Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

Abstract

The last decade has provided a wealth of experimental data on the role played by lipids belonging to the endocannabinoid family in several facets of physiopathology of dopamine neurons. We currently suggest that these molecules, being intimately connected with diverse metabolic and signalling pathways, might differently affect various functions of dopamine neurons through activation not only of surface receptors, but also of nuclear receptors. It is now emerging how dopamine neurons can regulate their constituent biomolecules to compensate for changes in either internal functions or external conditions. Consequently, dopamine neurons use these lipid molecules as metabolic and homeostatic signal detectors, which can dynamically impact cell function and fitness. Because dysfunctions of the dopamine system underlie diverse neuropsychiatric disorders, including schizophrenia and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Particularly, because dopamine neurons are critical in controlling incentive-motivated behaviours, the involvement of endocannabinoid molecules in fine-tuning dopamine cell activity opened new avenues in both understanding and treating drug addiction. Here, we review recent advances that have shed new light on the understanding of differential roles of endocannabinoids and their cognate molecules in the regulation of the reward circuit, and discuss their anti-addicting properties, particularly with a focus on their potential engagement in the prevention of relapse.

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

“…Given the widespread and strong expression of ECS molecules, it is not surprising that exposure of the developing and maturing nervous system to marijuana-derived cannabinoid impacts behavioural aspects in the control of emotions and cognitive responses. Given the implications of cannabinoid exposure in human neuropsychiatric disorders (see Puighermanal et al [11]; Melis & Pistis [12]; Campos et al [13]), investigations on the mechanism of action and neurobiological substrate underlying the developmental action of cannabinoids have gained traction. Endocannabinoids, acting via the CB1 receptor comprise, in effect, neurodevelopmental signalling cues which exert a regulatory role on the molecular and cellular mechanisms involved in brain development.…”

“…Today we know a great deal about the role played by the endocannabinoid family lipids in several facets of DA neuron physiopathology. In their article prepared for this issue, Melis & Pistis [12] review recent advances that have shed light on understanding the differential roles of endocannabinoids and their cognate molecules in regulation of the reward circuit, and discuss their anti-addicting properties, particularly with a focus on their potential engagement in the prevention of relapse. Further, the authors suggest that anandamide and 2-AG, being intimately connected with diverse metabolic and signalling pathways, might differently affect various functions of DA neurons through activation not only of surface receptors, but also of nuclear receptors [31].…”

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors

“…The endocannabinoid system, mainly through type 1 cannabinoid receptors (CB1) located on glutamatergic (glutamatergic CB1) and GABAergic neurons (GABAergic CB1), control both excitatory and inhibitory neurotransmission, thereby modulating dopaminergic-dependent behaviors (Melis and Pistis, 2012;Dubreucq et al, 2013), including cocaine seeking (De Vries and Schoffelmeer, 2005). Full pharmacological antagonism of CB1 decreases the influence of conditioned factors on cocaine seeking and on extracellular Glu and DA in the NAc (Caillé and Parsons, 2006;Cheer et al, 2007;Oleson and Cheer, 2012;De Vries et al, 2001;Xi et al, 2006), as well as expression of cocaine-induced behavioral sensitization in a context-specific manner (Gerdeman et al, 2008).…”

Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes

“…All addictive drugs affect the brain’s reward circuitry by enhancing DA levels in the nucleus accumbens (NAc), which is a primary target of DA neurons in ventral tegmental area (VTA) (Gardner, 2011). The endogenous cannabinoid (eCB) system is increasingly seen to play an important role in modulating reward-related changes of DA levels in the NAc and other forebrain targets to thereby regulate addictive behaviors (Melis and Pistis, 2012; Oleson et al, 2012). …”