Targeting endocannabinoid pathways

A recent study has extended on earlier findings that PCP-induced social withdrawal results from deficient endocannabinoid transmission and that FAAH inhibition with URB597 could reverse these deficits [1]:

Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia.

Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia. Using in vivo extracellular recordings in chloral hydrate-anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats. Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity. Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity.


Numerous findings implicate endocannabinoids in the pathophysiology of schizophrenia:

“…preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG . Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia” [2]

“In addition to longitudinal relationships between marijuana exposure and the etiology of schizophrenia, considerable evidence points to dysregulation of naturally occurring ECBs as correlative factors linked to the occurrence of schizophrenia. Thus, several reports have shown that cerebrospinal fluid (CSF) levels of anandamide, a naturally occurring ECB, in medication-naive patients with schizophrenia are significantly elevated and negatively correlated with the presence of psychotic symptoms. Analysis of post-mortem brain tissue samples from schizophrenia patients revealed that the levels 2-AG, were significantly elevated relative to controls in several neural regions including the cerebellum, hippocampus, and PFC. Further evidence implicating a specific role for prefrontal cortical cannabinoid dysregulation as an etiological mechanism in schizophrenia has come from post-mortem studies of schizophrenia brain samples. An important study from Dalton et al. analyzed cannabinoid CB(1) receptor binding levels and mRNA expression in the dorsolateral prefrontal cortex (DLPFC), comparing sub-populations of paranoid or non-paranoid schizophrenia patients, relative to healthy controls. Interestingly, this study reported a paranoid schizophrenia-subtype specific effect with paranoid schizophrenia subjects displaying 22% higher levels of CB1 receptor binding compared to controls or non-paranoid schizophrenia patients. Similar results were reported by Jenko et al., wherein CB1 receptor binding in the DLPFC was reported to be 20% higher in schizophrenia relative to healthy control subjects. Similarly, Zavitsanou et al. reported increased CB1 binding levels in samples of anterior cingulate cortex from schizophrenia patients. Such findings strongly suggested that abnormalities in CB1 receptor signaling within the PFC may relate specifically to paranoia-related schizophrenia symptomology and more specifically, suggest that a hyperactive state of CB1 activity within frontal cortical regions may be linked to the emotional regulation disturbances found in paranoid schizophrenia populations.”  [3]

The role of cannabinoid transmission in emotional memory formation has been investigated:
“Research in our laboratory has focused on how cannabinoid transmission both within and extrinsic to the mesolimbic DA system, including the BLA→mPFC circuitry, can modulate both rewarding and aversive emotional information. In this review, we will summarize clinical and basic neuroscience research demonstrating the importance of cannabinoid signaling within this neural circuitry. In particular, evidence will be reviewed emphasizing the importance of cannabinoid signaling within the BLA→mPFC circuitry in the context of emotional salience processing, memory formation and memory-related plasticity. We propose that aberrant states of hyper or hypoactive ECB signaling within the amygdala-prefrontal cortical circuit may lead to dysregulation of mesocorticolimbic DA transmission controlling the processing of emotionally salient information. These disturbances may in turn lead to emotional processing, learning, and memory abnormalities related to various neuropsychiatric disorders, including addiction and schizophrenia-related psychoses.” [3]
Schematic summary of the effects of hyperactive vs. hypoactive CB1 receptor states in the mammalian PFC. While a state of CB1 hyperactivity is linked to an amplification in emotional salience, particularly in terms of increased sensitivity to fear-related stimuli in rats and increased paranoid psychosis in human subjects. CB1 receptor overstimulation also switches normally rewarding stimuli into aversive effects, mediated through down-stream signaling of KOR receptor substrates in the VTA. In contrast, a state of CB1 hypoactivity is linked to the blunting of emotional salience, a blockade of fear-related memory formation. In contrast, CB1 receptor blockade potentiates the reward salience of opiate-related cues, via the activation of a MOR receptor substrate in the VTA.

“Interestingly, antipsychotic treatment seems to affect anandamide levels. While first-episode patients briefly treated with dopamine D2/3 receptor antagonists, such as first generation antipsychotics or amisulpride, showed anandamide levels comparable to those of healthy controls, patients treated with second generation antipsychotics with additional antagonistic effects at serotonin 5-HT2A receptors still had significantly elevated levels of anandamide in CSF (Giuffrida et al., 2004). Nevertheless, these levels did not reach the concentrations in antipsychotic-naïve patients. Since treatment with D2/3 receptor antagonistic antipsychotics is associated with anandamide concentrations close to normal levels, it has been assumed that the ECS modulates the dopaminergic system. This hypothesis is supported by animal studies. A microdialysis study (Giuffrida et al., 1999) demonstrated that both neuronal activity of the dorsal striatum and local injection of a D2 receptor agonist stimulated anandamide release, an effect that was prevented by administration of a D2 receptor antagonist. The effects of D2 receptor agonists on locomotor activity and stereotypes of rats can be enhanced by pretreatment with a CB1R antagonist (Giuffrida et al., 1999) and reduced by the inhibition of the anandamide transport (Beltramo et al., 2000 and Martin et al., 2008). These findings indicate that the ECS operates as a negative feedback system that counteracts dopamine release”

cbs d2r
Model of the proposed negative feedback mechanism based on dopamine–endocannabinoid interaction in schizophrenia. A severe activation of dopamine receptors seems to result in psychotic symptoms in schizophrenia patients. In parallel, this activation is accompanied by increased anandamide release that in turn seems to alleviate psychotic symptoms [source]

Dysregulation of the HPA axis response to stress in animals has been beneficially restored by FAAH inhibition: “the basolateral amygdala is a key structure involved in the anti-stress effects of URB597” providing evidence that “enhancement of endogenous cannabinoid signaling by inhibiting FAAH represents a potential therapeutic strategy for the management of stress-related disorders.” [4]

While administration of CB1 agonists has the potential to worsen psychosis, non-psychoactive doses of CB1 agonists may protect against inflammation-induced cognitive damage [5] Inflammation has also been modulated by inhibiting endocannabinoid degradation pathways [6]

CB2 agonism has recently been studied and may prove beneficial [7] Modulation of dopaminergic pathways by CB2 agonism has antipsychotic and anti-addictive potential: activation of CB2Rs inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of a CB2 agonist into the VTA inhibited cocaine self-administration [8] CB2 agonists, via skewing towards an anti-inflammatory M2 polarisation of microglia, may provide beneficial therapies for multiple psychiatric disorders [9, 10]

Dietary modification of the intake ratio of n-3 to n-6 PUFAs may modulate CB1 receptor dependent pathways, providing a safe intervention [11, 12]

Vitamin E has been described as a lipid modulator of the endocannabinoid system [13]

Pregnenolone can act as a signaling-specific inhibitor of the CB1 receptor [14]

Monoacylglycerol lipase inhibitors may provide a novel neuroprotective intervention:

“…monoacylglycerol lipase (MAGL) inactivation robustly preserved myelin integrity and suppressed microglial activation in the cuprizone-induced model of T-cell-independent demyelination. These findings suggest that MAGL blockade may be a useful strategy for the treatment of immune-dependent and -independent damage to the white matter.” [15]

It is possible that endocannabinoid modulation of TLR-immune responses may provide a novel therapeutic target for schizophrenia. [16]


See more:

Cognitive performance and peripheral endocannabinoid system receptor expression in schizophrenia.

Endocannabinoid signalling and the deteriorating brain

Endocannabinoid signaling in innate and adaptive immunity.

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