Genetic variation and the D2 dopamine receptor: implications for the treatment of neuropsychiatric disease

Written by Mickey BJ

The D2 dopamine receptor is a G-protein-coupled receptor that is highly expressed in the brain, particularly in the striatum. Striatal circuitry is critical to the regulation of movement and motivational states. Accordingly, D2 receptors are a key target of pharmacologic agents used to treat neurologic and psychiatric diseases. Agonists of the D2 receptor (and the closely related D3 receptor) improve disordered movements and depressed mood in Parkinson disease, and they quiet the overwhelming urge to move one’s legs in restless legs syndrome.
D2 receptor antagonists, on the other hand, quell the delusions and hallucinations that commonly occur in schizophrenia, bipolar disorder and major depressive disorder. D2 antagonists also suppress the involuntary movements of Huntington disease. Furthermore, because of the variety of pharmacotherapies and drugs of abuse that indirectly influence the D2 receptor, this system is relevant to a range of other conditions, from drug addictions to disorders of attention and arousal. The societal impact of these afflictions, and neuropsychiatric disorders in general, is truly astounding. It is no surprise, therefore, that the D2 receptor has been a focus of intense research in basic science and drug development circles for decades.

In recent years, researchers have paid increasing attention to inter-individual variation of the D2 receptor system. Postmortem studies of human brain and, increasingly, in vivo molecular imaging (positron emission tomography and single-photon emission tomography) can reliably quantify D2/D3 receptor density at the individual level. Substantial variation in striatal D2 receptor expression has been noted in these studies, with typical coefficients of variation in the range of 20–60% [1–3].

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