Tag Archives: CB1

On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

Posted on by
Reply

Abstract

“Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/15450934

Targeting the endocannabinoid system in the amygdala kindling model of temporal lobe epilepsy in mice

Posted on by
Reply

“The endocannabinoid system can be considered as a putative target to affect ictogenesis as well as the generation of a hyperexcitable epileptic network… These data give first evidence that CB1-receptor activation might render a disease-modifying approach. Future studies are necessary that further analyze the role of CB1 receptors and to confirm the efficacy of CB1-receptor agonists in other models of chronic epilepsy.”

http://www.ncbi.nlm.nih.gov/pubmed/21627644

The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus

Posted on by
Reply

“Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.”

“In conclusion, our study reveals a mechanism through which the endocannabinoid system is able to provide on-demand protection against acute behavioral seizures. CB1 expression on hippocampal glutamatergic circuits accounts for this protection and might represent a suitable target for the treatment of neurological disorders associated with excessive neuronal excitation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769341/

Endocannabinoids and Their Implications for Epilepsy

Posted on by
Reply

“This review covers the main features of a newly discovered intercellular signaling system in which endogenous ligands of the brain’s cannabinoid receptors, or endocannabinoids, serve as retrograde messengers that enable a cell to control the strength of its own synaptic inputs. Endocannabinoids are released by bursts of action potentials, including events resembling interictal spikes, and probably by seizures as well. Activation of cannabinoid receptors has been implicated in neuroprotection against excitotoxicity and can help explain the anticonvulsant properties of cannabinoids that have been known since antiquity.”

“Cannabis in its various forms, including marijuana and hashish, is produced from the flowers and leaves of the hemp plant, Cannabis sativa. Through their primary psychoactive ingredient, Δ9-tetrahydrocannabinol (THC), these drugs affect the central nervous system by activating specific membrane-bound receptors. The primary brain receptors, cannabinoid receptors type 1 (CB1), are G protein–coupled, seven-transmembrane domain proteins that share numerous similarities with heterotrimeric G protein–coupled receptors for conventional neurotransmitters such as γ-aminobutyric acid (GABA) and glutamate. The CB1s bind THC with a high degree of selectivity and are heterogeneously distributed throughout the brain. Inasmuch as THC is a plant-derived compound not produced in mammals, endogenous ligands must exist for the cannabinoid receptor, that is, endocannabinoids. Indeed, several endogenous ligands for CB1 have been discovered, with anandamide being the first. Anandamide and 2-arachidonoyl glycerol (2-AG), are thought to be the major brain endocannabinoids, with regional differences in which one or the other predominates. Endocannabinoids have been strongly implicated in a growing variety of physiologic phenomena, including regulation of eating, anxiety, pain, extinction of aversive memories, and neuroprotection. Potent agonists and antagonists for CB1 exist and may serve as the foundation of new therapeutic strategies for treating pathologies. The voluminous work summarized here has been extensively covered in recent reviews on cannabinoid neurochemistry and pharmacology as well as neurophysiology. This review focuses on the neurophysiology of the endocannabinoid systems.”

“Conclusion

From what is known about their synthesis and release, endocannabinoids should be produced under many conditions of increased neuronal excitability and specific intercellular signaling. For example, an epileptic seizure, with its large swings in transmembrane voltage, increases in intracellular calcium, and marked release of neurotransmitters, such as acetylcholine and glutamate, should prominently release endocannabinoids. Indeed, seizures induced by kainic acid (a glutamate agonist) increase hippocampal levels of anandamide in normal and wild-type mice. Intriguingly, CB1 knockout mice and normal mice treated with a CB1 antagonist had more pronounced seizures and more severe excitotoxic cell death than untreated normal mice. Although the detailed mechanisms of neuroprotection have not been worked out, the rapid increases in expression of the immediate early genes, c-fos and zipf268, and subsequent increase in brain-derived neurotrophic factor (BDNF) normally induced by kainic acid, were absent in the CB1 knockout mice. The results complement previous evidence that exogenous cannabinoids can be neuroprotective and show that CB1 activation by seizure-induced release of endocannabinoids also is normally neuroprotective.”

