Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.
Ontology highlight
ABSTRACT:
SUBMITTER: Hirvonen J
PROVIDER: S-EPMC3223558 | biostudies-literature | 2012 Jun
REPOSITORIES: biostudies-literature
Publications
Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.
Hirvonen J J Goodwin R S RS Li C-T CT Terry G E GE Zoghbi S S SS Morse C C Pike V W VW Volkow N D ND Huestis M A MA Innis R B RB
Molecular psychiatry 20110712 6
Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB(1) receptors in human subjects who chronically smoke c ...[more]
Similar Datasets
Project description:BACKGROUND:Previous studies showed reduction of brain cannabinoid CB1 receptors in adults with cannabis and alcohol use disorders. Preclinical data suggest that these receptors also contribute to nicotine reward and dependence. Tobacco smoking may confound clinical studies of psychiatric disorders because many patients with such disorders smoke tobacco. Whether human subjects who smoke tobacco but are otherwise healthy have altered CB1 receptor binding in brain is unknown. METHODS:We measured CB1 receptors in brains of 18 healthy men who smoke tobacco (frequent chronic cigarette smokers), and 28 healthy men who do not smoke tobacco, using positron emission tomography and [18F]FMPEP-d2, a radioligand for CB1 receptors. We collected arterial blood samples during scanning to calculate the distribution volume (VT), which is nearly proportional to CB1 receptor density. Repeated-measures analysis of variance compared VT between groups in various brain regions. RESULTS:Brain CB1 receptor VT was about 20% lower in subjects who smoke tobacco than in subjects who do not. Decreased VT was found in all brain regions, but reduction did not correlate with years of smoking, number of cigarettes smoked per day, or measures of nicotine dependence. CONCLUSIONS:Tobacco-smoking healthy men have a widespread reduction of CB1 receptor density in brain. Reduction of CB1 receptors appears to be a common feature of substance use disorders. Future clinical studies on the CB1 receptor should control for tobacco smoking.
| S-EPMC6388688 | biostudies-literature
Project description:PurposeAqueous deficiency dry eye (ADDE) is a chronic condition affecting millions, with symptoms ranging from a dry itchiness to blurred vision and accompanied by an increased risk of eye infections. ADDE typically arises from disorders of the lacrimal gland that produces tears necessary for eye lubrication. Cannabis users frequently report dry eye, but the basis for this is unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of tearing.MethodsWe examined expression of cannabinoid CB1 receptors in the lacrimal gland using immunohistochemistry, Western blotting, and PCR and tested tetrahydrocannabinol (THC) regulation of tearing in wild-type and CB1-null mice.ResultsWe now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the lacrimal gland. Little if any staining is seen in lacrimal gland epithelial cells (acinar and ductal) or myoepithelial cells (MECs). Activation of CB1 receptors by THC or the cannabinoid agonist CP55940 reduces tearing in male mice. In female mice, THC has no effect, but CP55940 increases tearing. In both sexes, the effect of CP55940 is absent in CB1 knockout mice. CB1 mRNA and protein levels are approximately four- to fivefold higher in males than females. In male knockouts, THC increases tearing, suggesting that THC also acts through different receptors.ConclusionsOur results suggest a novel, albeit sex-dependent, physiologic basis for the dry eye symptoms experienced by cannabis users: activation of neuronal CB1 receptors in the lacrimal gland reduces tearing.
| S-EPMC7452851 | biostudies-literature
Project description:Cannabinoid type 1 (CB1) receptors are expressed in the nervous and cardiovascular systems. In mice, CB1 receptor deficiency protects from metabolic consequences of a high-fat diet (HFD), increases sympathetic activity to brown fat, and entails sleep anomalies. We investigated whether sleep-wake and diet-dependent cardiorespiratory control is altered in mice lacking CB1 receptors. CB1 receptor knock-out (KO) and intact wild-type (WT) mice were fed standard diet or a HFD for 3 months, and implanted with a telemetric arterial pressure transducer and electrodes for sleep scoring. Sleep state was assessed together with arterial pressure and heart rate (home cage), or breathing (whole-body plethysmograph). Increases in arterial pressure and heart rate on passing from the light (rest) to the dark (activity) period in the KO were significantly enhanced compared with the WT. These increases were unaffected by cardiac (?1) or vascular (?1) adrenergic blockade. The breathing rhythm of the KO during sleep was also more irregular than that of the WT. A HFD increased heart rate, impaired cardiac vagal modulation, and blunted the central autonomic cardiac control during sleep. A HFD also decreased cardiac baroreflex sensitivity in the KO but not in the WT. In conclusion, we performed the first systematic study of cardiovascular function in CB1 receptor deficient mice during spontaneous wake-sleep behavior, and demonstrated that CB1 receptor KO alters cardiorespiratory control particularly in the presence of a HFD. The CB1 receptor signaling may thus play a role in physiological cardiorespiratory regulation and protect from some adverse cardiovascular consequences of a HFD.
