D1/2 receptor essay plan

Question 1

Overall paragraphs structure

Answer 1

1. Introduction
2. Types of D receptor
3. Negative hypothesis theory
4. Evidence of negative hypothesis theory
5. How D1 receptor problem could be mitigated
6. Expression of D2 receptors
7. Evidence suggesting predisposition
8. Evidence suggesting plasticity of D2
9. D2 treatments
10. Conclusion

Question 2

Main points of introduction

Answer 2

1. Relapse is a major problem
   2.There are 3 major stimuli
2. The mesolimbic dopaminergic pathway from the VTA projects to the nucleus accumbens encodes natural reward
3. Drugs of abuse work on the same pathway and can lead to positive reinforcement

Question 3

Main points of types of D receptor

Answer 3

1. D1 family which are Gs coupled GPCRs (excitatory) and D2 family which are Gi/o coupled GPCRs (inhibitory).
2. dopamine activates both at the same time.
3. two different populations of neurons in Nac, these project to different brain regions
4. D2 project to the frontal cortex and are responsible for the euphoric effects of drugs.
5. D1 feed back to VTA in a negative feedback loop.
6. two main hypotheses on how dopamine receptors can lead to addictive behaviours.

Question 4

Main points for negative hypothesis theory

Answer 4

1.drug of abuse initially leads to euphoria followed by dysphoric effect
2. With repeated use leads to a semi-permanent shift in baseline mood.
3. Caused by dysregulation of stress hormones.
4. D1 receptors, cascade of events, phosphorylation of (CREB).
5. CREB is a transcription factor for dynorphin
6. Neurons in the nucleus accumbens release dynorphin - endogenous agonist at kappa opioid receptors.
7. Kappa found on the mesolimbic dopaminergic pathway and inhibit the dopaminergic neurons, reducing dopamine release = dysphoric effects.

Question 5

Main points for evidence of negative hypothesis

Answer 5

1. Di Chiara et al 1988.
2. kappa receptor agonists induce a negative emotional state
3. Carlezon et al 2006
4. Di Nieri et al 2009,
5. evidence that the activation of this pathway in response to a drug lead to the dysphoric effects= increase tendency for addiction.
6. transcription factor so last longer than euphoric effects.

Question 6

What is Di chiaras study

Answer 6

1. 1988
2. Research by Di Chiara et al 1988. demonstrated the impact of kappa receptor activation on dopamine release using brain dialysis coupled with HPLC in rats.
3. They observed decreased dopamine levels with all the kappa receptor agonists.

Question 7

What is Carlezons study

Answer 7

1. Carlezon et al 2006, observed depressive behaviour in rats on systemic administration of salvinorin A (a potent kappa opioid agonist)
2. such as increased immobility in the forced swim test and elevated thresholds intracranial self-stimulation test

Question 8

What is Di Niaris study

Answer 8

1. Di Nieri et al 2009,
2. investigated the effect of disrupting CREB using inducible bitransgenic mice expressing dominant negative CREB in the NAc
3. found using ICCS that this enhanced the rewarding impact of brain stimulation in rats and reduced depressive-like effects.

Question 9

How D1 receptor problem could be mitigated

Answer 9

1. kappa receptor antagonist to counteract the increased dynorphin levels
2. Gerra et al 2006 study

Question 10

Describe Gerra et al study

Answer 10

1. Gerra et al. 2006 tested the effect of a partial kappa opioid receptor antagonist (buprenorphine) alongside a u antagonist (naltrexone)
   2.Demonstrated a significant difference in relapse
2. dysphoric symptoms significantly decreased, indicating the potential efficacy of this approach alongside other treatments in reducing relapse.

Question 11

Expression of D2 receptors

Answer 11

1. Volkow et al 1997,
2. However, However, additional research was needed to determine if the lower D2 density in cocaine abusers is a consequence of drug abuse or a pre-existing factor predisposing them to addiction.

Question 12

Describe Volkow et al 1997

Answer 12

1. Found using a methylphenidate injection (a drug which blocks dopamine uptake), that cocaine abusers had a lower baseline PET signal due to fewer D2 receptors compared to control subjects.

Question 13

Evidence suggesting predisoposition

Answer 13

1 Volkow et al 1999
2. Dalley et al 2007
3. A well-known (SNP) reduce the levels of D2 receptors, correlation between this polymorphism and drug addiction
4. Moyer et al 2011
5. Clarke et al 2014, did not find this association but instead found it for opioid addicts.
6. Moyer et al analysed abusers rather than addicts and overlap between addictions
7. Both studies suggest a predisposition to addiction in individuals with lower D2 receptor levels.
I

Question 14

Describe Volkow et al study

Answer 14

1. correlation between number of D2 receptors and enjoyment of the methylphenidate injection
2. people who found the experience pleasant had a lower number of D2 receptors (Volkow et al 1999).

Question 15

Dalley et al

Answer 15

1. 2007,.
2. found that those with low D2 receptor density correlated with cocaine self-administration.

Question 16

Moyer et al

Answer 16

1. This was seen when Moyer et al 2011, found a particular SNP to be significantly overrepresented in cocaine abusers.

Question 17

Plasticity evidence

Answer 17

1. Nader et al 2006.
2. Further Nader studies
3. The dominant animals tended to have higher expression levels of D2 receptors in the striatum and also took less cocaine than the submissive.
4. An unrewarding environment decreased D2 levels and increased cocaine intake showing that D2 levels are plastic.
5. Lower levels of D2 receptors were then associated with increase in craving and consumption of drug
6. intruder test where submissive monkeys saw a large increase in cocaine use after the test compared to dominant monkeys
7. people are predisposed to addiction due to a lower D2 receptor density
8. which is further exacerbated by drug use itself and the environmental factors
9. low levels of receptor density led to increase in craving and therefore likelihood of relapse.
10. Therefore, increase D2 intensity through pharmacological methods and improve environment

Question 18

Describe Nadar et al

Answer 18

1. 2006
2. a study of monkeys who could self-administer cocaine
3. suggested that chronic use of cocaine could drive down D2 receptor density

Question 19

Describe treatments

Answer 19

1. The plasticity of D2 receptors has suggested that enriching a patient’s environment may be an effective way to prevent relapse as this increases the levels of D2 expression in the nucleus accumbens, but this can be expensive and complicated.
2. The idea of boosting D2 expression has also formed the basis for some pharmacological treatments of addiction.
3. bupropion and bromocriptine.
4. Bupropion is a noradrenaline dopamine reuptake inhibitor so boosts endogenous levels of dopamine in the nucleus accumbens.
5. Bromocriptine is a partial D2 receptor agonist, so slightly elevates endogenous reward level.
6. Currently these are not used regularly as they have not been proved to be particularly effective.
7. However, recent studies have suggested that they have a greater effect when used on people with the D2 polymorphism.
8. These results suggest that a personalised medicine approach, where you can test if the addict has the SNP and then use pharmacological treatments to boost D2 levels may be an effective way to reduce relapse for those that are predisposed to addiction.
   9.However, one issue with this model of D2 receptors and addiction is it is not known which D2 receptors the PET scans (and other methods) used in the various studies are looking at as there are multiple different D2 receptor sites presynaptically and on glutamatergic neurons which may increase the complexity of these findings.
9. Furthermore, most of the evidence for this hypothesis is based on studies using psychostimulants like cocaine and not on other addictive substances which may show different effects.