“Social defeat leads to changes in the endocannabinoid system; an overexpression of calreticulin and motor impairment in mice… the aim of this study was to investigate the long-lasting effects of chronic psychosocial stress on motor coordination and motor learning, CB1 receptor expression, endogenous cannabinoid ligands and gene expression in the cerebellum. After chronic psychosocial stress, motor coordination and motor learning were impaired… The present study provides evidence that chronic stress activates calreticulin and might be one of the pathological mechanisms underlying the motor coordination and motor learning dysfunctions seen in social defeat mice.” http://www.ncbi.nlm.nih.gov/pubmed/26815100
Category Archives: Endocannabinoid System
Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.
“In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction.
In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization.
Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could contribute to the specifically increased GluN1 expression observed in the hippocampus of cocaine-sensitized mice.”
Molecular Mechanisms of Cannabis Signaling in the Brain.
“Cannabis has been cultivated and used by humans for thousands of years. Research for decades was focused on understanding the mechanisms of an illegal/addictive drug. This led to the discovery of the vast endocannabinoid system.
Research has now shifted to understanding fundamental biological questions related to one of the most widespread signaling systems in both the brain and the body.
Our understanding of cannabinoid signaling has advanced significantly in the last two decades. In this review, we discuss the state of knowledge on mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in both brain reward/addiction and psychiatric disorders.
It is highly probable that various cannabinoids will be found to be efficacious in the treatment of a number of psychiatric disorders.
We are at crossroads for research on endocannabinoid function and therapeutics (including the use of exogenous treatments such as Cannabis).
With over 100 cannabinoid constituents, the majority of which have not been studied, there is much Cannabis research yet to be done. With more states legalizing both the medicinal and recreational use of marijuana the rigorous scientific investigation into cannabinoid signaling is imperative.”
Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex – possible involvement of 5-HT1A and CB1 receptors.
“Systemic administration of Cannabidiol (CBD), the main non-psychotomimetic constituent of Cannabis sativa, induces antidepressant-like effects.
The mechanism of action of CBD is thought to involve the activation of 5-HT1A receptors and the modulation of endocannabinoid levels with subsequent CB1 activation…
Administration of CBD into the vmPFC induces antidepressant-like effects possibly through indirect activation of CB1 and 5-HT1A receptors.”
Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ9-tetrahydrocannabinol.
“Anatomical, biochemical and pharmacological evidences suggest the existence of a cross-talk between the orexinergic and the endocannabinoid system.
The hypothermia, supraspinal antinociception and anxiolytic-like effects induced by THC were modulated by orexins through OX2 signalling.
OX1 did not seem to be involved in these THC responses. No differences in CB1 receptor levels were found between wild-type and PPO KO mice…
Our results provide new findings to further clarify the interaction between orexins and cannabinoids. OX1 and OX2 are differently implicated in the pharmacological effects of cannabinoids.”
Rescue of Impaired mGluR5-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats.
“Rescue of Impaired metabotropic glutamate receptor 5 (mGluR5)-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats…
Restoring endocannabinoid signaling allows mGluR5 activation to increase infralimbic output hence inhibit pain behaviors and mitigate pain-related cognitive deficits.”
The selective monoacylglycerol lipase inhibitor MJN110 produces opioid sparing effects in a mouse neuropathic pain model.
“Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction.
A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents.
The combination of opiates with the primary active constituent of cannabis, Δ9-tetrahydrocannabinol, produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing…
Here, we tested whether elevating the endogenous cannabinoid 2-arachidonylglycerol (2-AG) through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid sparing effects…
These findings, taken together, suggest that MAGL inhibition produces opiate sparing events with diminished tolerance, constipation, and cannabimemetic side effects.”
Opposite regulation of cannabinoid CB1 and CB2 receptors in the prefrontal cortex of rats treated with cocaine during adolescence.
“The endocannabinoid system is implicated in the neurobiology of cocaine addiction, although it is not clear how cocaine regulates brain CB1 and CB2receptors, especially during adolescence, a critical moment for shaping adult response to drug use.
This study evaluated CB1 and CB2 protein levels in prefrontal cortex (PFC) and hippocampus (HC) by western blot analysis with specific and validated antibodies: (1) basally during adolescence (post-natal day PND 40, PND 47, PND 54), (2) by a sensitizing regimen of cocaine (15mg/kg, 7 d, i.p.) during different windows of adolescence vulnerability (PND 33-39, PND 40-46, PND 47-53), and (3) following repeated cocaine administration during adolescence (PND 33-39) in adulthood (PND 64).
The results demonstrated a dynamic and opposite basal modulation of CB1 and CB2 receptors in PFC and HC during adolescence. CB1 receptor levels were increased while CB2 receptors were decreased as compared to adulthood with asymptotes values around mid adolescence (PND 47) both in PFC (CB1: +45±22, p<0.05; CB2: -24±6%, p<0.05) and HC (CB1: +53±23, p<0.05; CB2: -20±8%, p<0.05).
Interestingly, cocaine only altered CB1(+55±10%, p<0.05) and CB2 (-25±10%, p<0.05) receptors when administered during early adolescence and only in PFC. However, the changes observed in PFC by repeated cocaine administration in adolescence were transient and did not endure into adulthood.
These results identified a period of vulnerability during adolescence at which cocaine dysregulated the content of CB receptors in PFC, suggesting an opposite role for these receptors in the effects mediated by cocaine.“
Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala.
“The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety-driven alcohol drinking and relapse.
The endogenouscannabinoid/type 1 cannabinoid receptor (eCB/CB1 ) system curbs BLA-driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB1 activation reduces GABA release and drives anxiogenesis.
Additionally, decreased amygdala CB1 is observed in abstinent alcoholic patients and ethanol withdrawn rats.
Here, we investigated the potential disruption of eCB/CB1signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2-3 weeks intermittent ethanol.
In the naïve rat BLA, the CB1agonist WIN 55,212-2 (WIN) decreased GABA release, and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity.
This retrograde tonic eCB/CB1 signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1 system.
In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both presynaptic and postsynaptic mechanisms.
Notably, CB1 activation impaired ethanol’s facilitation of GABAergic transmission across both groups, but the AM251-induced and ethanol-induced facilitation of GABA release was additive, suggesting independent presynaptic sites of action.
Collectively, the present findings highlight a critical CB1 influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol-dependent state.”
The endocannabinoid system and neuropathic pain.
“The research of new therapeutic strategies for neuropathic pain represents a major current priority.
Important drawbacks to advance in the development of these therapies are the limited translational value of the animal models now available and the elucidation of the complex neuronal and immune pathophysiological mechanisms underlying neuropathic pain.
One of the neurotransmitter systems participating in neuropathic pain control that has recently raised a particular interest is the endocannabinoid system.
This system is highly expressed in neurons and immune cells, and it plays a crucial role in the development of neuropathic pain.
Preclinical studies have provided important findings, revealing the potential interest of the endocannabinoid system for the treatment of neuropathic pain.
These studies have reported the analgesic effects of cannabinoid agonists in multiple neuropathic pain models, and they have identified specific targets within this system to develop more effective and safe analgesic compounds.
Several clinical studies suggest that cannabinoids significantly reduced neuropathic pain…“