Chronic use of marijuana decreases cannabinoid receptor binding and mRNA expression in the human brain

doi:10.1016/j.neuroscience.2006.11.012

Neuroscience

Volume 145, Issue 1, 2 March 2007, Pages 323-334

https://doi.org/10.1016/j.neuroscience.2006.11.012 Get rights and content

Abstract

Chronic exposure to Cannabis sativa (marijuana) produced a significant down-regulation of cannabinoid receptor in the postmortem human brain. The significant decrease in maximal binding capacity was not accompanied by changes in the affinity constant. [³H]SR141716A binding was reduced in the caudate nucleus, putamen and in the accumbens nucleus. A significant decrease of binding sites was seen in the globus pallidus. Also in the ventral tegmental area and substantia nigra pars reticulata quantitative analysis of the density of receptors shows a significant reduction in [³H]SR141716A binding. In Cannabis sativa user brains, compared with normal brains [³H]SR141716A binding was reduced only in the hippocampus. The density of cannabinoid receptor 1 mRNA-positive neurons was significantly lower in Cannabis sativa users than in control brains for the caudate nucleus, putamen, accumbens nucleus and hippocampal region (CA1–CA4, areas of Ammon’s horn). No hybridization was seen in the mesencephalon and globus pallidus.

Section snippets

Subjects

The study was performed on postmortem brain tissue obtained from six control subjects with no history of neurological or psychiatric illness and no history of drug abuse, and six subjects with history of regular and heavy use of Cannabis sativa. The subjects of the control group were not consumers of alcohol. All subjects had no traumatic brain injury. The characteristics of control and Cannabis sativa user subjects providing postmortem brain tissues are presented in Table 1.

The Cannabis sativa

Characterization of [³H]SR141716A binding in the human mesencephalon and hippocampus

The detection of [³H]SR141716A binding determined on tissue sections of the mesencephalon and the hippocampus was saturable. The saturation curve of [³H]SR141716A analyzed on serial tissue sections of the mesencephalon and hippocampus was linear indicating the existence of single class binding sites. Non-specific binding determined in the presence of SR141716A represented 12% of total binding at the Kd value. Scatchard analysis in the mesencephalon and hippocampus of control and Cannabis sativa

Discussion

One cellular mechanism for tolerance is the down-regulation of receptors and attenuation of G-protein activation (Martin et al., 2004). The tolerance does not develop equally to all cannabinoid-mediated effects (Bass et al 2004, Martin 2005) and was shown to be regionally specific and temporally distinct (Whitlow et al., 2003). Therefore, one would predict that chronic exposure to Δ⁹-THC would result in a decreased number of cannabinoid receptors in the brain of human cannabis smoke users,

Conclusion

In summary, the present data are consistent with a possible decrease in receptors in the mesencephalon, basal ganglia and hippocampus of chronic Cannabis sativa users, which might occur in parallel to continuous use of marijuana (Δ⁹-THC). The expression of cDNA for CB1 and CB1 receptor binding in human brain decreases after chronic cannabis use in some regions studied, reflecting down-regulation of the CB1 receptor. The reduction in binding levels was accompanied by parallel decreases in CB1

Acknowledgments

The author thanks Sanofi-Research for providing SR141617A drug and Dr. C. Gérard (Faculté de Médicine Université Libre de Bruxelles, Belgium) for providing the hCB1 cDNA clone.

Tissue specimens were obtained from the Instituto Médico Legal da Capital (IML), São Paulo-Brazil. The study was supported by the Fundação de Amparo a Pesquisa do Estado de São Paulo, FAPESP, São Paulo-Brazil (grant 98/14213-4). The author also thanks M. E. Frazzato and I. C. Guazzelli for technical assistance.

References (62)

C.E. Bass et al.
Reversal of Δ⁹-tetrahydrocannabinol-induced tolerance by specific kinase inhibitors
Eur J Pharmacol
(2004)
C.S. Breivogel et al.
The effects of Δ⁹-tetrahydrocannabinol physical dependence on brain cannabinoid receptors
Eur J Pharmacol
(2003)
P.C. Chan et al.
Toxicity and carcinogenicity of Δ⁹-tetrahydrocannaninol in Fischer rats and B6C3F1 mice
Fundam Appl Toxicol
(1996)
B. Dean et al.
Studies on [³H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use
Neuroscience
(2001)
F. Fan et al.
Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP-55,940 on adenyl cyclase in the cerebellum of CP-55,940-tolerant mice
Brain Res
(1996)
A.N. Gifford et al.
Examination of the effect of the cannabinoid receptor agonists, CP-55,940, on electrically evoked transmitter release from rat brain slices
Eur J Pharmacol
(1997)
M. Glass et al.
Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain
Neuroscience
(1997)
M. Glass
The role of cannabinoids in neurodegenerative diseases
Prog Neuropsychopharmacol Biol Psychiatry
(2001)
M. Glass et al.
Loss of cannabinoid receptors in the substantia nigra in Huntington’s disease
Neuroscience
(1993)
S. González et al.
Chronic exposure to morphine, cocaine or ethanol in rats produced different effects in brain cannabinoid CB1 receptor binding and mRNA levels
Drug Alcohol Depend
(2002)