“The important new directions being opened by investigations of endocannabinoids underscore the prescient opinion of Robert Christison, who, in 1848, noting its various beneficial effects, argued that cannabis “is a remedy which deserves a more extensive inquiry…””

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1176361/

The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy

Posted on by
Reply

“Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Δ9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus… These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor… By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.”

“Characterized by spontaneously recurrent seizures, epilepsy is one of the most common neurological conditions. Understanding the factors that contribute to seizure initiation and termination has important implications for our ability to treat epilepsy and for the potential development of novel anticonvulsant agents. Previous evidence has suggested that the endogenous cannabinoid system may be a novel locus of anticonvulsant activity in the brain. Using the maximal electroshock model of short-term seizure, our laboratory determined that cannabinoid compounds block seizure spread via a cannabinoid CB1 receptor-dependent mechanism. Further study revealed that application of a CB1 receptor antagonist lowered the electroshock seizure threshold, indicating that elimination of endogenous cannabinoid tone at the CB1 receptor may increase seizure susceptibility.”

“The CB1 receptor is the most highly expressed G-protein-coupled receptor in brain and has been implicated in regulation of neuronal excitability. The endogenous cannabinoids, arachidonylethanolamine and 2-arachidonylglycerol (2-AG), are synthesized “on demand” in response to sustained neuronal depolarization and elevated intracellular calcium levels; both of these events occur with seizure activity. The neuronal hyperexcitability that accompanies seizure discharge may stimulate endogenous cannabinoid synthesis and subsequently result in CB1 receptor activation. In light of cannabinoid effects on neurotransmission, increased CB1 receptor activation could influence seizure activity. However, no studies have evaluated the role of the endogenous cannabinoid system in an intact model of epilepsy.”

“This study was initiated to evaluate the role of the CB1 receptor and the endogenous cannabinoid system in regulating seizure activity in a long-term model of epilepsy. We used the pilocarpine model of temporal lobe, partial-complex epilepsy; a rat model of acquired, refractory epilepsy that produces spontaneous recurrent seizures for the lifetime of the animal. The pilocarpine model has been shown to closely resemble human refractory partial-complex epilepsy. In this study, seizure frequency and duration were determined by continuous electrographic and video recording of each epileptic animal. The CB1 receptor agonists R(+)WIN55,212 and Δ9-tetrahydrocannabinol (THC) were evaluated for anticonvulsant efficacy. In addition to agonist effects on seizure activity, the effect of CB1 receptor antagonism on seizure frequency and duration was evaluated using the specific antagonist SR141716A. Hippocampal levels of 2-AG during short-term, pilocarpine-induced seizures were measured to determine whether a correlation exists between endogenous cannabinoid synthesis and seizure activity. In addition, Western blot and immunohistochemical analyses were used to evaluate hippocampal CB1 receptor protein expression in the brains of chronically epileptic and sham control rats. The findings presented suggest an anticonvulsant role for the endogenous cannabinoid system and demonstrate that long-term plasticity of the CB1 receptor occurs with epilepsy.”

“Therapeutic Implications for Cannabinoids in the Treatment of Epilepsy. Seizures in patients with refractory, partial-complex epilepsy can be difficult to control despite the use of currently available anticonvulsant medications and surgical interventions. Therefore, there is a clear need for the development of more effective anticonvulsant agents. Some epilepsy patients, seeking alternative treatments, have perceived improvement with marijuana. This has prompted several countries to consider the legalization of marijuana for epilepsy treatment. The pilocarpine model represents a refractory epileptic condition that is not readily treated by conventional anticonvulsants. Our results demonstrate that activation of the CB1 receptor by cannabinoid drugs and possibly endogenous ligands significantly alters seizure activity and is more effective than conventional anticonvulsants in treating the refractory seizures produced in the pilocarpine model. Although the dose dependence and long-term effects of cannabinoid administration on epilepsy must be further investigated, the results presented here provide evidence that warrants a comprehensive assessment of cannabinoid use in the control of refractory epilepsy via the use of animal models and placebo-controlled clinical trials. Although the psychoactive side effects of cannabinoids make their use in the treatment of epilepsy impractical, understanding the mechanisms of endogenous cannabinoid-mediated anticonvulsant action may lead to the development of novel compounds that do not manifest behavioral toxicity. Further investigation of the cannabinoid anticonvulsant phenomenon may illuminate novel therapeutic targets for the treatment of temporal lobe epilepsy as well as more clearly define the physiological function of the endogenous cannabinoid system in brain.”

http://jpet.aspetjournals.org/content/307/1/129.long

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

Posted on by
Reply

“Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.”

