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Review
. 2013 Dec 20;7:256.
doi: 10.3389/fnins.2013.00256.

Cannabinoid-hypocretin Cross-Talk in the Central Nervous System: What We Know So Far

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Free PMC article
Review

Cannabinoid-hypocretin Cross-Talk in the Central Nervous System: What We Know So Far

Africa Flores et al. Front Neurosci. .
Free PMC article

Abstract

Emerging findings suggest the existence of a cross-talk between hypocretinergic and endocannabinoid systems. Although few studies have examined this relationship, the apparent overlap observed in the neuroanatomical distribution of both systems as well as their putative functions strongly point to the existence of such cross-modulation. In agreement, biochemical and functional studies have revealed the existence of heterodimers between CB1 cannabinoid receptor and hypocretin receptor-1, which modulates the cellular localization and downstream signaling of both receptors. Moreover, the activation of hypocretin receptor-1 stimulates the synthesis of 2-arachidonoyl glycerol culminating in the retrograde inhibition of neighboring cells and suggesting that endocannabinoids could contribute to some hypocretin effects. Pharmacological data indicate that endocannabinoids and hypocretins might have common physiological functions in the regulation of appetite, reward and analgesia. In contrast, these neuromodulatory systems seem to play antagonistic roles in the regulation of sleep/wake cycle and anxiety-like responses. The present review attempts to piece together what is known about this interesting interaction and describes its potential therapeutic implications.

Keywords: antinociception; endocannabinoid system; energy balance; heteromerization; hypocretinergic system; reward; sleep/wake cycle.

Figures

Figure 1
Figure 1
Schematic representation of the main areas expressing CB1, HcrtR1 and HcrtR2 in the mouse brain and location of hypocretinergic neurons. (A) CB1 receptor distribution. (B) HcrtR1 and HcrtR2 distribution and localization of hypocretinergic neurons. A4, A5, A7, pons cell groups; AMG, amygdala; CPu, caudate putamen; Ctx, cortex; DCN, deep cerebellar nuclei; DRN, dorsal raphe nucleus; GP, globus pallidus; LC, locus coeruleus; NAc, nucleus accumbens; NTS, nucleus of the solitary tract; OB, olfactory bulb; OT, olfactory tubercle; PAG, periaqueductal gray; PVT, paraventricular nucleus of thalamus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; TMN, tuberomammillary nucleus; VTA, ventral tegmental area.
Figure 2
Figure 2
Overview of the main synaptic signaling mechanisms of endocannabinoid and hypocretinergic systems. (A) Endocannabinoid-mediated synaptic signaling. (1) Glutamate is released from presynaptic terminals and stimulates both ionotropic and metabotropic glutamate receptors, leading to postsynaptic depolarization through Ca2+ entrance and Gq-protein activation. (2) High Ca2+ concentration stimulates endocannabinoid synthesis through PLC and PLD. 2-AG synthesis is also mediated by Gq-protein activation. (3) Endocannabinoids are released to the synaptic cleft and activate CB1 and CB2 presynaptic receptors. Some of the main downstream consequences of CB receptor activation and subsequent Gi-protein stimulation are: (3a) inhibition of AC activity, (3b) membrane hyperpolarization after modulation of K+ and Ca2+ channels, and subsequent inhibition of NT release, (3c) activation of protein kinase cascades such as MAPK pathway. (B) Hypocretin-mediated synaptic signaling. (1) Hypocretins are released from presynaptic terminals and activate postsynaptic HcrtR1 and HcrtR2. (2) HcrtR stimulation is mainly associated with Gq-protein activation, but it can activate also other G-protein subtypes. Some of the main downstream consequences of HcrtR activation and subsequent Gq-protein stimulation are: (2a) activation of PLC activity, and subsequent DAG and 2-AG synthesis (2b) membrane depolarization after modulation of K+ channels, non-specific cationic channels and Na+/Ca2+ exchanger, (2c) activation of protein kinase cascades such as MAPK pathway. NT, neurotransmitter; iGluR, ionotropic glutamate receptor; mGluR, metabotropic glutamate receptor; PIP2, phosphatidylinositol bisphosphate; DAG, diacylglicerol; 2-AG, 2-arachidonoylglycerol; NAPE, N-arachidonoyl-phosphatidylethanolamine; AEA, anandamide; PLC, phospholipase C; DAGL, diacylglycerol lipase; PLD, phospholipase D; AC, adenyl cyclase; cAMP, cyclic AMP; MAPK, mitogen-activated protein kinase; Hcrt-1, hypocretin-1; Hcrt-2, hypocretin-2; PKC, protein kinase C; X+, unspecific cation.
Figure 3
Figure 3
Schematic representation of the main brain pathways involved in the homeostatic control of food intake. Ghrelin released during fasting from stomach and leptin from adipose tissue, among other mediators, bind to receptors on orexigenic and/or anorexigenic neurons in the ARC of the hypothalamus. This induces the release of either the orexigenic neuropeptides NPY and AgRP or the anorexigenic neuropeptides CART and the POMC-derived peptide α-MSH. These neuropeptides from the ARC travel along axons to secondary neurons in other areas of the hypothalamus such as the PVN and the LH. The ultimate effects of these signaling cascades are changes in the sensation of hunger and satiety in the NTS. Hypocretinergic and MCH neurons are modulated differently by inhibitory or excitatory CB1-expressing inputs. ARC, arcuate nucleus; PVN, paraventricular nucleus; LH, lateral hypothalamus; NTS, nucleus of the tractus solitarius; 3V, third ventricle; NPY, neuropeptide Y; AgRP, Agouti-related peptide; CART, cocaine- and amphetamine-regulated transcript; POMC, pro-opiomelanocortin; MCH, melanin-concentrating hormone; CRH, corticotropin-releasing hormone; Hcrt1, hypocretin-1; Hcrt2, hypocretin-2.

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