Tag Archives: cannabinoid receptors

Inflammation and aging: can endocannabinoids help?

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“Aging often leads to cognitive decline due to neurodegenerative process in the brain. As people live longer, a growing concern exist linked to long-term, slowly debilitating diseases that have not yet found a cure, such as Alzheimer’s disease. Recently, the role of neuroinflammation has attracted attention due to its slow onset, chronic nature and its possible role in the development of many different neurodegenerative diseases. In the future, treatment of chronic neuroinflammation may help counteract aspects of neurodegenerative disease. Our recent studies have focused upon the endocannabinoid system for its unique effects on the expression of neuroinflammation. The basis for the manipulation of the endocannabinoid system in the brain in combination with existing treatments for Alzheimer’s disease will be discussed in this review.”

“Endocannabinoids

Cannabinoid refers to naturally occurring or synthetic molecules mimicking the activity of plant-derived cannabinoids from Cannabis Sativa. Two types of cannabinoid receptors have been so far identified in the body, named CB1 and CB2. Discovery of cannabinoid receptors (CBr) lead to the finding of endogenous agonists for these receptors called endocannabinoids (EC). EC are derived from arachidonic acid, arachidonoylethanolamide (anandamide), and 2-arachidonoyl glycerol (2-AG), synthesized on-demand post-synaptically and released in response to the entry of calcium ions. These EC in combination with the two known CBr constitute the endocannabinoid system (ECS). In the central nervous system (CNS), CB1 is overwhelmingly represented over CB2 and particularly abundant in cortical regions, the hippocampus, cerebellum and basal ganglia while CB2 may be restricted to microglia or neurons in the brainstem  and cerebellum. Deactivation of the EC is due to a rapid enzymatic degradation in the synaptic cleft or after membrane transport. The ECS is thought to be a neuromodulator and an immunomodulator. In the CNS, the ECS can influence food intake, endocrine release, motor control, cognitive processes, emotions and perception. Cannabinoids treatment has been shown to be neuroprotective under many experimental conditions. Drugs that manipulate the ECS are currently evaluated in various diseases ranging from cancer to AIDS for their peripheral analgesic and immunosuppressive properties. Their anti-inflammatory actions may make them useful in the treatment of multiple sclerosis, Parkinson’s disease and AD. Very little in vivo evidence to support the use of EC receptor agonists has been reported, although in vitro studies have found evidence for their anti-inflammatory effectiveness. Our recent work demonstrated the anti-inflammatory effect of a chronic treatment of a low dose of the CBr agonist WIN-55,212-2 (without psychoactive effects) on the consequences of chronic neuroinflammation induced by the infusion of LPS into the 4th ventricle of young rats. Moreover, that same anti-inflammatory effect was found using a non-psychoactive dose given by slow subcutaneous infusion of WIN-55,212-2 to healthy aged rats; these rats also demonstrated improved spatial memory. Our ongoing work in aged rats has shown that treatment with the CBr agonist WIN-55,212-2 increases neurogenesis in the hippocampus. Our preliminary data suggest that the neurogenic and anti-inflammatory effects in aged rats are due to the agonist/antagonist properties of WIN-55,212-2 at multiple receptors.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408719/

Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis.

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Abstract

“WIN-55,212-2 (WIN-2) can elicit anti-inflammatory and cognitive-enhancing effect in aged rats. The current study was designed to determine the differential role of the endocannabinoid receptor sub-types 1 (CB1) and 2 (CB2) and transient receptor potential vanilloid 1 receptor (TRPV1) in the reduction of age-associated brain inflammation and their effects on neurogenesis in the dentate gyrus of aged rats. Our results demonstrate that 1) the antagonist actions of WIN-2 at the TRPV1 receptor are responsible for the reduction in microglial activation and 2) the agonist actions of WIN-2 at CB1/2 receptors can trigger neurogenesis in the hippocampus of aged rats. Chronic treatment with WIN-2 established an anti-inflammatory cytokine profile within the hippocampus. Our results provide insight into the role of the endocannabinoid and vanilloid systems upon two different and detrimental aspects of normal and pathological aging, chronic neuroinflammation and decline in neurogenesis.”

http://www.ncbi.nlm.nih.gov/pubmed/19385063

How Cannabinoids May Slow Brain Aging

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Stoners aren’t known for their memory prowess but a new review suggests that drugs similar to marijuana’s active ingredients may hold promise for preventing— or even reversing— brain aging and possibly Alzheimer‘s and other degenerative brain diseases.

