A Critical Role for the Cannabinoid CB<sub>1</sub>Receptors in Alcohol Dependence and Stress-Stimulated Ethanol Drinking

Rácz, Ildikó; Bilkei-Gorzó, András; Tóth, Zsuzsanna; Michel, Kerstin; Palkóvits, M.; Zimmer, Andreas

doi:10.1523/jneurosci.23-06-02453.2003

Cited by 137 publications

(110 citation statements)

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“…It therefore seems conceivable that the decrease in CB1R binding we found in the same region could have been an endogenous compensatory response. Of special interest, CB1R-deficient mice appear to suffer no signs of withdrawal upon alcohol discontinuation [42]. However, results concerning the relationship between anxiety levels and alcohol drinking are still ambiguous, and we did not measure behavioural aspects of withdrawal in this study [43].…”

Section: Discussionmentioning

confidence: 97%

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study

Ceccarini

Casteels

Bormans³

et al. 2013

Eur J Nucl Med Mol Imaging

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Purpose Recent biochemical and post-mortem evidence suggests involvement of the endocannabinoid system in alcohol drinking behaviour and dependence. Using [ 18 F]MK-9470 small-animal PET imaging, our primary objective was to evaluate in vivo type 1 cannabinoid receptor (CB1R) binding changes in rats subjected to several ethanol conditions: (1) at baseline, (2) after acute intraperitoneal administration of ethanol (4 g/kg) or saline, (3) after 7 days of forced chronic ethanol consumption, and (4) after abstinence for 7 and 14 days. Secondly, levels of anandamide (AEA) in the nucleus accumbens (NAcc) were investigated in the same animals using in vivo microdialysis and correlated with the changes in CB1R binding. Methods In total, 28 male Wistar rats were investigated. Small-animal PET was done on a FOCUS-220 tomograph with [18 F]MK-9470. Parametric images of [18 F]MK-9470 binding based on standard uptake values (SUV, as a measure of CB1R binding) were generated. Images were normalized to Paxinos space and analysed voxel-wise using SPM8 (p height =0.005; k ext =200). The AEA content was quantified using HPLC with tandem mass spectrometry detection. Results Acute ethanol administration increased relative CB1R binding in the NAcc that was positively correlated with the change in AEA levels of that region. In contrast, compared to rats at baseline, AEA levels in the NAcc were not significantly different in rats after chronic ethanol consumption or after a 14-day abstinence period. Chronic ethanol consumption decreased relative CB1R binding in the hippocampus and caudate-putamen, whereas same regions showed increased relative CB1R binding after 7 and 14 days of abstinence compared to the baseline condition. After 7 and 14 days of abstinence, relative CB1R binding additionally decreased in the orbitofrontal cortex. The magnitude of the hippocampal and frontal changes was highly correlated with daily ethanol intake. Conclusion This study provides in vivo evidence that acute ethanol consumption is associated with enhanced endocannabinoid signalling in the NAcc, indicated by an increased CB1R binding and AEA content. In addition, chronic ethanol exposure leads to regional dysfunctions in CB1R levels, involving the hippocampus and caudateputamen that are reversible within 2 weeks in this animal model. J.C. and C.C. contributed equally to this work.

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Section: Discussionmentioning

confidence: 97%

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study

Ceccarini

Casteels

Bormans³

et al. 2013

Eur J Nucl Med Mol Imaging

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“…Our data extend this concept by showing that alterations of synaptic plasticity induced by addictive drugs can be compensated by homeostatic processes that, at least in the case of the psychoactive ingredient of marijuana, rescue synaptic functions up to a certain point. How this new form of homeostatic synaptic plasticity relates to the behavioral aspects of addiction is beyond the goal of this study, but it is remarkable that pharmacological manipulations of both CB1R and mGluR2/3 modulate addictive-drug-evoked behaviors (Fundytus et al, 1997;Helton et al, 1997;Ledent et al, 1999;Vandergriff and Rasmussen, 1999;Racz et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Presynaptic Homeostatic Plasticity Rescues Long-Term Depression after Chronic Δ⁹-Tetrahydrocannabinol Exposure

Mato¹,

Robbe²,

Puente³

et al. 2005

J. Neurosci.

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Alterations of long-term synaptic plasticity have been proposed to participate in the development of addiction. To preserve synaptic functions, homeostatic processes must be engaged after exposure to abused drugs. At the mouse cortico-accumbens synapses, a single in vivo injection of ⌬ 9-tetrahydrocannabinol (THC) suppresses endocannabinoid-mediated long-term depression. Using biochemical and electrophysiological approaches, we now report that 1 week of repeated in vivo THC treatment reduces the coupling efficiency of cannabinoid CB1 receptors (CB1Rs) to G i/o transduction proteins, as well as CB1R-mediated inhibition of excitatory synaptic transmission at the excitatory synapses between the prefrontal cortex and the nucleus accumbens (NAc). Nonetheless, we found that cortico-accumbens synapses unexpectedly express normal long-term depression because of a reversible switch in its underlying mechanisms. The present data show that, in THC-treated mice, long-term depression is expressed because a presynaptic mGluR2/3 (metabotropic glutamate receptor 2/3)-dependent mechanism replaces the impaired endocannabinoid system. Thus, in the NAc, a novel form of presynaptic homeostasis rescues synaptic plasticity from THC-induced deficits.