N. Hájos et al.

Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus

Neuroscience

(2001)

M. Herkenham et al.

Neuronal localization of cannabinoid receptors in the basal ganglia of the rat

Brain Res

(1991)

F. Javoy-Agid et al.

Decreased tyrosine hydroxylase messenger RNA in the surviving dopamine neurons of the substantia nigra in Parkinson’s disease: an in situ hybridization study

Neuroscience

(1990)

J. Lawston et al.

Changes in hippocampal morphology following chronic treatment with the synthetic cannabinoid WIN 55,212-2

Brain Res

(2000)

S.E. Lukas et al.

Ethanol increases plasma Δ⁹-tetrahydrocannabinol (THC) levels and subjective effects after marihuana smoking in human volunteers

Drug Alcohol Depend

(2001)

P. Mailleux et al.

Distribution of neuronal cannabinoid receptor in the adult rat: a comparative receptor binding radioautography and in situ hybridization histochemistry

Neuroscience

(1992)

P. Mailleux et al.

Localization of cannabinoid receptor in the human developing and adult basal gangliaHigher levels in the striatonigral neurons

Neuroscience Lett

(1992)

B.R. Martin

Role of lipids and lipid signaling in the development of cannabinoid tolerance

Life Sci

(2005)

B.R. Martin et al.

Signaling pathways involved in the development of cannabinoid tolerance

Trends Pharmacol Sci

(2004)

F. Mátyás et al.

Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia

Neuroscience

(2006)

R. Mechoulam et al.

Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptor

Biochem Pharmacol

(1995)

A. Oviedo et al.

Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study

Brain Res

(1993)

M. Rinaldi-Carmona et al.

Biochemical and pharmacological characterization of SR141716A, the first potent and selective brain cannabinoid receptor antagonist

Life Sci

(1995)

J. Romero et al.

Effects of chronic exposure to Δ⁹-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions

Mol Brain Res

(1997)

J. Romero et al.

Changes in rat brain cannabinoid binding sites after acute or chronic exposure to their endogenous agonist, anandamide, or to Δ⁹-tetrahydrocannabinol

Pharmacol Biochem Behav

(1995)

A.C. Scallet

Neurotoxicology of cannabis and THC: a review of chronic exposure studies in animals

Pharmacol Biochem Behav

(1991)

A. Scallet et al.

Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC)

Brain Res

(1987)

D. Shire et al.

Structural features of the central cannabinoid CB1 receptor involved in the binding of specific CB1 antagonist SR141716 A

J Biol Chem

(1996)

M.A. Silverdale et al.

Striatal cannabinoid CB1 receptor mRNA expression is decreased in the reserpine-treated rat model of Parkinson’s disease

Exp Neurol

(2001)

K. Tsou et al.

Immunohistochemical distribution of cannabinoid CB1 receptor in the rat central nervous system

Neuroscience

(1998)

T.M. Westlake et al.

Chronic exposure to Δ⁹-tetrahydrocannabinol fails to irreversibly alter brain cannabinoid receptor

Brain Res

(1991)

Cited by (109)

