The Role of Dopamine D2 Receptors

Dopamine D2 Receptor
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Dopamine (DA) plays an important role in addiction as the dopaminergic reward pathways are targeted by every drug of abuse. So, it is imperative to study this system and its receptors, the dopamine receptors, in order to understand the neurobiological mechanisms that underlie addiction. Specifically, dopamine D2 autoreceptors have been found to play a modulatory role in addiction by regulating dopamine levels [1], drug sensitivity [1] and performance on cognitive tasks [2], shown experimentally through mice knock-out models. Furthermore, drug administration itself has been implicated in modifying these mechanisms, and this modification may underlie the transition from drug use to drug addiction [2]. Recently, research is focusing on investigating the role of genes in addiction and finding genetic markers associated with addiction and the D2 autoreceptor [3][4].

1. The Dopaminergic Reward System

1.1 Pathways

Drug Effects on Dopaminergic Pathway [5]
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The evidence for a common pathway for all drugs of abuse is quite extensive in the literature. All drugs of abuse target the mesolimbic dopamine pathway that includes mainly the pathway from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens (NAc) [5]. Some drugs act directly on the dopaminergic neurons of the VTA, directly causing an increased release of dopamine in the NAc, whereas others may act on non-dopaminergic neurons but still work to indirectly increase dopamine transmission in the NAc [5]. Stimulants, such as nicotine and caffeine, are involved in the direct pathway whereas opioids function indirectly by inhibiting GABAergic neurons which will cause the disinhibition of VTA dopaminergic neurons, thereby increasing dopamine transmission in the NAc [5].

1.2 D2 Receptors

There are several DA receptor subtypes, however, the subtype important in addiction are the D2 auto-receptors [1]. D2 auto-receptors are found on DA neurons and play a modulatory role in DA regulation [1]. One of the major roles of D2 auto-receptors, and their role in addiction, involves negative feedback where the presence of DA activates these receptors and inhibits further release [1]. Thus, DA levels are regulated and kept at a balance [1]. It has been shown that this auto-receptor function is served only by the D2 subtype and not by other DA receptors [6][7].

2. Effects of drug administration

2.1 D2 Receptor levels

D2 Receptor Levels After Cocaine Administration [2]
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LgA rats = long-term self administration

Long term administration of a drug may lead to reduced D2 receptor levels in the brain [2]. Rats that self-administer cocaine long-term (6 days) but not short-term (1 day), show a marked decrease in D2 receptor mRNA and protein levels in specific regions of prefrontal cortex [2]. This association between cocaine abuse and reduced DA receptor levels has been documented several times including as early as 1990 [8]. Cocaine abusers that have been detoxified for 1 week have significantly lower DA receptor levels than those detoxified for 1 month and healthy controls [8]. Although in 1990, the authors did not specify which subtype of DA receptor this was, other later studies have also arrived at the same conclusion [3]. Interestingly, the same results have also been shown in a markedly different type of addiction: Internet addiction [9].

The relationship between D2 receptor levels and drug abuse/addiction may also work in the opposite direction. Healthy controls with low D2 receptor levels are found to be more likely to experience the effects of psychostimulants as rewarding and pleasurable than healthy controls with greater D2 receptor levels [10]. In fact, as D2 levels increase, the individuals are actually more likely to experience the unpleasant effects of these same psychostimulants [10]. Furthermore, it has been found that rats that are more susceptible to the effects of cocaine, and are thus more likely to also self-administer the drug, show decreased levels of D2 receptors [3][11][12].

There is consistent evidence of the relationships discussed above in both animals and humans [3]. So, initially reduced D2 levels may place an individual at risk of abusing a drug and this abuse may develop into an addiction as these drugs further reduce D2 levels [3].

