Cannabinoid receptor 1/2 double-knockout mice develop epilepsy.


“The endocannabinoid system has gained attention as an important modulator of activity in the central nervous system. Initial studies focused on cannabinoid receptor 1 (CB1), which is widely expressed in the brain, but recent work also implicates cannabinoidreceptor 2 (CB2) in modulating neuronal activity.

Both receptors are capable of reducing neuronal activity, generating interest in cannabinoid receptor agonists as potential anticonvulsants.

CB1 (Cnr1) and CB2 (Cnr2) single-knockout mice have been generated, with the former showing heightened seizure sensitivity, but not overt seizures. Given overlapping and complementary functions of CB1 and CB2 receptors, we queried whether double-knockout mice would show an exacerbated neurological phenotype.

Strikingly, 30% of double-knockout mice exhibited provoked behavioral seizures, and 80% were found to be epileptic following 24/7 video-electroencephalographic monitoring. Single-knockout animals did not exhibit seizures. These findings highlight the importance of the endocannabinoid system for maintaining network stability.”

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The G1359A-CNR1 gene polymorphism is associated to glioma in Spanish patients.

“The cannabinoid receptor gene 1 (CNR1) encodes the human cannabinoid receptor CB1.

This receptor has a widespread distribution in the central nervous system (CNS), the main ligands being anandamide, 2-araquidonoil glycerol and marijuana constituents.

There is evidence to suggest an anti-neoplastic effect of these ligands in glial tissues mediated through stimulation of the receptor.

Our results suggest that allele G of the CNR1 gene could be associated with a lower susceptibility to glioma.”

“A glioma is a primary brain tumor that originates from the supportive cells of the brain, called glial cells.”

“Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death.”

“Cannabinoids, the active components of Cannabis sativa…”

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Pharmacological blockade of the fatty acid amide hydrolase (FAAH) alters neural proliferation, apoptosis and gliosis in the rat hippocampus, hypothalamus and striatum in a negative energy context.

“Endocannabinoids participate in the control of neurogenesis, neural cell death and gliosis.

The pharmacological effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which limits the endocannabinoid degradation, was investigated in the present study…

Main results indicated that FAAH inhibitor URB597 decreased neural proliferation, glia and apoptosis in a brain region-dependent manner, which were coupled to local changes in Faah and/or Cnr1 expression and a negative energy context.”

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A common variation in the cannabinoid 1 receptor (CNR1) gene is associated with pre-eclampsia in the Central European population.

“Recently it has been proposed that tightly regulated levels of endogenous cannabinoids play a fundamental role in early placental development.

The aim of this study was to investigate associations of three single-nucleotide polymorphisms (SNPs) in the cannabinoid 1 receptor (CNR1) gene (rs1049353, rs12720071 and rs806368) and their inferred haplotypes with pre-eclampsia, a severe pregnancy-associated condition characterized by abnormal development and remodeling of spiral decidual arteries…

This is the first study focusing on the relationship between SNPs in the CNR1 gene and pre-eclampsia risk.

Although limited by a relatively small sample size, the study indicates that rs806368 in the CNR1 gene may act as a susceptibility marker for pre-eclampsia in humans.”

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Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

“Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits.

Mice lacking the Cnr1 gene (Cnr1−/−), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1−/− mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1−/− mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells.

Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.”

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