Inhibition of endocannabinoid neuronal uptake and hydrolysis as strategies for developing anxiolytic drugs

Batista, Luara A; Gobira, Pedro H.; Viana, Thércia Guedes; Aguiar, Daniele C.; Moreira, Fabrício A.

doi:10.1097/fbp.0000000000000073

Cited by 36 publications

(22 citation statements)

References 74 publications

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“…It has been reported that endocannabinoids have a wide range of regulatory effects in a variety of physiological processes. One of their most promising actions has to do with their effect on various types of cancers and their potential use in the treatment of these diseases ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…Endocannabinoids are then eliminated in a two step process: first, an intracellular accumulation, followed by an enzymatic metabolization by an enzyme that belongs to the serine hydrolase family, the fatty acid amide hydrolase (or FAAH) or by the monoacyl glycerol lipase (a soluble serine hydrolase enzyme). These two enzymes are the main proteins in charge of degrading endocannabinoids ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

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Proapoptotic effect of endocannabinoids in prostate cancer cells

et al. 2015

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In the early stages, prostate cancer is androgen- dependent; therefore, medical castration has shown significant results during the initial stages of this pathology. Despite this early effect, advanced prostate cancer is resilient to such treatment. Recent evidence shows that derivatives of Cannabis sativa and its analogs may exert a protective effect against different types of oncologic pathologies. The purpose of the present study was to detect the presence of cannabinoid receptors (CB1 and CB2) on cancer cells with a prostatic origin and to evaluate the effect of the in vitro use of synthetic analogs. In order to do this, we used a commercial cell line and primary cultures derived from prostate cancer and benign prostatic hyperplasia. The presence of the CB1 and CB2 receptors was determined by immunohistochemistry where we showed a higher expression of these receptors in later stages of the disease (samples with a high Gleason score). Later, treatments were conducted using anandamide, 2-arachidonoyl glycerol and a synthetic analog of anandamide, methanandamide. Using the MTT assay, we proved that the treatments produced a cell growth inhibitory effect on all the different prostate cancer cultures. This effect was demonstrated to be dose-dependent. The use of a specific CB1 receptor blocker (SR141716) confirmed that this effect was produced primarily from the activation of the CB1 receptor. In order to understand the MTT assay results, we determined cell cycle distribution by flow cytometry, which showed no variation at the different cell cycle stages in all the cultures after treatment. Treatment with endocannabinoids resulted in an increase in the percentage of apoptotic cells as determined by Annexin V assays and caused an increase in the levels of activated caspase-3 and a reduction in the levels of Bcl-2 confirming that the reduction in cell viability noted in the MTT assay was caused by the activation of the apoptotic pathway. Finally, we observed that endocannabinoid treatment activated the Erk pathway and at the same time, produced a decrease in the activation levels of the Akt pathway. Based on these results, we suggest that endocannabinoids may be a beneficial option for the treatment of prostate cancer that has become nonresponsive to common therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proapoptotic effect of endocannabinoids in prostate cancer cells

et al. 2015

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“…In addition to general antiinflammatory and analgesic effects, the modulation of EC tissue concentrations is a promising therapeutic approach to treat diseases related to the central nervous system (CNS) (8,9). Pharmacological strategies to treat neuropsychiatric disorders currently focus on the inhibition of EC degradation (10). FAAH and MAGL inhibitors such as URB597 (11) and JZL184 (12), respectively, have been instrumental to elucidate the role of AEA and 2-AG in rodent models of anxiety and depression (6,(12)(13)(14).…”

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confidence: 99%

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

Chicca

Nicolussi

Bartholomäus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

155

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The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived -substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC = 10 nM) inhibitor -(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.

