The vital role of constitutive GPCR activity in the mesolimbic dopamine system

The midbrain dopamine system has an important role in processing rewards and the stimuli associated with them, and is implicated in various psychiatric disorders. This system is tightly regulated by various G protein-coupled receptors (GPCRs). It is becoming increasingly clear that these receptors are not only activated by (endogenous) agonists but that they also exhibit agonist-independent intrinsic constitutive activity. In this review we highlight the evidence for the physiological role of such constitutive GPCR activity (in particular for cannabinoid 1, serotonin 2C and mu-opioid receptors) in the ventral tegmental area and in its output regions like the nucleus accumbens. We also address the behavioral relevance of constitutive GPCR signaling and discuss the repercussions of its abolition in dopamine-related psychiatric diseases.