| S-EPMC4065065 | biostudies-literature
Project description:To date, the endogenous ligands described for cannabinoid receptors have been derived from membrane lipids. To identify a peptide ligand for CB(1) cannabinoid receptors, we used the recently described conformation-state sensitive antibodies and screened a panel of endogenous peptides from rodent brain or adipose tissue. This led to the identification of hemopressin (PVNFKFLSH) as a peptide ligand that selectively binds CB(1) cannabinoid receptors. We find that hemopressin is a CB(1) receptor-selective antagonist, because it is able to efficiently block signaling by CB(1) receptors but not by other members of family A G protein-coupled receptors (including the closely related CB(2) receptors). Hemopressin also behaves as an inverse agonist of CB(1) receptors, because it is able to block the constitutive activity of these receptors to the same extent as its well characterized antagonist, rimonabant. Finally, we examine the activity of hemopressin in vivo using different models of pain and find that it exhibits antinociceptive effects when administered by either intrathecal, intraplantar, or oral routes, underscoring hemopressin's therapeutic potential. These results represent a demonstration of a peptide ligand for CB(1) cannabinoid receptors that also exhibits analgesic properties. These findings are likely to have a profound impact on the development of novel therapeutics targeting CB(1) receptors.
| S-EPMC2154475 | biostudies-literature
Project description:Background: Because delta-9-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, binds to cannabinoid 1 (CB1) receptors, levels of CB1 protein could serve as a potential biomarker for response to THC. To date, available techniques to characterize CB1 expression and function in vivo are limited. In this study, we developed an assay to quantify CB1 in lymphocytes to determine how it relates to cannabis use in 58 daily cannabis users compared with 47 nonusers. Furthermore, we tested whether CB1 levels are associated with mutations in a single nucleotide polymorphism known to regulate CB1 functioning (i.e., rs2023239). Methods: Total protein concentration was analyzed through the Pierce BCA Protein assay kit. CB1 protein was quantified through CNR1 enzyme-linked immunosorbent assay (ELISA) kit from MyBioSource. CB1 concentration and total protein concentration were quantified and used to calculate a ratio of CB1 to total protein. Results: Inherent levels of peripheral lymphocyte CB1 were sufficient for quantification through ELISA without protein amplification. We found a group×genotype interaction such that users with the G allele had greater CB1 concentration than users with the A/A genotype, and a trend-level difference between genotypes in nonusers. Conclusions: This study demonstrates a minimally invasive technique of CB1 quantification that holds promise for the use of CB1 protein concentration, along with rs2023239 genotype, as a potential biomarker for susceptibility to cannabis use. These results suggest a gene (rs2023239 G)×environment (cannabis use) effect on CB1 density.
| S-EPMC5628563 | biostudies-literature
Project description:There are no FDA-approved treatments for cannabis use disorder (CUD). Preclinical research has shown that the 5HT-2C agonist lorcaserin attenuates cue-induced reinstatement of THC seeking and self-administration. The goal of this placebo-controlled, counterbalanced, within-subject human laboratory study was to examine lorcaserin's effects on cannabis intoxication and self-administration. Lorcaserin (10 mg BID) was administered during one of two 13-day inpatient phases and placebo during the other; each phase was separated by ≥7 days of washout. Inpatient phases comprised (1) standardized cannabis administration (7.0% THC) at no financial cost (intoxication), counterbalanced with (2) the option to self-administer cannabis following either 0 or 3 days of abstinence. Cognitive task performance, food intake, subjective ratings of drug effects, objective/subjective sleep measures, and tobacco cigarette use were also assessed. Fifteen normal-weight, daily cannabis users (4F, 11M) not seeking treatment for CUD completed the study. Lorcaserin significantly reduced cannabis self-administration following 0 and 3 days of cannabis abstinence and also reduced craving for cannabis during abstinence. Lorcaserin produced small but significant increases in positive cannabis ratings and body weight relative to placebo. Lorcaserin also reduced tobacco cigarette smoking on days of cannabis administration relative to placebo. During abstinence, subjective but not objective measures of sleep quality worsened during lorcaserin maintenance. Overall, lorcaserin's ability to decrease drug taking and cannabis craving in nontreatment-seeking cannabis users supports further investigation of 5HT-2C agonists as potential pharmacotherapies for CUD.
