scholarly journals Chronic Effects of Indirect and Direct Cannabinoid Receptor Agonists on Addiction-Related Behaviors and Dopamine Release

2020 ◽  
Author(s):  
Kevin M. Honeywell ◽  
Timothy G. Freels ◽  
Megan A. McWain ◽  
Abigail S. Chaffin ◽  
Hunter G. Nolen ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Cannabinoid Receptor ◽  
Acid Amide ◽  
Abuse Liability ◽  
List Type ◽  
Cannabinoid System ◽  
Cannabinoid Type 1 Receptor ◽  
Neurochemical Changes ◽  
Cannabinoid Agonist

AbstractA 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.HighlightsThe 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.

scholarly journals Benzyl-1,2,4-triazoles as CB1 Cannabinoid Receptor Ligands: Preparation and In Vitro Pharmacological Evaluation

2016 ◽  
Vol 2016 ◽  
pp. 1-9
Author(s):  
Laura Hernandez-Folgado ◽  
Juan Decara ◽  
Fernando Rodríguez de Fonseca ◽  
Pilar Goya ◽  
Nadine Jagerovic
Keyword(s):  
Cannabinoid Receptor ◽  
Radioligand Binding ◽  
Pharmacological Properties ◽  
Binding Assays ◽  
Receptor Ligands ◽  
Cannabinoid Type 1 Receptor ◽  
Cb1 Cannabinoid Receptor ◽  
Nanomolar Range

In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type 1 receptor (CB1R) antagonists. In order to expand the number of cannabinoid ligands with a central 1,2,4-triazole scaffold, we have synthesized a novel series of 1-benzyl-1H-1,2,4-triazoles, and some of them were evaluated by CB1R radioligand binding assays. Compound 12a showed the most interesting pharmacological properties, possessing a CB1R affinity in the nanomolar range.

scholarly journals Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells

2002 ◽  
Vol 366 (1) ◽  
pp. 137-144 ◽  
Author(s):  
Mauro MACCARRONE ◽  
Riccardo PAUSELLI ◽  
Marianna di RIENZO ◽  
Alessandro FINAZZI-AGRÒ
Keyword(s):  
Biological Activity ◽  
Acid Amide ◽  
Glioma Cells ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
C6 Cells ◽  
Cannabinoid Type 1 Receptor ◽  
Apoptotic Activity ◽  
Rat C6 Glioma

Stearoylethanolamide (SEA) is present in human, rat and mouse brain in amounts comparable with those of the endocannabinoid anandamide (arachidonoylethanolamide; AEA). Yet, the biological activity of SEA has never been investigated. We synthesized unlabelled and radiolabelled SEA to investigate its binding, degradation and biological activity in rat C6 glioma cells. We report that SEA binds to a specific site distinct from known cannabinoid or vanilloid receptors, and that AEA and capsazepine partly (approx. 50%) antagonized this binding. Treatment of C6 cells with SEA inhibits cellular nitric oxide synthase and does not affect adenylate cyclase, whereas treatment with cannabinoid type 1 agonist 2-arachidonoylglycerol activates the former enzyme and inhibits the latter. C6 cells also have a specific SEA membrane transporter, which is inhibited by NO, and a fatty acid amide hydrolase capable of cleaving SEA. In these cells, SEA shows pro-apoptotic activity, due to elevation of intracellular calcium, activation of the arachidonate cascade and mitochondrial uncoupling. NO further enhances SEA-induced apoptosis. Moreover, the cannabinoid type 1 receptor-mediated decrease in cAMP induced by AEA in C6 cells is potentiated by SEA, suggesting that this compound also has an ‘entourage’ effect. Taken together, this study shows that SEA is an endocannabinoid-like compound which binds to and is transported by new components of the endocannabinoid system. It seems noteworthy that degradation and pro-apoptotic activity of SEA are regulated by NO in a way opposite to that reported for AEA.

scholarly journals The C-terminal Helix 9 motif regulates cannabinoid receptor type 1 trafficking and surface expression

2018 ◽  
Author(s):  
Alexandra Fletcher-Jones ◽  
Keri L Hildick ◽  
Ashley J Evans ◽  
Yasuko Nakamura ◽  
Kevin Wilkinson ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Cannabinoid Receptor ◽  
Surface Expression ◽  
Surface Polarity ◽  
Time Resolved ◽  
Surface Stability ◽  
Cannabinoid Type 1 Receptor ◽  
Time Resolved Imaging ◽  
Dual Mechanism

Cannabinoid type 1 receptor (CB1R) is only stably surface expressed in axons, where it downregulates neurotransmitter release. How this tightly regulated axonal surface polarity is established and maintained is unclear. To address this question, we used time-resolved imaging to determine the trafficking of CB1R from biosynthesis to mature polarised localisation. We show that the secretory pathway delivery of CB1R is axonally biased and that surface expressed CB1R is more stable in axons than in dendrites. This dual mechanism is mediated by the CB1R C-terminal and involves the Helix 9 (H9) domain. Removal of the H9 domain increases dendrite secretory pathway delivery and decreases in surface stability. Furthermore, CB1RΔH9 is more sensitive to agonist-induced internalisation and less efficient at downstream signalling than CB1RWT. Together, these results shed new light on how polarity of CB1R is mediated and indicate that the C-terminal H9 domain plays key roles in this process.

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