Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction

Abstract

The family of lipid neuromodulators has been rapidly growing, as the use of different -omics techniques led to the discovery of a large number of naturally occurring N-acylethanolamines (NAEs) and N-acyl amino acids belonging to the complex lipid signaling system termed endocannabinoidome. These molecules exert a variety of biological activities in the central nervous system, as they modulate physiological processes in neurons and glial cells and are involved in the pathophysiology of neurological and psychiatric disorders. Their effects on dopamine cells have attracted attention, as dysfunctions of dopamine systems characterize a range of psychiatric disorders, i.e., schizophrenia and substance use disorders (SUD). While canonical endocannabinoids are known to regulate excitatory and inhibitory synaptic inputs impinging on dopamine cells and modulate several dopamine-mediated behaviors, such as reward and addiction, the effects of other lipid neuromodulators are far less clear. Here, we review the emerging role of endocannabinoid-like neuromodulators in dopamine signaling, with a focus on non-cannabinoid N-acylethanolamines and their receptors. Mounting evidence suggests that these neuromodulators contribute to modulate synaptic transmission in dopamine regions and might represent a target for novel medications in alcohol and nicotine use disorder.

Keywords: N-acylethanolamines; alcohol; dopamine neurons; endocannabinoids; nicotine; peroxisome proliferator-activated receptors-α.

Figure 1

Schematic diagram illustrating the biosynthetic and catabolic pathways for N-acylethanolamine (NAE) and canonical endocannabinoid formation and catabolism, and their cellular mechanisms of actions through their receptors. Phosphatidylethanolamine (Peth) is converted into N-acyl-phosphatidylethanolamine (NAPE) by N-acyltransferase (NAT). Ca²⁺ entry mediated by α7-nAChRs activates NAEs synthesis through the Ca²⁺ dependent NAT. The resulting NAPE is hydrolyzed by NAPE-PLD to the corresponding NAEs anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoylethanolamide (PEA). Activation of PPARα by NAEs results in genomic effects (gene transcription) and in non-genomic actions, such as activation of a tyrosine kinase and phosphorylation of β2^*nAChRs (i.e., α4β2). Fatty acid amide hydrolase (FAAH) and NAE-hydrolyzing acid amidase (NAAA) are the major inactivating enzymes for OEA, PEA, and AEA and convert them in ethanolamine and corresponding fatty acids (oleic, palmitic, and arachidonic acids, respectively). NAAA preferentially hydrolyzes PEA. N-oleoyl glycine is one member of the N-acyl amino acid family and is known to activate PPARα. The figure illustrates that AEA and 2-arachidonoylglycerol (2-AG) are produced on demand by NAPE-PLD and DAG lipase, respectively. Raises in intracellular Ca²⁺ can be induced, as in the example, by activation of metabotropic glutamate receptors (mGluR). 2-AG and AEA bind to presynaptic CB1 receptors expressed on GABA and glutamate terminals and depress neurotransmitter release. AEA also activates TRPV1 receptors located on presynaptic glutamatergic terminals. Abbreviations: NAPE-PLD, N-acyl phosphatidylethanolamine phospholipase D; DAG, diacylglycerol; MAG, monoacylglycerol; FAAH, fatty acid amide hydrolase; Glu, glutamate; CB1, cannabinoid type-1 receptor; TRPV1, transient receptor potential vanilloid type-1; PPARα, peroxisome proliferator-activated receptor type-α; nAChRs, nicotinic acetylcholine receptors. This figure is adapted, with permission, from Melis and Pistis (2012) and Pistis and Muntoni (2017).