Read more: http://healthland.time.com/2012/10/29/how-cannabinoids-may-slow-brain-aging/#ixzz2AjCxutuI

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

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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

Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans.

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Abstract

“We tested if cannabinoid type 2 receptor (CB2) in the central nervous system plays a role in alcohol abuse/dependence in animal model and then examined an association between the CB2 gene polymorphism and alcoholism in human. Mice experiencing more alcohol preference by drinking showed reduced Cb2 gene expression, whereas mice with little preference showed no changes of it in ventral midbrain. Alcohol preference in conjunction with chronic mild stress were enhanced in mice treated with CB2 agonist JWH015 when subjected to chronic stress, whereas antagonist AM630 prevented development of alcohol preference. There is an association between the Q63R polymorphism of the CB2 gene and alcoholism in a Japanese population (P=0.007; odds ratio 1.25, 95% CI, (1.06-1.47)). CB2 under such environment is associated with the physiologic effects of alcohol and CB2 antagonists may have potential as therapies for alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/17189959

Blockade of the cannabinoid CB1 receptor and alcohol dependence: preclinical evidence and preliminary clinical data.

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Abstract

“The present paper summarizes the results of a number of pharmacological studies implicating the cannabinoid CB(1) receptor in the neural circuitry regulating different alcohol-related behaviors in rodents. Specifically, cannabinoid CB(1) receptor antagonists–including the prototype, rimonabant–have been reported to suppress: (a) acquisition and maintenance of alcohol drinking behavior under the 2-bottle “alcohol vs water” choice regimen; (b) the increase in alcohol intake occurring after a period of alcohol abstinence (an experimental model of alcohol relapse); (c) alcohol’s reinforcing and motivational properties measured in rats trained to perform a specific task (e.g., lever-pressing) to access alcohol; (d) reinstatement of extinguished alcohol-seeking behavior triggered in rats by a nicotine challenge or presentation of cues previously associated to alcohol availability (another model of alcohol relapse). Additional data indicate that the opioid receptor antagonists, naloxone and naltrexone, synergistically potentiate the suppressing effect of rimonabant on alcohol intake and alcohol’s motivational properties in rats. Conversely, the two clinical studies conducted to date (one in alcohol-dependent individuals and one in nontreatment-seeking heavy alcohol drinkers) yielded less conclusive results. Unfortunately, the recent discontinuation–due to the occurrence of some psychiatric adverse effects–of all trials with cannabinoid CB(1) receptor antagonists apparently hinders further investigations on the potential of rimonabant in the treatment of alcohol dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/20201816

Positron Emission Tomography Shows Elevated Cannabinoid CB (1) Receptor Binding in Men with Alcohol Dependence.

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Abstract

“BACKGROUND:

Several lines of evidence link cannabinoid (CB) type 1 (CB (1) ) receptor-mediated endogenous CB (eCB) signaling to the etiology of alcohol dependence (AD). However, to date, only peripheral measures of eCB function have been collected in living humans with AD and no human in vivo data on the potentially critical role of the brain CB (1) receptor in AD have been published. This is an important gap in the literature, because recent therapeutic developments suggest that these receptors could be targeted for the treatment for AD.”

 

“CONCLUSIONS:

These findings agree with preclinical evidence and provide the first, albeit still preliminary in vivo evidence suggesting a role for brain CB (1) receptors in AD. The current study design does not answer the important question of whether elevated CB (1) receptors are a preexisting vulnerability factor for AD or whether elevations develop as a consequence of AD.”

http://www.ncbi.nlm.nih.gov/pubmed/22551199

Reduced cannabinoid CB(1) receptor binding in alcohol dependence measured with positron emission tomography.