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“…CB1Rs are predominately expressed in the central nervous system where they are found in high densities in brain regions associated with the regulation of emotional process including anxiety such as the prefrontal cortex, basolateral amygdala, and ventral hippocampus and at significantly higher levels on GABAergic than glutamatergic neurons [12][13][14][15]. Postsynaptic neuron depolarization triggers the release of endocannabinoids (eCBs) including N-arachidonoylethanolamide (AEA) that binds to CB1Rs and 2-arachidonoylglycerol (2-AG) that binds to CB1/2Rs , which both inhibit presynaptic neurotransmission before being trafficked by fatty acid binding protein-5 (FAB5) and fatty acid binding protein-7 (FAB7) and metabolized by fatty acid amide hydrolase (FAAH) in presynaptic terminals and monoacylglycerol lipase (MAGL) in postsynaptic terminals respectively [12,13,[16][17][18][19][20][21][22][23][24][25]. The pharmacological manipulation of the cannabinoid system can be used as a target for anxiolytic treatment.…”

Section: Introductionmentioning

confidence: 99%

Indirect and Direct Cannabinoid Agonists Differentially Affect Mesolimbic Dopamine Release and Related Behaviors

Honeywell

Freels

McWain

et al. 2020

Preprint

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Abbreviations: 2-AG, 2-arachidonoylglycerol; AA-5-HT, N-arachidonoyl serotonin; ACEA, arachidinoyl-2'chloroethylamide; AEA, arachidonoylethanolamide; B6, C57BL/6J mice; CB1R, cannabinoid type 1 receptor; CB2R, cannabinoid type 2 receptor; CPA, conditioned place aversion; CPP, conditioned place preference; DAR, dopamine autoreceptor; DAT, dopamine transporter; D2R, dopamine receptor D2; D3R, dopamine receptor D3; eCB, endocannabinoid; EPM, elevated plus maze; FAB5, fatty acid binding protein-5; FAB7, fatty acid binding protein 7; FAAH, fatty acid amide hydrolase; LDB, light/dark box; MAGL, monoacylglycerol lipase; NAc, Nucleus accumbens; OF, open field, THC, Δ 9 -tetrahydracannabinol; TRPV1, transient receptor potential vanilloid type 1 channel; VTA, ventral tegmental area anad Highlights • The indirect cannabinoid agonist AA-5-HT did not alter dopamine release or measured behaviors.• The direct cannabinoid receptor agonist ACEA did not alter measured behaviors.• ACEA decreased dopamine release and the dopaminergic response to cocaine.• Neither drug indicated abuse liability, although ACEA did alter dopamine functioning. Abstract A major problem with current anxiolytic medications is abuse liability; thus, new pharmaceutical targets are being explored. The cannabinoid system is one potential target. The current paper examined behavioral and neurochemical changes related to abuse liability following chronic administration of the indirect cannabinoid agonist arachidonoyl serotonin (AA-5-HT) and the direct cannabinoid type 1 receptor (CB1R) agonist arachidonyl-2-chloro-ethylamide (ACEA). AA-5-HT indirectly agonizes the cannabinoid system via inhibition of the dual fatty acid amide hydrolase (FAAH) while also inhibiting transient vanilloid type 1 (TRPV1) channels. Neither AA-5-HT nor ACEA induced conditioned place preference (CPP) or altered behaviors during open field (OF) or saccharin preference testing. AA-5-HT did not alter phasic dopamine release in the nucleus accumbens, as measured with in vivo fixed potential amperometry; however, ACEA decreased dopamine release and enhanced the dopaminergic effect of cocaine. Overall, neither AA-5-HT nor ACEA induced behavioral or neurochemical changes associated with abuse liability; however, indirect mechanisms of agonizing the cannabinoid system may be a better alternative than direct mechanisms if concerned with disrupting dopamine function.

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Inhibition of endocannabinoid neuronal uptake and hydrolysis as strategies for developing anxiolytic drugs

Cited by 36 publications

References 74 publications

Proapoptotic effect of endocannabinoids in prostate cancer cells

Proapoptotic effect of endocannabinoids in prostate cancer cells

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

Indirect and Direct Cannabinoid Agonists Differentially Affect Mesolimbic Dopamine Release and Related Behaviors

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