Abstract
There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands for a variety of mental health disorders. DA D3 receptors have been implicated in Parkinson’s disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10–15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from pre-clinical studies. Recently, with the advent of [11C]-(+)-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [11C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [11C]-(+)-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [11C]-(+)-PHNO binding by region of interest. This novel methodology can be used in pre-clinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [11C]-(+)-PHNO can provide insights into the function of D3 receptors in addiction is also presented.
Highlights
Dopamine (DA) is a neurotransmitter that has been implicated in a variety of psychiatric disorders such as Parkinson’s disease, schizophrenia, and addiction
In a study by Kiss et al (2011), [3H]-(+)PHNO binding in various brain areas was antagonized by either the D3 antagonist SB-277011-A or the D2 antagonist SV-156 to determine whether binding of [3H]-(+)-PHNO was due to occupation of D2 or D3 receptors
They found that [3H]-(+)-PHNO binding in the rat cerebellar lobules 9 and 10 but not in the striatum was blocked by administration of a D3 antagonist, whereas the opposite was true for a D2 antagonist (Kiss et al, 2011)
Summary
Dopamine (DA) is a neurotransmitter that has been implicated in a variety of psychiatric disorders such as Parkinson’s disease, schizophrenia, and addiction. Effects on drug taking behaviors There is considerable pre-clinical evidence suggesting that D3 receptor antagonists may be effective as treatments for addiction. Treatment strategies that block the rewarding effects of a drug may lead to its increased self-administration These compensatory increases in behavior have been a disadvantage of D2 receptor antagonists, as opposed to D3 antagonists, in pre-clinical models. The latter study did not observe any effects on the first day of testing, with effects being observed only after repeated exposure of the animals to responding for food under the effects of pimozide, which suggests that D2/3 receptors are involved in the learning of this behavior This may explain the lack of effect of eticlopride on food intake following a single treatment (Ball et al, 2011). Based on these and other observations (Nakajima et al, 2013), we and others have proposed that D3 antagonists, but not D2 antagonists, may serve as cognitive enhancers
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