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Abstract

“Brain cannabinoid CB(1) receptors contribute to alcohol-related behaviors in experimental animals, but their potential role in humans with alcohol dependence is poorly understood. We measured CB(1) receptors in alcohol dependent patients in early and protracted abstinence, and in comparison with control subjects without alcohol use disorders, using positron emission tomography and [(18)F]FMPEP-d(2), a radioligand for CB(1) receptors. We scanned 18 male in-patients with alcohol dependence twice, within 3-7 days of admission from ongoing drinking, and after 2-4 weeks of supervised abstinence. Imaging data were compared with those from 19 age-matched healthy male control subjects. Data were also analyzed for potential influence of a common functional variation (rs2023239) in the CB(1) receptor gene (CNR1) that may moderate CB(1) receptor density. On the first scan, CB(1) receptor binding was 20-30% lower in patients with alcohol dependence than in control subjects in all brain regions and was negatively correlated with years of alcohol abuse. After 2-4 weeks of abstinence, CB(1) receptor binding remained similarly reduced in these patients. Irrespective of the diagnostic status, C allele carriers at rs2023239 had higher CB(1) receptor binding compared with non-carriers. Alcohol dependence is associated with a widespread reduction of cannabinoid CB(1) receptor binding in the human brain and this reduction persists at least 2-4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB(1) receptors in alcohol dependence in humans.”

http://www.ncbi.nlm.nih.gov/pubmed/22776901

A Critical Role for the Cannabinoid CB1 Receptors in Alcohol Dependence and Stress-Stimulated Ethanol Drinking

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“Although many people drink alcohol regularly, only some become addicted. Several studies have shown that genetic and environmental factors contribute to individual differences in the vulnerability to the effects of alcohol. Among the environmental factors, stress is perhaps the most important trigger for relapse after a period of abstinence. Here we show that ethanol withdrawal symptoms were completely absent in cannabinoid CB1 receptor-deficient mice, although acute effects of ethanol and ethanol tolerance and preference were basically normal. Furthermore, foot-shock stress had no affect on alcohol preference in Cnr1−/− mice, although it induced a dramatic increase in Cnr1+/+ animals. These results reveal a critical role for the CB1 receptor in clinically important aspects of alcohol dependence and provide a rationale for the use of CB1 receptor antagonists in the treatment of alcohol addiction.”

“In summary, the endocannabinoid system does not seem to be crucial for the rewarding effects of ethanol and the manifestation of normal ethanol drinking behaviors. However, it appears to play an important role in the manifestation of stress-induced alcohol drinking and ethanol withdrawal. These results support the notion that the neuronal mechanisms involved in drug reinforcement are dissociable from those involved in withdrawal and reinstatement. Indeed, our results demonstrate that ethanol tolerance and physical dependence can be separated. Thus, CB1 receptor antagonists may be useful for the treatment of alcohol addiction.”

http://www.jneurosci.org/content/23/6/2453.long

Cannabinoid receptor 1 gene is associated with alcohol dependence.

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Abstract

“BACKGROUND:

Alcohol dependence (AD) vulnerability is determined by a complex array of genetic factors. Given the potential role of endocannabinoid system in AD, polymorphisms within cannabinoid receptor 1 gene (CNR1) have been potentially associated with susceptibility to this disease. We thus aimed to examine the relationship between 3 allelic variants of CNR1 (rs6454674, rs1049353, and rs806368) and AD.

METHODS:

Genotyping of the aforementioned polymorphisms was carried out by PCR in 298 male alcoholics (187 of them with AD) and 155 healthy controls. Single-marker, haplotype, and interaction analysis were performed to analyze the influence of CNR1 gene on AD susceptibility.

RESULTS:

We found an association between CNR1 gene and AD after haplotype analysis. Alcoholic patients with TGT haplotype (corresponding to rs6454674-rs1049353-rs806368 polymorphisms in this order) were less prone to have AD (p = 0.017). Besides, alcoholics with a G/T substitution of the first marker (GGT haplotype) or a C/T substitution of the third marker (TGC haplotype) were more likely to develop AD (p = 0.006 and 0.004, respectively) and an interaction was found between the G allele of rs6454674 single nucleotide polymorphism (SNP) and the C allele of rs806368 SNP (p = 0.009).

CONCLUSIONS:

Our findings support previously reported associations of CNR1 with dependence to alcohol and other substances and emphasizes the relevance of endocannabinoid system in AD.”

http://www.ncbi.nlm.nih.gov/pubmed/22085192