| S-EPMC8225547 | biostudies-literature
Project description:The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo)cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.
| S-EPMC4050577 | biostudies-literature
Project description:Recent studies have demonstrated that the majority of endogenous cannabinoid type 1 (CB(1)) receptors do not reach the cell surface but are instead associated with endosomal and lysosomal compartments. Using calcium imaging and intracellular microinjection in CB(1) receptor-transfected HEK293 cells and NG108-15 neuroblastoma × glioma cells, we provide evidence that anandamide acting on CB(1) receptors increases intracellular calcium concentration when administered intracellularly but not extracellularly. The calcium-mobilizing effect of intracellular anandamide was dose-dependent and abolished by pretreatment with SR141716A, a CB(1) receptor antagonist. The anandamide-induced calcium increase was reduced by blocking nicotinic acid-adenine dinucleotide phosphate- or inositol 1,4,5-trisphosphate-dependent calcium release and abolished when both lysosomal and endoplasmic reticulum calcium release pathways were blocked. Taken together, our results indicate that, in CB(1) receptor-transfected HEK293 cells, intracellular CB(1) receptors are functional; they are located in acid-filled calcium stores (endolysosomes). Activation of intracellular CB(1) receptors releases calcium from endoplasmic reticulum and lysosomal calcium stores. In addition, our results support a novel role for nicotinic acid-adenine dinucleotide phosphate in cannabinoid-induced calcium signaling.
| S-EPMC3190724 | biostudies-literature
Project description:AIMS:To develop and validate empirically a mathematical model for identifying new cannabis use in chronic, daily cannabis smokers. DESIGN:Models were based on urinary creatinine-normalized (CN) cannabinoid excretion in chronic cannabis smokers. SETTING:For model development, participants resided on a secure research unit for 30 days. For model validation, participants were abstinent with daily observed urine specimens for 28 days. PARTICIPANTS:A total of 48 (model development) and 67 (model validation) daily cannabis smokers were recruited. MEASUREMENTS:All voided urine was collected and analyzed for 11-nor-9-carboxy-?9-tetrahydrocannabinol (THCCOOH) by gas chromatography-mass spectrometry (GCMS; limit of quantification 2.5 ng/ml) and creatinine (mg/ml). Urine THCCOOH was normalized to creatinine, yielding ng/mg CN-THCCOOH concentrations. Urine concentration ratios were determined from 123,513 specimen pairs collected 2-30 days apart. FINDINGS:A mono-exponential model (with two parameters, initial urine specimen CN-THCCOOH concentration and time between specimens), based on the Marquardt-Levenberg algorithm, provided a reasonable data fit. Prediction intervals with varying probability levels (80, 90, 95, 99%) provide upper ratio limits for each urine specimen pair. Ratios above these limits suggest cannabis re-use. Disproportionate numbers of ratios were higher than expected for some participants, prompting development of two additional rules that avoid misidentification of re-use in participants with unusual CN-THCCOOH excretion patterns. CONCLUSIONS:For the first time, a validated model is available to aid in the differentiation of new cannabis use from residual creatinine-normalized 11-nor-9-carboxy-?9-tetrahydrocannabinol (CN-THCCOOH) excretion in chronic, daily cannabis users. These models are valuable for clinicians, toxicologists and drug treatment staff and work-place, military and criminal justice drug-testing programs.
| S-EPMC3461262 | biostudies-literature
Project description: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.
| S-EPMC3131310 | biostudies-literature