Chronic Δ9-tetrahydrocannabinol treatment has dose-dependent effects on open field exploratory behavior and [<sup>3</sup>H] SR141716A receptor binding in the rat brain
2023, Life Sciences
Acute and chronic Δ⁹-THC exposure paradigms affect the body differently. More must be known about the impact of chronic Δ⁹-THC on cannabinoid-1 (CB1R) and mu-opioid (MOR) receptor levels in the brain. The present study examined chronic Δ⁹-THC's effects on CB1R and MOR levels and locomotor activity.
Adolescent Sprague-Dawley rats were given daily intraperitoneal injections of Δ⁹-THC [0.75mg/kg (low dose or LD) or 2.0 mg/kg (high dose or HD)] or vehicle for 24 days, and locomotion in the open field was tested after the first and fourth weeks of chronic Δ⁹-THC exposure. Brains were harvested at the end of treatment. [³H] SR141716A and [³H] DAMGO autoradiography assessed CB1R and MOR levels, respectively.
Relative to each other, chronic HD rats showed reduced vertical plane (VP) entries and time, while LD rats had increased VP entries and time for locomotion, as assessed by open-field testing; no effects were found relative to the control. Autoradiography analyses showed that HD Δ⁹-THC significantly decreased CB1R binding relative to LD Δ⁹-THC in the cingulate (33%), primary motor (42%), secondary motor (33%) somatosensory (38%), rhinal (38%), and auditory (50%) cortices; LD Δ⁹-THC rats displayed elevated binding in the primary motor (33% increase) and hypothalamic (33% increase) regions compared with controls. No significant differences were observed in MOR binding for the LD or HD compared to the control.
These results demonstrate that chronic Δ⁹-THC dose-dependently altered CB1R levels throughout the brain and locomotor activity in the open field.
Cannabis Use Patterns and Whole-Blood Cannabinoid Profiles of Emergency Department Patients With Suspected Cannabinoid Hyperemesis Syndrome
2023, Annals of Emergency Medicine
The objectives of this study were to characterize the detailed cannabis use patterns (eg, frequency, mode, and product) and determine the differences in the whole-blood cannabinoid profiles during symptomatic versus asymptomatic periods of participants with suspected cannabinoid hyperemesis syndrome recruited from the emergency department (ED) during a symptomatic episode.
This is a prospective observational cohort study of participants with symptomatic cyclic vomiting onset after chronic cannabis use. Standardized assessments were conducted to evaluate for lifetime and recent cannabis use, cannabis use disorder, and cannabis withdrawal symptoms. Quantitative whole-blood cannabinoid testing was performed at 2 times, first when symptomatic (ie, baseline) and at least 2 weeks after the ED visit when asymptomatic. The differences in cannabinoid concentrations were compared between symptomatic and asymptomatic testing. The study was conducted from September 2021 to August 2022.
There was a difference observed between delta-9-tetrahydrocannabinol metabolites, but not the parent compound during symptomatic episodes and asymptomatic periods. Most participants (84%) reported using cannabis > once per day (median 3 times per day on weekdays, 4 times per day on weekends). Hazardous cannabis use was universal among participants; the mean cannabis withdrawal discomfort score was 13, indicating clinically significant rates of cannabis withdrawal symptoms with cessation of use. Most participants (79%) previously tried to stop cannabis use, but a few (13%) of them had sought treatment.
Patients presenting to the ED with cannabinoid hyperemesis syndrome have high cannabis use disorder scores. Further studies are needed to better understand the influence of THC metabolism and concentrations on symptomatic cyclic vomiting.
Synaptic changes induced by cannabinoid drugs and cannabis use disorder
2022, Neurobiology of Disease
Citation Excerpt :
Furthermore, chronic exposure to cannabinoids impairs synaptic plasticity, and this impairment is accompanied by the desensitization of CB1 receptors (Hoffman et al., 2003; Mato et al., 2005). The desensitization and downregulation of CB1 receptors have been consistently implicated in the development of cannabis tolerance (Maldonado, 2002; Martin et al., 2004; Sim-Selley, 2003) and have been observed in individuals that regularly use cannabis (Villares, 2007). Chronic cannabinoid exposure produces widespread reversible downregulation and desensitization of CB1 receptors (Sim-Selley, 2003).
The legalization of cannabis in many countries, as well as the decrease in perceived risks of cannabis, have contributed to the increase in cannabis use medicinally and recreationally. Like many drugs of abuse, cannabis and cannabis-derived drugs are prone to misuse, and long-term usage can lead to drug tolerance and the development of Cannabis Use Disorder (CUD). These drugs signal through cannabinoid receptors, which are expressed in brain regions involved in the neural processing of reward, habit formation, and cognition. Despite the widespread use of cannabis and cannabinoids as therapeutic agents, little is known about the neurobiological mechanisms associated with CUD and cannabinoid drug use. In this article, we discuss the advances in research spanning animal models to humans on cannabis and synthetic cannabinoid actions on synaptic transmission, highlighting the neurobiological mechanisms following acute and chronic drug exposure. This article also highlights the need for more research elucidating the neurobiological mechanisms associated with CUD and cannabinoid drug use.
Cannabis use and hippocampal subfield volumes in males with a first episode of a schizophrenia spectrum disorder and healthy controls
2021, Schizophrenia Research
