Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors

Bilkei-Gorzó, András; Rácz, Ildikó; Valverde, Olga; Otto, Margot; Michel, Kerstin; Sarstre, M.; Zimmer, Andreas

doi:10.1073/pnas.0504640102

Cited by 139 publications

(91 citation statements)

References 44 publications

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“…However, this result rules out that the differences in BDNF mRNA levels simply relate to an age-dependent decline in the number of neurons in CB1 À/À mice. 24 In summary, we propose that impaired CB1 receptor signaling, which seems to compromise BDNF expression in the hippocampus, can lead to increased passive stresscoping behaviors in the FST and slightly altered behavioral responses to acute antidepressant treatment. Thus, our results generally support the findings from the human rimonabant phase-III trials reporting a slightly increased percentage of patients with anxiety and depressed mood as compared to placebo controls.…”

Section: Discussionmentioning

confidence: 87%

“…13 CB1 receptor-deficient mice share several symptoms with patients suffering from melancholic depression such as, for example, altered responsiveness to reward stimuli, 22 altered neurovegetative functions, 23 a predominance and persistence of aversive memories, 8,9 and possibly neurodegeneration. 24 Furthermore, it was shown by us and others that impaired endocannabinoid signaling can lead to sustained hyperreactivity of the hypothalamic-pituitaryadrenocortical (HPA) axis 23,25 and might also interfere with the proliferation of neural progenitor cells. 26 Human postmortem studies of depressed suicide victims, which have revealed dysregulations of the endocannabinoid system in the prefrontal cortex 27,28 further strengthen the notion of a potential role of the endocannabinoid system in depression.…”

Section: Introductionmentioning

confidence: 99%

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Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

et al. 2007

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Dysregulation of the endocannabinoid system is known to interfere with emotional processing of stressful events. Here, we studied the role of cannabinoid receptor type 1 (CB1) signaling in stress-coping behaviors using the forced swim test (FST) with repeated exposures. We compared effects of genetic inactivation with pharmacological blockade of CB1 receptors both in male and female mice. In addition, we investigated potential interactions of the endocannabinoid system with monoaminergic and neurotrophin systems of the brain. Naive CB1 receptor-deficient mice (CB1 À/À ) showed increased passive stress-coping behaviors as compared to wild-type littermates (CB1 þ / þ ) in the FST, independent of sex. These findings were partially reproduced in C57BL/6N animals and fully reproduced in female CB1 þ / þ mice by pharmacological blockade of CB1 receptors with the CB1 receptor antagonist SR141716. The specificity of SR141716 was confirmed in female CB1 À/À mice, where it failed to affect behavioral performance. Sensitivity to the antidepressants desipramine and paroxetine was preserved, but slightly altered in female CB1 À/À mice. There were no genotype differences between CB1 þ / þ and CB1 À/À mice in monoamine oxidase A and B activities under basal conditions, nor in monoamine content of hippocampal tissue after FST exposure. mRNA expression of vesicular glutamate transporter type 1 was unaffected in CB1 À/À mice, but mRNA expression of brain-derived neurotrophic factor (BDNF) was reduced in the hippocampus. Our results suggest that impaired CB1 receptor function promotes passive stress-coping behavior, which, at least in part, might relate to alterations in BDNF function.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

et al. 2007

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“…Interestingly, recent work has shown that mature, but not young, CB 1 receptor (À/À) mice display cognitive deficits resembling those seen in aged ( + / + ) mice, suggesting that the endocannabinoid system may serve to protect against age-related cognitive decline (Bilkei-Gorzo et al, 2005). Collectively, these results raise the provocative possibility that facilitation of the endocannabinoid system may represent a novel target for nootropic activity.…”

Section: Discussionmentioning

confidence: 89%

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

Varvel

Wise

Niyuhire

et al. 2006

Neuropsychopharmacol

156

113

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Recent reports have demonstrated that disruption of CB 1 receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (À/À) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAHcompromised mice also exhibited a significant increase in acquisition rate. The CB 1 receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB 1 receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, D 9 -tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB 1 receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

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“…And in reality, genetic deletion of CB1 receptors leads to an age-related change in the learning and memory abilities of mice. Young CB1 receptor knockout (CB1 2/2 ) mice showed a superior performance in a broad range of models including object [231] and social recognition tests, in skill and operant learning models [232] as well as enhanced long-term potentiation [233]. The learning ability of 12-month-old CB1 2/2 mice is, however, impaired and this impairment was accompanied by a loss of principal neurons in the hippocampus.…”

Section: Age-dependent Effect Of the Cannabinoid System On Learning Amentioning

confidence: 99%

The endocannabinoid system in normal and pathological brain ageing

Bilkei-Gorzó

2012

Phil. Trans. R. Soc. B

121

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The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, proageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brainderived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.

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Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors

Cited by 139 publications

References 44 publications

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

The endocannabinoid system in normal and pathological brain ageing

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