Tag Archives: CB1Rs

Cannabinoid receptor-interacting protein 1a modulates CB1 receptor signaling and regulation.

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“Cannabinoid CB1 receptors (CB1Rs) mediate the presynaptic effects of endocannabinoids in the central nervous system (CNS) and most behavioral effects of exogenous cannabinoids.

Cannabinoid receptor-interacting protein 1a (CRIP1a) binds to the CB1R C-terminus and can attenuate constitutive CB1R-mediated inhibition of Ca(2+) channel activity.

We now demonstrate cellular colocalization of CRIP1a at neuronal elements in the CNS and show that CRIP1a inhibits both constitutive and agonist-stimulated CB1R-mediated guanine nucleotide-binding regulatory protein (G-protein) activity.

These results confirm that CRIP1a inhibits constitutive CB1R activity and demonstrate that CRIP1a can also inhibit agonist-stimulated CB1R signaling and downregulation of CB1Rs. Thus, CRIP1a appears to act as a broad negative regulator of CB1R function.”

http://www.ncbi.nlm.nih.gov/pubmed/25657338

Abnormal mGlu 5 Receptor/Endocannabinoid Coupling in Mice Lacking FMRP and BC1 RNA

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“Transcriptional silencing of the gene encoding the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS)…

Our data indicate for the first time that mGlu5R-driven endocannabinoid signaling in the striatum is under the control of both FMRP and BC1 RNA. The abnormal mGlu5R/2-AG coupling found in FMRP-KO mice emphasizes the involvement of mGlu5Rs in the synaptic defects of FXSand identifies the modulation of the endocannabinoid system as a novel target for the treatment of this severe neuropsychiatric disorder.

In conclusion, this is the first study addressing endocannabinoid system in a model of FXS. Our results show that dysfunctional mGlu5R signaling leads to abnormal 2-AG metabolism and physiological activity, and indicate that inhibition of 2-AG synthesis or activity at CB1Rs might be a useful treatment option in FXS patients. In this respect, recent investigations suggest that this modulation could be achieved not only by direct pharmacological blockade of CB1Rs, but also indirectly, for example through the inhibition of anandamide degradation or the stimulation of transient receptor potential vanilloid 1 (TRPV1) channels. These two components of the endocannabinoid system, in fact, have been shown to selectively interact with mGlu5R/2-AG coupling in striatal neurons, and might interfere with the synaptic alterations seen after FMRP ablation with less side effects than those of widespread pharmacological inhibition of CB1Rs, which control not only GABA but also glutamate synapses.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055456/

Current evidence supporting a role of cannabinoid CB1 receptor (CB1R) antagonists as potential pharmacotherapies for drug abuse disorders.

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Abstract

“Since the discovery of the cannabinoid CB1 receptor (CB1R) in 1988, and subsequently of the CB2 receptor (CB2R) in 1993, there has been an exponential growth of research investigating the functions of the endocannabinoid system. The roles of CB1Rs have been of particular interest to behavioral pharmacologists because of their selective presence within the central nervous system (CNS) and because of their association with brain-reward circuits involving mesocorticolimbic dopamine systems. One potential role that has become of considerable recent focus is the ability of CB1Rs to modulate the effects of drugs of abuse. Many drugs of abuse elevate dopamine levels, and the ability of CB1R antagonists or inverse agonists to attenuate these elevations has suggested their potential application as pharmacotherapies for treating drug abuse disorders. With the identification of the selective CB1R antagonist, SR141716, in 1994, and its subsequent widespread availability, there has been a rapid expansion of research investigating its ability to modulate the effects of drugs of abuse. The preliminary clinical reports of its success in retarding relapse in tobacco users have accelerated this expansion. This report critically reviews preclinical and clinical studies involving the ability of CB1R antagonists to attenuate the effects of drugs of abuse, while providing an overview of the neuroanatomical and neurochemical points of contact between the endocannabinoid system and systems mediating abuse-related effects.”

http://www.ncbi.nlm.nih.gov/pubmed/16148435