Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor CB₁R signaling and anxiety-like behavior.
Roberta Imperatore, Giovanna Morello, Livio Luongo, Ulrike Taschler, Rosaria Romano, Danilo de Gregorio, Carmela Belardo, Sabatino Maione, Vincenzo Di Marzo, Luigia Cristino
Journal of Neurochemistry November 2015 DOI: 10.1111/jnc.13267 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal model study (genetic knockout mouse) Peer reviewed |
|---|---|
| Population | MAGL knockout mice (MAGL-/-), a genetic model of congenital and sustained elevation of brain 2-AG levels |
| Measures | light/dark box test, marble burying test |
| Topics | Neuroplasticity Anxiety |
| Keywords | 2-arachidonoylglycerol 2-ag Cb1r Magl-ko mice Anxiety-like behavior Endocannabinoids |
| Key points | In MAGL-/- mice, congenitally elevated 2-AG was accompanied by β-arrestin2-mediated CB1 receptor desensitization in the mPFC, amygdala, and hippocampus, impaired ERK signaling, altered VGluT1/VGAT expression, and enhanced excitatory drive in the BLA-mPFC circuit. The authors report these changes alongside anxiety-like and obsessive-compulsive behaviors on the light/dark box and marble burying tests, and propose the findings may be relevant to chronic CB1 receptor overstimulation in cannabis users. |
Abstract
Endocannabinoids (eCB) are key regulators of excitatory/inhibitory neurotransmission at cannabinoid-1-receptor (CB1 R)-expressing axon terminals. The most abundant eCB in the brain, that is 2-arachidonoylglycerol (2-AG), is hydrolyzed by the enzyme monoacylglycerol lipase (MAGL), whose chronic inhibition in the brain was reported to cause CB1 R desensitization. We employed the MAGL knock-out mouse (MAGL-/-), a genetic model of congenital and sustained elevation of 2-AG levels in the brain, to provide morphological and biochemical evidence for β-arrestin2-mediated CB1 R desensitization in brain regions involved in the control of emotional states, that is, the prefrontal cortex (PFC), amygdala, hippocampus and cerebellar cortex. We found a widespread CB1 R/β-arrestin2 co-expression in the mPFC, amygdala and hippocampus accompanied by impairment of extracellular signal-regulated kinase signaling and elevation of vesicular glutamate transporter (VGluT1) at CB1 R-positive excitatory terminals in the mPFC, or vesicular GABA transporter (VGAT) at CB1 R-positive inhibitory terminals in the amygdala and hippocampus. The impairment of CB1 R signaling in MAGL-/- mice was also accompanied by enhanced excitatory drive in the basolateral amygdala (BLA)-mPFC circuit, with subsequent elevation of glutamate release to the mPFC and anxiety-like and obsessive-compulsive behaviors, as assessed by the light/dark box and marble burying tests, respectively. Collectively, these data provide evidence for a β-arrestin2-mediated desensitization of CB1 R in MAGL-/- mice, with impact on the synaptic plasticity of brain circuits involved in emotional functions. In this study, the authors provide evidence that congenitally enhanced endocannabinoid levels in the neuronal circuits underlying anxiety-like behavioral states (mainly medial prefrontal cortex, amygdala and hippocampus) lead to CB1R desenistization and anxiety and depression. MAGL-/- mice, a model of congenital overactivity of the eCB system, exhibited a compensatory impairment of CB1R signaling in anxiety-associated brain areas and a subsequent change in excitatory/inhibitory tone associated with altered score in the marble burying and light/dark box test, in concomitance with anxiety and depression behavior states. These findings may have potential relevance to the understanding of the neurochemical effects of chronic CB1R overstimulation in cannabis abusers.
Comparable studies
Other preclinical and animal studies on anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| Chronic, Intermittent Microdoses of the Psychedelic N , N -Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents Male rats | 2019 | Animal study | |
| 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning Mice | 2015 | Preclinical experimental study | |
| Repeated lysergic acid diethylamide (LSD) reverses stress-induced anxiety-like behavior, cortical synaptogenesis deficits and serotonergic neurotransmission decline Male mice exposed to chronic restraint stress | 2022 | Preclinical experimental study |
Citations in the library
Cited by 6
- Psilocybin mitigates behavioral despair and cognitive impairment in treatment-resistant depression model using wistar kyoto rats. Scientific Reports May 26, 2025
- Psilocybin Mitigates Behavioral Despair and Cognitive Impairment in Treatment-resistant Depression Model using Wistar Kyoto Rats Research Square May 6, 2025
- Relationships between cannabis use and mental disorders: assessing the coherence of evidence from studies with different methodologies. The Lancet Psychiatry July 1, 2026
- Cannabinoids, interoception, and anxiety. Pharmacology, Biochemistry, and Behavior May 1, 2019
- Cannabinoid Modulation of the Stressed Hippocampus. Frontiers in Molecular Neuroscience December 19, 2017
and 1 more in the library