The dopamine D3 receptor, a quarter century later.

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The dopamine D3 receptor, a quarter century later.

Eur J Neurosci. 2016 Sep 7;

Authors: Sokoloff P, Le Foll B

This review updates the existing knowledge suggesting a role for the D3 receptor in schizophrenia and drug addiction. The D3 receptor is expressed in brain regions controlling reward, emotions and motivation. Antipsychotics bind in vitro to the D3 receptor with similar affinity as to the D2 receptor, and occupancy of D3 receptors in vivo by these compounds given acutely at clinical dosage have been demonstrated in Positron Emission Tomography (PET) studies. The D3 receptor modulates glutamatergic pathways from the prefrontal cortex to subcortical areas, either directly by interacting with N-methyl-D-aspartate (NMDA) receptors in the nucleus accumbens, or indirectly by controlling dopamine release from ventral tegmental area neurons. In animals, D3 receptor antagonists reverse behavioral manifestations of NMDA receptor blockade and improve cognitive performances in various paradigms. Two D3 receptor-selective compounds have reached clinical trials in schizophrenia, with negative results seemingly due to insufficient target engagement; the results with a third compound, F17464, have not been disclosed yet. There is converging evidence that D3 receptors do not control the reinforcing effects of drugs of abuse (with the exception of alcohol under low requirement), but rather affects the motivation to take the drugs under high requirement, reactivity to drug-associated cues, and drug seeking behaviors triggered by stimuli associated with relapse in humans. D3 receptor expression measured by PET is upregulated in humans with various drug addictions. A single administration of the D3 receptor-selective antagonist GSK598809 in humans transiently alleviated craving in smokers after overnight abstinence. The clinical development of D3-selective compounds will benefit from initial assessment of target engagement through the use of PET. This article is protected by copyright. All rights reserved.

PMID: 27600596 [PubMed - as supplied by publisher]