2.2 Drug sensitivity

Drugs’ effects on D2 receptor levels indirectly increases sensitivity to both the drugs’ effects and to drug seeking behavior [13]. Rats that self-administer higher doses of cocaine, compared to rats that self-administer lower doses, are more sensitive to a D2 receptor agonist which triggers cocaine seeking behavior [13]. Furthermore, this effect is only noted for D2 receptors and responses to D1 agonists, used to inhibit cocaine seeking, are actually lower than normal [13]. D2 receptor mediated sensitivity to drug seeking also exists in rats trained to self-administer cocaine [13]. However, these effects seem to be time-dependent as they are evident at 1 week of withdrawal but heavily reduced at 3 weeks of withdrawal when D2 receptor levels have increased[13]. This has strong implications for relapse, and consequently, treatments for addiction. Overall, drug administration increases sensitivity to drug seeking behavior via D2 receptors but the effects are strong only early in withdrawal [13].

3. D2 Receptor Knock-Out Models

3.1 Dopamine levels

D2 auto-receptors are involved in a negative feedback loop. When dopamine binds to D2, the end result is inhibition of further dopamine release [1]. So, when D2 Receptors are knocked out in mice, there is no more autoinhibition of DA release, resulting in a significant increase in DA levels [1][14][15]. This translates to addiction models because addicted individuals and those at greater risk of developing an addiction, have lower levels of D2 receptors [3]. Lower levels of D2 results in greater dopamine release in response to drugs of abuse, thus increasing the feeling of reward and placing the individual at risk of abusing the drug and developing an addiction [3]. Furthermore, in addition to greater release of DA in D2 knock-out models, there is a larger amount of DA synthesis [1]. Knock-out models have also shown that D2 receptors are also involved in the timing of DA signaling [14]. Overall, D2 receptor knock-out models have shown that D2 auto-receptors regulate DA levels by regulating DA synthesis, release and timing of DA signaling.

3.2 Drug sensitivity & Reward motivation

Conditioned Place Preference
Testing phase of conditioned place preference

D2 knock-out mice show increased sensitivity to both the locomotor and rewarding effects of cocaine [1]. The greater sensitivity to the rewarding effects of cocaine is shown through a conditioned place preference task [1]. Mice lacking D2 auto-receptors still show a preference for the cocaine associated place at very small doses of cocaine [1]. Controls on the same dosage do not show this preference [1]. However, this might not be true for all types of drugs as sensitivity to opiates and alcohol does not increase, but rather decreases, in D2 knock-out mice models [16][17].

Reward motivation is also increased in D2 knock-out mice. These mice will put in more work to obtain food than mice that do not lack D2 auto-receptors [1].

4. The Role of Genes

4.1 SNP rs1076560

Investigation of genes lies at the forefront of addiction research. The single nucleotide polymorphism (SNP) rs1076560 of the D2 receptor is found mainly in cocaine abusers and so, there might be a relationship between this SNP and abuse of cocaine or development of cocaine addiction [18]. However, there is contradicting evidence as other studies find that this is not true. Furthermore, SNP rs1076560 might also be linked to opioid dependence [18]. Further research is still necessary to help elucidate the role of this polymorphism.

4.2 PER2 Gene

The PER2 gene plays an important role in circadian rhythms and its expression is regulated by dopamine and its actions via D2 receptors [3]. Irregular PER2 expression is linked to cocaine abuse and this gene has also been found to be associated with more adverse effects of cocaine in animal models [3]. Recently, a variable number tandem repeat (VNTR) polymorphism of the PER2 gene has been identified and the short allele (3 repeats) is significantly more common in cocaine abusers than healthy controls, who have the long allele (4 repeats) [3]. Furthermore, individuals with the short allele also have lower levels of D2 receptors in the striatum [3]. The link between low D2 receptor levels, which is characteristic of drug abusers, and the short PER2 allele may be a key finding for the role of genes in addiction [3].

The finding discussed above is from 2012, and so, is very recent. Its main limitation is that this is a correlational study and other confounds may underlie the association between the PER2 gene and cocaine abuse. Future investigations focusing on causal relationships should provide further support for this finding.

Bibliography
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