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.

Figure 1.

Synaptic mechanisms of action for anandamide, 2-arachidonoylglycerol and oleoylethanolamide (OEA)/palmitoylethanolamide (PEA) in dopamine neurons. The mechanisms by which endocannabinoids and N-acylethanolamines (OEA and PEA) regulate synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons are illustrated. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are produced on demand by the Ca²⁺-dependent enzymes NAPE-PLD and DAG lipase, respectively. Increases in intracellular Ca²⁺ can be induced, as in the example, by activation of metabotropic glutamate receptors (mGluR). 2-AG binds to presynaptic CB1 receptors expressed on GABA and glutamate terminals and depresses neurotransmitter release. AEA activates TRPV1 receptors located on presynaptic glutamatergic terminals, but whether it stimulates CB1 receptors is not clear (dashed line). 2-AG is catabolized by MAG lipase located on presynaptic terminals, whereas FAAH is expressed postsynaptically on DA neurons. OEA and PEA, endogenous PPARα ligands, are formed by NAPE-PLD and degraded mainly by FAAH. Activated PPARα regulate nicotinic cholinergic transmission by negatively modulating somatodendritic nicotinic acetylcholine receptors (nAChRs). FAAH, fatty acid amide hydrolase; NAPE-PLD, N-acylphosphatidylethanolamine hydrolyzing phospholipase D.