“Cannabidiol is a non-psychotropic component of marijuana that binds to CB1 receptors with only comparably very low affinity and is devoid of overt cannabimimetic or pro-psychotic properties. Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH).Furthermore, preliminary clinical case reports suggest that cannabidiol might exert antipsychotic effects in schizophrenic patients. In addition, experimental studies show that cannabidiol reduces psychosis-like effects of Δ9-tetrahydrocannabinol and synthetic analogs.“

Read more:: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

Posted on by
1

“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.”

Regulatory Role of Cannabinoid Receptor 1 in Stress-Induced Excitotoxicity and Neuroinflammation

Posted on by
Reply

 “Exposure to stress elicits excitoxicity and neuroinflammation in the brain, contributing to cell death and damage in stress-related neurological and neuropsychiatric diseases. The endocannabinoid system is present in stress-responsive neural circuits and has been proposed as an endogenous neuroprotective system activated in some neuropathological scenarios to restore homeostasis. To elucidate the possible regulatory role of cannabinoid receptor 1 (CB1) in stress-induced excitotoxicity and neuroinflammation, both genetic and pharmacological approaches were used alternatively… These multifaceted neuroprotective effects suggest that CB1 activation could be a new therapeutic strategy against neurological/neuropsychiatric pathologies with HPA axis dysregulation and an excitotoxic/neuroinflammatory component in their pathophysiology.”

“Antiinflammatory Effects Elicited by CB1 Activation. Mechanisms Involved”

“In general, ECS has been proposed as an endogenous protective system against excessive inflammatory/immune responses in multiple CNS pathologies. Our following studies were aimed at clarifying the particular role of CB1 as a possible regulator of stress-induced inflammatory response.”

“In summary, the multifaceted neuroprotective effects described here suggest that CB1 activation is an attractive therapeutic strategy against diverse neuropsychiatric pathologies with HPA axis dysregulation and an excitotoxic/neuroinflammatory component in their pathophysiology.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055736/

The endocannabinoid system in normal and pathological brain ageing.

Posted on by
1

Abstract

“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, pro-ageing, 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 brain-derived 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.”

http://www.ncbi.nlm.nih.gov/pubmed/23108550

Involvement of the endogenous cannabinoid system in the effects of alcohol in the mesolimbic reward circuit: electrophysiological evidence in vivo.

Posted on by
Reply

Abstract

“RATIONALE:

Several lines of evidence indicate that the endogenous cannabinoid system is involved in the pharmacological and behavioural effects of alcohol. The mesolimbic dopaminergic (DA) system and the nucleus accumbens (NAc) process rewarding properties of drugs of abuse, including alcohol and cannabinoids, whereas endocannabinoids in these regions modulate synaptic function and mediate short- and long-term forms of synaptic plasticity.

OBJECTIVES:

The present study was designed to investigate the contribution of the endogenous cannabinoid system in alcohol electrophysiological effects in the mesolimbic reward circuit.

METHODS:

We utilized extracellular single cell recordings from ventral tegmental area (VTA) DA and NAc neurons in anesthetized rats. DA neurons were antidromically identified as projecting to the shell of NAc, whereas NAc putative medium spiny neurons were identified by their evoked responses to basolateral amygdala (BLA) stimulation.

RESULTS:

Alcohol stimulated firing rate of VTA DA neurons and inhibited BLA-evoked NAc neuron spiking responses. The cannabinoid type-1 receptor (CB1) antagonist rimonabant (SR141716A) fully antagonized alcohol effect in both regions. In the NAc, either inhibition of the major catabolic enzyme of the endocannabinoid anandamide, the fatty-acid amyd hydrolase, with URB597 or a pretreatment with the CB1 receptor agonist WIN55212-2 significantly depressed alcohol-induced effects in the NAc.

CONCLUSIONS:

These results corroborate the notion of the involvement of endocannabinoids and their receptors in the actions of alcohol and highlight the endocannabinoid system as a valuable target in the therapy for alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/16228194