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“…Post-hoc analysis of the effects of strain, collapsed across stress condition, showed that no strain significantly differed from another ( Figure 2). Previous studies have found inconsistent effects of various stress procedures on EtOH selfadministration in rats and mice [1,10,32,33,41,47,49,55,[59][60][61][62]. Similarly, work examining the effects of stress on sensitivity to the behavioral effects of acute EtOH challenge has not produced a clear consensus [7,16,20,21,26,34,45,48].…”

mentioning

confidence: 99%

Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice

Boyce-Rustay

Janos

Holmes

2008

Behavioural Brain Research

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There is a strong clinical relationship between stress and stress-related disorders and the incidence of alcohol abuse and alcoholism, and this relationship appears to be partly genetic in origin. There are marked strain differences in ethanol (EtOH)-related behaviors and reactivity to stress, but little investigation of the interaction between the two. The present study assessed the effects of chronic exposure to swim stress on EtOH-related behavior in three common inbred strains of mice, C57BL/ 6J, DBA/2J and BALB/cByJ. After establishing baseline (10%) EtOH self-administration in a twobottle free choice test, mice were exposed to daily swim stress for 14 consecutive days and EtOH consumption measured as a percent of baseline both during stress and for 10 days afterwards. A separate experiment examined the effects of 14 days of swim stress on sensitivity to the sedative/ hypnotic effects of an acute injection of 4 g/kg EtOH. Results showed that stress produced a marked and prolonged decrease in EtOH consumption in DBA/2J and BALB/cByJ, but not C57BL/6J mice. By contrast, stress increased sensitivity to the sedative/hypnotic effects of EtOH across all 3 strains. These findings demonstrate that chronic swim stress produces reductions in EtOH self-administration in a strain-dependent manner, and that these effects may be restricted to low-consuming strains. Present data also indicate a dissociation between effects of this stressor on EtOH self-administration and sensitivity to EtOH's sedative/hypnotic effects. In conclusion, strain differences, that are likely in large part genetic in nature, modify the effects of this stressor on EtOH's effects in a behaviorspecific manner. Keywords mouse; strain; ethanol; sedation; gene; drinking; swim stress; preference; two-bottle choice There is a strong epidemiological link between stress-related psychiatric disorders and alcoholism. Individuals suffering from depression or anxiety disorders, conditions often associated with stress, are more likely to abuse alcohol and become alcoholic, and tend to respond less well to therapeutic interventions [8,9,29,54]. Moreover, a history of adverse life events positively correlates with increased rates of alcoholism; although, interestingly, a proportion of individuals become abstinent following stress [19,35,46,51]. These clinic data lend support to the influential hypothesis that stress represent a significant risk factor for alcoholism [12,28]. *Corresponding author: R4N5 AP9A-L018, Abbott Laboratories, 100 Abbott Park Rd, Abbott Park, IL 60064, Ph. +1-847-937-2559, Fax +1-847-938-0072, E-mail: janel.boyce-rustay@abbott.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered wh...

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A Critical Role for the Cannabinoid CB₁Receptors in Alcohol Dependence and Stress-Stimulated Ethanol Drinking

Cited by 137 publications

References 50 publications

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study

Presynaptic Homeostatic Plasticity Rescues Long-Term Depression after Chronic Δ⁹-Tetrahydrocannabinol Exposure

Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice

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A Critical Role for the Cannabinoid CB1Receptors in Alcohol Dependence and Stress-Stimulated Ethanol Drinking

Cited by 137 publications

References 50 publications

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study

Presynaptic Homeostatic Plasticity Rescues Long-Term Depression after Chronic Δ9-Tetrahydrocannabinol Exposure

Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice

Contact Info

Product

Resources

About

A Critical Role for the Cannabinoid CB₁Receptors in Alcohol Dependence and Stress-Stimulated Ethanol Drinking

Presynaptic Homeostatic Plasticity Rescues Long-Term Depression after Chronic Δ⁹-Tetrahydrocannabinol Exposure