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

Villares, Joào

doi:10.1016/j.neuroscience.2006.11.012

Cited by 113 publications

(86 citation statements)

References 61 publications

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“…Indeed, animal studies have shown that behavioral tolerance to the motor effects of THC is likely mediated by CB1 downregulation throughout the cerebellum (Sim et al, 1996;Romero et al, 1998). More recently, it has been found that chronic cannabis use in humans does in fact lead to significant CB1 downregulation as determined via postmortem [ 3 H]SR141716A binding (Villares, 2007). These data provide indirect evidence that cerebellar changes in CB1 induced by chronic cannabis intake may partly explain the impaired EBC performance observed in the current study.…”

Section: Discussionsupporting

confidence: 66%

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Skosnik

Edwards

O’Donnell

et al. 2007

Neuropsychopharmacol

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While the cerebellum contains the highest density of cannabinoid receptor (CB1) in the brain, no studies have assessed the effect of exogenous cannabinoids on cerebellar-dependent learning in humans. The current study, therefore, examined the effect of chronic cannabis use on classical eyeblink conditioning (EBC), a cerebellar-mediated task which has been shown to be disrupted in CB1 knockout mice. Chronic cannabis users (24 h abstinence before study; positive THC urine drug test) free of DSM-IV Axis-I or -II disorders, were evaluated. A delay EBC task was utilized, in which a conditioned stimulus (CS; 400 ms tone) co-terminated with a corneal air puff unconditioned stimulus (US; 50 ms), thus eliciting a conditioned blink response (CR). The cannabis group exhibited markedly fewer, and more poorly timed CRs as compared to drug-naive controls. There were no differences between the groups in either the unconditioned response (UR) or an EEG measure of selective attention to the CS (N100 auditory ERP), indicating that the disruption observed in the cannabis group was specific to CR acquisition. These results suggest that cannabis use is associated with functional deficits in the cerebellar circuitry underlying EBC, a finding which corroborates the recent work in CB1 knockout mice.

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Section: Discussionsupporting

confidence: 66%

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Skosnik

Edwards

O’Donnell

et al. 2007

Neuropsychopharmacol

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“…While the mechanism underlying hippocampal shape changes is not known, the altered regions are dense with cannabinoid receptors (Glass et al, 1997), which may be dysfunctional in the pathology of schizophrenia and as a result of long-term exposure to cannabis (Villares, 2007). Our findings support an interpretation of dosedependent neurotoxic effects, broadly across the hippocampus, as evidenced also by animal studies (see Solowij et al, 2012).…”

Section: Discussionsupporting

confidence: 79%

Alteration to hippocampal shape in cannabis users with and without schizophrenia

Solowij

Walterfang

Lubman

et al. 2013

Schizophrenia Research

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Abnormalities in hippocampal morphology are characteristic of schizophrenia and have also been reported in chronic cannabis users. There is a paucity of research investigating potential additive effects of cannabis use on brain pathology associated with schizophrenia. In this study, we performed hippocampal shape analysis in cannabis-using and non-using patients with schizophrenia, healthy cannabis users and healthy non-using controls. Hippocampal shape changes were observed in each group relative to controls, with the greatest degree of alterations (i.e., deflations across the hippocampus, and with an anterior predisposition), in cannabis-using schizophrenia patients. These alterations were associated with cannabis use patterns and psychotic symptoms. AbstractAbnormalities in hippocampal morphology are characteristic of schizophrenia and have also been reported in chronic cannabis users. There is a paucity of research investigating potential additive effects of cannabis use on brain pathology associated with schizophrenia. In this study we performed hippocampal shape analysis in cannabis-using and non-using patients with schizophrenia, healthy cannabis users and healthy non-using controls. Hippocampal shape changes were observed in each group relative to controls, with the greatest degree of alterations (i.e., deflations across the hippocampus, and with an anterior predisposition), in cannabis-using schizophrenia patients. These alterations were associated with cannabis use patterns and psychotic symptoms.

