The dopamine D3 receptor, a quarter century later

Area of Science:

• Neuroscience
• Psychiatry
• Pharmacology

Background:

• The D3 receptor is implicated in reward, emotion, and motivation circuits.
• Antipsychotics exhibit affinity for D3 receptors, with in vivo occupancy confirmed by PET studies.
• D3 receptor activity modulates glutamatergic pathways and dopamine release.

Purpose of the Study:

• To review current knowledge on the D3 receptor's role in schizophrenia and drug addiction.
• To evaluate the therapeutic potential of D3 receptor-selective compounds.
• To highlight the importance of target engagement assessment for clinical development.

Main Methods:

• Review of existing literature on D3 receptor function.
• Analysis of in vitro and in vivo studies, including PET imaging.
• Examination of clinical trial data for D3 receptor antagonists.

Main Results:

• D3 receptor antagonists show promise in animal models for reversing NMDA receptor blockade effects and improving cognition.
• Clinical trials with D3-selective compounds in schizophrenia yielded mixed results, potentially due to insufficient target engagement.
• D3 receptors influence motivation for drug use, cue reactivity, and relapse behaviors, with expression upregulated in addiction.
• A D3 antagonist transiently reduced craving in smokers, suggesting a role in modulating addiction-related behaviors.

Conclusions:

• The D3 receptor is a significant target for treating schizophrenia and drug addiction.
• Clinical development of D3-selective drugs requires robust assessment of target engagement, preferably using PET.
• Further research is needed to optimize D3-targeted therapies for psychiatric and addiction disorders.