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

Abstract

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.

Figure 1

Constitutive GPCR activity and inverse agonism. (a) Although G-protein coupled receptors (GPCRs) will typically be in inactive conformations (red) in the absence of an (endogenous) ligand, some spontaneously adopt an active conformation (blue). The extent of this phenomenon makes up the constitutive activity of the receptor population, which is arbitrarily given as 50% (right) in this example purely for illustrative purposes. (b) Agonist (blue ellipse) binding to GPCRs shifts the balance toward more active GPCRs, whereas (c) an inverse agonists (purple rounded rectangle) shifts the balance towards more inactive receptors. The latter is achieved by a double action: (1) suppression of constitutive GPCR activity and (2) ‘antagonistic' prevention of GPCR activation by (endogenous) agonists. (d) In contrast, neutral antagonists (yellow squares) only prevent GPCR activation by (endogenous) agonists, leaving constitutive GPCR activation intact. Notably, neutral antagonists also prevent inverse agonists from suppressing constitutive GPCR activation.

Figure 2

Schematic representation of the main connections of the midbrain dopamine neurons and their control by several key GPCRs. VTA dopamine neurons receive GABAergic inhibition from local GABA neurons, as well as GABA neurons from the rostromedial tegmental nucleus (RMTg). Medium spiny neurons in the NAc receive dopaminergic input from the VTA and project back either monosynaptically (direct pathway) or disynaptically through the ventral pallidum (VP; indirect pathway). The prefrontal cortex (PFC) provides an important glutamatergic (Glu) input to both the medium spiny neurons in the NAc and to neurons in the VTA, while also receiving dopaminergic input itself. Cannabinoid 1 (CB1), dopamine 1 (D1) and 2 (D2), serotonin 2 C (HTR2C) and mu-opioid receptors (MORs) impinge on this network at various levels.

Figure 3

In vivo relevance of CB1R constitutive activity. (a) Ventral tegmental area dopamine (DA) neurons are regulated by cannabinoid 1 receptor (CB1R)-expressing GABAergic neurons. Some of these CB1Rs (green; CB1R*) are constitutively active, whereas others are not (red, CB1R). (b) In mouse brain VTA dopamine neurons, CB1R agonist WIN55,212-2 reduces GABAergic input (miniature inhibitory postsynaptic currents; mIPSCs), whereas the inverse agonists SR141716A (rimonabant) and AM251 increase such GABAergic inhibition. This inverse agonistic effect is presumably by suppressing CB1R constitutive activity, because neutral CB1R antagonists O-2050 and NESS0327 do not affect GABAergic input themselves, whereas the latter does block the effect of both CB1R agonist WIN55,212-2 and SR141716A. Indeed, the effect of the inverse agonists in this slice preparation is not due to the interference with endocannabinoid-CB1R signaling, because indirect agonists URB597 and URB602, which act by preventing the degradation of the endocannabinoids anandamide and 2-Ag respectively, were ineffective in slice preparation. (c, top) SR141716A reduces motivation for sucrose reward on a progressive ratio schedule. NESS0327 does not, but does block the effect of SR141716A. (Bottom) Similarly, SR141716A is anxiogenic in the elevated plus maze. NESS0327 is not, although it does block the effect of SR141716A. (d) SR141716A and NESS0327 reduce body weight gain to a similar extent. *P<0.05; ***P<0.001.