Both schizophrenia and cannabis use are associated with structural brain changes. The hippocampus is a region of particular interest due to its role in memory and select cognitive functions, impairment of which is a core feature of schizophrenia and has also been observed in substance abuse. This study aimed to explore the effects of recent/current cannabis use on hippocampal subfield volumes in male patients with first-episode schizophrenia spectrum disorders and matched controls.
This cross-sectional, case-control study included 63 patients and 58 controls scanned on 3T MRI scanners, with hippocampal segmentation performed using recently validated Freesurfer v6.0 software. Cannabis use status was determined by self and carer report together with urine toxicology screening, and patients were categorised as recent/current users or non-users. We used multivariate analysis of covariance (MANCOVA) with age, scan sequence, scan quality, and total intracranial volume as covariates, with subsequent analysis of variance (ANOVA) to test the effects of diagnosis and cannabis use status on individual hippocampal subfields.
We found a group (patient/control) by cannabis use interaction effect in the subiculum, with decreased volumes observed in the cannabis non-using patients compared to the cannabis using patients, and decreased volumes in the cannabis using controls compared to the cannabis non-using controls.
The increased subiculum volume in cannabis using patients compared to cannabis non-using patients raises important questions regarding the pathophysiology of schizophrenia and the role of cannabis use therein.
Further evidence of anxiety- and depression-like behavior for total genetic ablation of cannabinoid receptor type 1
2021, Behavioural Brain Research
Cannabinoid receptor type 1 (CB1R) is the most abundant cannabinoid receptor in central nervous system. Clinical studies and animal models have shown that the attenuation of endocannabinoid system signaling correlates with the development of psychiatric disorders such as anxiety, depression and schizophrenia. In the present work, multiple behavioral tests were performed to evaluate behaviors related to anxiety and depression in CB1R^+/− and CB1R^−/−. CB1R^+/− mice had anxiety-related behavior similar to wild type (CB1R^+/+) mice, whereas CB1R^−/− mice displayed an anxious-like phenotype, which indicates that lower expression of CB1R is sufficient to maintain the neural circuits modulating anxiety. In addition, CB1R^−/− mice exhibited alterations in risk assessment and less exploration, locomotion, grooming, body weight and appetite. These phenotypic characteristics observed in CB1R^−/− mice could be associated with symptoms observed in human psychiatric disorders such as depression. A better knowledge of the neuromodulatory role of CB1R may contribute to understand scope and limitations of the development of medical treatments.
Chlorpyrifos and Δ<sup>9</sup> Tetrahydrocannabinol exposure and effects on parameters associated with the endocannabinoid system and risk factors for obesity
2021, Current Research in Toxicology
Marilyn Silva.
Retired from a career in toxicology and risk assessment.
Increased childhood and adult obesity are associated with chlorpyrifos (CPF), an organophosphate pesticide. Cannabis (Δ⁹Tetrahydrocannabinol: Δ⁹THC) use has increased globally with legalization. CPF applications on cannabis crops lacks federally regulated tolerances and may pose health risks through exposure during development and in adulthood. Both CPF and Δ⁹THC affect the endocannabinoid system (eCBS), a regulator of appetite, energy balance, and gut microbiota, which, if disrupted, increases risk for obesity and related diseases. CPF inhibits eCB metabolism and Δ⁹THC is a partial agonist/antagonist at the cannabinoid receptor (CB1R). Effects of each on obesogenic parameters were examined via literature search. Male rodents with CPF exposure showed increased body weights, dysbiosis, inflammation and oxidative stress, potentially associated with increased eCBs acting through the gut-microbiota-adipose-brain regulatory loop. Δ⁹THC generally decreased body weights via partial agonism at the CB1R, lowering levels of eCBs. Dysbiosis and/or oxidative stress associated inflammation occurred with CPF, but these parameters were not tested with Δ⁹THC. Database deficiencies included limited endpoints to compare between chemicals/age-groups, inter-study variables (dose ranges, dosing vehicle, rodent strain, treatment duration, etc.). CPF and Δ⁹THC were not tested together, but human co-chemical effects would depend on exposure ratio, subject age, exposure duration, and health status, among others. An overriding concern is that both chemicals are well-documented developmental neurotoxins in addition to their low dose effects on energy balance. A co-exposure risk assessment is warranted with increased use and lack of federal CPF regulation on cannabis.

View all citing articles on Scopus

View full text

NeuropharmacologyChronic use of marijuana decreases cannabinoid receptor binding and mRNA expression in the human brain

Abstract

Section snippets

Subjects

Characterization of [3H]SR141716A binding in the human mesencephalon and hippocampus

Discussion

Conclusion

Acknowledgments

Eur J Pharmacol

Eur J Pharmacol

Fundam Appl Toxicol

Neuroscience

Brain Res

Eur J Pharmacol

Neuroscience

Prog Neuropsychopharmacol Biol Psychiatry

Neuroscience

Drug Alcohol Depend

Neuroscience

Brain Res

Neuroscience

Brain Res

Drug Alcohol Depend

Neuroscience

Neuroscience Lett

Life Sci

Trends Pharmacol Sci

Neuroscience

Biochem Pharmacol

Brain Res

Life Sci

Mol Brain Res

Pharmacol Biochem Behav

Pharmacol Biochem Behav

Brain Res

J Biol Chem

Exp Neurol

Neuroscience

Brain Res

Neuropharmacology
Chronic use of marijuana decreases cannabinoid receptor binding and mRNA expression in the human brain

Characterization of [³H]SR141716A binding in the human mesencephalon and hippocampus