CB1 Cannabinoid Receptors and On-Demand Defense Against Excitotoxicity

Marsicano, Giovanni; Goodenough, Sharon; Monory, Krisztina; Hermann, H; Eder, Matthias; Cannich, Astrid; Azad, Shahnaz Christina; Cascio, Maria Grazia; Gutierrez, Silvia Ortega; Stelt, Mario van der; López-Rodrı́guez, Marı́a L.; Casanova, Emilio; Schütz, Günther; Zieglgänsberger, W.; Marzo, Vincenzo Di; Behl, Christian; Lutz, Beat

doi:10.1126/science.1088208

Cited by 1,111 publications

(1,032 citation statements)

References 38 publications

Supporting

Mentioning

948

Contrasting

Unclassified

Order By: Relevance

“…This includes in vivo models of maximal electroshock in mice (Wallace et al, 2001) and the pilocarpine model in rats (Wallace et al, 2003), and in vitro, in hippocampal neuronal culture models of acquired epilepsy and status epilepticus (Blair et al, 2006). Moreover, endocannabinoids such as AEA and 2-AG have been shown to exhibit neuroprotective effects (Marsicano et al, 2003) and antiepileptic effects when applied exogenously (Wallace et al, 2002). In addition, it has been demonstrated that prolonged febrile seizures enhanced endocannabinoid-mediated depolarizationinduced suppression of inhibition (DSI) (Chen et al, 2003;.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

Coomber

O’Donoghue

Mason

2008

Synapse

View full text Add to dashboard Cite

The endogenous cannabinoid system regulates neuronal excitability. The effects of inhibiting fatty acid amide hydrolase (FAAH), the enzyme responsible for metabolism of the endocannabinoid anandamide, on kainic acid (KA)-induced neuronal activity were investigated in the rat in vivo, using the selective FAAH inhibitor URB597. Hippocampal neuronal ensemble unit activity was recorded in isoflurane-anesthetized rats using 16-wire microelectrode arrays. Separate groups of rats were administered with single doses of KA alone, KA and URB597 (0.3 or 1 mg kg 21 , i.p.), or URB597 (1 mg kg 21 ) alone. The role of the cannabinoid CB1 receptor in mediating the effects of URB597 was explored using the CB1 selective antagonists AM251, either alone or prior to KA and URB597 (1 mg kg 21 ) administration, and SR141716A, administered prior to KA and URB597 (1 mg kg 21 ). Neuronal firing and burst firing rates were examined in animals with confirmed dorsal hippocampal placements. KA induced an increase in both firing and burst firing rates, effects which were attenuated by URB597 in a dose-related manner. Pretreatment with AM251 or SR141716A partly attenuated the URB597-mediated effects on firing and burst firing rate. Rats treated with AM251 or URB597 alone did not exhibit any significant change in either firing or burst firing rates compared with basal activity. These results suggest that the inhibition of endocannabinoid metabolism can suppress hyperexcitability in the rat hippocampus, partly via a CB1 receptormediated mechanism. Synapse 62: 746-755, 2008. V

show abstract

Section: Discussionmentioning

confidence: 99%

“…Cannabinoid compounds have been reported to exhibit both antiepileptic (Blair et al, 2006;Wallace et al, 2001; and neuroprotective properties (Marsicano et al, 2003) via cannabinoid receptors. The endogenous cannabinoid (endocannabinoid) system is integral in controlling neuronal excitability and synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

Coomber

O’Donoghue

Mason

2008

Synapse

View full text Add to dashboard Cite

show abstract

“…49 A downregulation of BDNF in the hippocampus, for example, is believed to correlate with depression-like behavior, and injections of BDNF into the hippocampus have been demonstrated to lead to decreased floating in the FST. 37 As we could recently demonstrate that endocannabinoid signaling via CB1 receptors regulates BDNF expression, 2,43 we investigated BDNF mRNA expression in the hippocampus of CB1 À/À and CB1 þ / þ mice. In situ hybridization revealed a specific downregulation of BDNF mRNA in the CA3 region of the hippocampus of CB1 À/À mice (Figure 7), which might, thus, be related to the depression-like FST phenotype in CB1 À/À mice.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

View full text Add to dashboard Cite

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.

show abstract

“…Although CNS CB1R KO mice have not been reported, CB1R KO in a subpopulation of neurons has been reported. 51 The latter is not appropriate to address the site-of-action question because not all CB1R's are removed from the CNS.…”

Section: Peripheral Physiological Effects Vs Peripheral Site Of Actiomentioning

confidence: 99%

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Fong

Heymsfield

2009

Int J Obes

View full text Add to dashboard Cite

Rimonabant and taranabant are two extensively studied cannabinoid-1 receptor (CB1R) inverse agonists. Their effects on in vivo peripheral tissue metabolism are generally well replicated. The central nervous system site of action of taranabant or rimonabant is firmly established based on brain receptor occupancy studies. At the whole-body level, the mechanism of action of CB1R inverse agonists includes a reduction in food intake and an increase in energy expenditure. At the tissue level, fat mass reduction, liver lipid reduction and improved insulin sensitivity have been shown. These effects on tissue metabolism are readily explained by CB1R inverse agonist acting on brain CB1R and indirectly influencing the tissue metabolism through the autonomic nervous system. It has also been hypothesized that rimonabant acts directly on adipocytes, hepatocytes, pancreatic islets or skeletal muscle in addition to acting on brain CB1R, although strong support for the contribution of peripherally located CB1R to in vivo efficacy is still lacking. This review will carefully examine the published literature and provide a perspective on what new tools and studies are required to address the peripheral site of action hypothesis.

show abstract

CB1 Cannabinoid Receptors and On-Demand Defense Against Excitotoxicity

Cited by 1,111 publications

References 38 publications

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

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

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Contact Info

Product

Resources

About