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“…Moreover, the results of this study are quite consistent with reports on behavioral tolerance to cannabinoids in humans. In light of the recent finding that CB 1 receptor down-regulation occurs in the human brain after chronic cannabis use (Villares, 2007), these results indicate that similar mechanisms of CB 1 receptor adaptation exist in humans and animal models. Moreover, these findings suggest that administering lower doses of THC might mitigate tolerance to certain cannabinoid effects.…”

Section: Discussionmentioning

confidence: 62%

“…In fact, down-regulation of CB 1 receptors has recently been found in the brains of human cannabis users (Villares, 2007). Studies have consistently found that cannabinoid receptor adaptation varies by brain region (reviewed by Sim-Selley, 2003).…”

mentioning

confidence: 99%

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

McKinney

Cassidy²,

Collier³

et al. 2007

J Pharmacol Exp Ther

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Chronic treatment with ⌬ 9 -tetrahydrocannabinol (THC) produces tolerance to cannabinoid-mediated behaviors and region-specific adaptation of brain cannabinoid receptors. However, the relationship between receptor adaptation and tolerance is not well understood, and the dose-response relationship of THC-induced cannabinoid receptor adaptation is unknown. This study assessed cannabinoid receptor function in the brain and cannabinoid-mediated behaviors after chronic treatment with different dosing regimens of THC. Mice were treated twice per day for 6.5 days with the following: vehicle, 10 mg/kg THC, or escalating doses of 10 to 20 to 30 or 10 to 30 to 60 mg/kg THC. Tolerance to cannabinoid-mediated locomotor inhibition, ring immobility, antinociception, and hypothermia was produced by both ramping THC-dose paradigms. Administration of 10 mg/kg THC produced less tolerance development, the magnitude of which depended upon the particular behavior. Decreases in cannabinoid-mediated G-protein activation, which varied with treatment dose and region, were 35 S]GTP␥S binding was reduced in the hippocampus, cingulate cortex, periaqueductal gray, and cerebellum after all treatments. Decreased agonist-stimulated [35 S]GTP␥S binding in the caudate-putamen, nucleus accumbens, and preoptic area occurred only after administration of 10 to 30 to 60 mg/kg THC, and no change was found in the globus pallidus or entopeduncular nucleus after any treatment. Changes in the CB 1 receptor B max values also varied by region, with hippocampus and cerebellum showing reductions after all treatments and striatum/globus pallidus showing effects only at higher dosing regimens. These results reveal that tolerance and CB 1 receptor adaptation exhibit similar dose-dependent development, and they are consistent with previous studies demonstrating less cannabinoid receptor adaptation in striatal circuits.Cannabinoids are used for their psychoactive effects and for therapeutic treatment of nausea/emesis and cachexia. Previous studies also suggest that cannabinoids may have clinical potential for the treatment of pain and degenerative disorders (Piomelli et al., 2000;van der Stelt and Di Marzo, 2003). Acute administration of cannabinoids produces antinociception, locomotor inhibition, hypothermia, and impairment of short-term memory (Howlett et al., 2002). ⌬ 9 -Tetrahydrocannabinol (THC) and other cannabinoids produce their psychoactive and behavioral effects via activation of CB 1 receptors in the central nervous system (CNS) (Ledent et al., 1999). Recent reports indicate that CB 2 and novel cannabinoid receptors might exist in the CNS (Mackie and Stella, 2006), but their role is unclear. CB 1 receptors are widely distributed in the brain where they exhibit a predominantly presynaptic location and modulate neurotransmitter release (Schlicker and Kathmann, 2001 [2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate; GP, globus pallidus; MPE, maximal possible effect; POA, preoptic a...

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

Cited by 113 publications

References 61 publications

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Alteration to hippocampal shape in cannabis users with and without schizophrenia

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

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

Cited by 113 publications

References 61 publications

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Alteration to hippocampal shape in cannabis users with and without schizophrenia

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ9-Tetrahydrocannabinol

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Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol