurones of the misolimibc pathway.
• Therefore, NMDA antagonists remove the inhibitory effect, causing disinhibition of the mesolimbic pathway, increasing dopaminergic activity into the NAc.

Question 10

List and describe how GABA agonists are addictive

Answer 10

• Barbiturates, benzodiazepines and ethanol (in part) are GABA agonists.
• Initially this appears contradictory to the above mechanism.
• However, Chandler Harris and Crews (1998) described how ethonal interacts with GABA recptors to interfere with NMDA receptors, cauing a similar increased release of dopamine as above.
• Benzodiazepines also exerts GABA-mediated effects on dopamine through interneurones.
• Two sequential GABA interneurones project to the misolimbic system (Riegel & Kalivas, 2010).
• Current BZDs are specific for the first interneurone, therefore causing disinhibition rather than inhibition of the mesolimib system, and increasing DA release into the NAc (Riegel & Kalivas, 2010).

Question 11

Describe why opiates, nicotine, and cannabis are addictive

Answer 11

• Other addictive drugs include opiates, nicotine, and cannabis.
• Opiates bind to mu and delta opioid receptors to exert an inhibitory effect on GABAergic neurones in the VTA, disinhibiting misolimbic dopaminergic neurones.
• Nicotine is a nicotinic acethylcholine agonist, another neurotransmitter inhibiting GABA.
• THC in cannabis mimics endocannabinoids. This acts on dopaminergic terminal buttons to increase NAc dopamine.

Question 12

Write a conclusion

Answer 12

• In conclusion, mesolimbic dopamine arguably is the most important element and common pahway of addiction.
• Behavioural studies have shown how dopamine antagonists and lesion during self-administration abolish naturally rewarding and drug-seeking behaviours.
• Critically, a central dopamine hypothesis links together vastly different addictive drugs and provides biological explanation for characteristic symptoms of dependence syndrome as depamine-seeking behaviours and cognitions.